WO2002099062A2 - Novel antibodies that bind to antigenic polypeptides, nucleic acids encoding the antigens, and methods of use - Google Patents

Abstract

Disclosed herein are nucleic acid sequences that encode polypeptides. Also disclosed are antibodies, which immunospecifically-bind to the polypeptide, as well as derivatives, variants, mutants, or fragments of the aforementioned polypeptide, polynucleotide, or antibody. The invention further discloses therapeutic, diagnostic and research methods for diagnosis, treatment, and prevention of disorders involving any one of these novel human nucleic acids, polypeptides, or antibodies, or fragments thereof.

Description

NOVEL ANTIBODIES THAT BIND TO ANTIGENIC POLYPEPTIDES, NUCLEIC ACIDS ENCODING THE ANTIGENS,

AND METHODS OF USE

FIELD OF THE INVENTION

The present itivention relates to novel antibodies that bind immunospecifically to antigenic polypeptides, wherein the polypeptides have characteristic properties related to biochemical or physiological responses in a cell, a tissue, an organ or an organism. The novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use of the antibodies encompass procedures for diagnostic and prognostic assay of the polypeptides, as well as methods of treating diverse pathological conditions.

BACKGROUND OF THE INVENTION

Eukaryotic cells are characterized by biochemical and physiological processes which under normal conditions are exquisitely balanced to achieve the preservation and propagation of the cells. When such cells are components of multicellular organisms such as vertebrates, or more particularly organisms such as mammals, the regulation of the biochemical and physiological processes involves intricate signaling pathways. Frequently, such signaling pathways involve extracellular signaling proteins, cellular receptors that bind the signaling proteins, and signal transducing components located within the cells. Signaling proteins may be classified as endocrine effectors, paracrine effectors or autocrine effectors. Endocrine effectors are signaling molecules secreted by a given organ into the circulatory system, which are then transported to a distant target organ or tissue. The target cells include the receptors for the endocrine effector, and when the endocrine effector binds, a signaling cascade is induced. Paracrine effectors involve secreting cells and receptor cells in close proximity to each other, for example two different classes of cells in the same tissue or organ. One class of cells secretes the paracrine effector, which then reaches the second class of cells, for example by diffusion through the extracellular fluid. The second class of cells contains the receptors for the paracrine effector; binding of the effector results in induction of the signaling cascade that elicits the corresponding biochemical or physiological effect. Autocrine effectors are highly analogous to paracrine effectors, except that the same cell type that secretes the autocrine effector also contains the receptor. Thus the autocrine effector binds to receptors on the same cell, or on identical neighboring cells. The binding process then elicits the characteristic biochemical or physiological effect.

Signaling processes may elicit a variety of effects on cells and tissues including by way of nonlimiting example induction of cell or tissue proliferation, suppression of growth or proliferation, induction of differentiation or maturation of a cell or tissue, and suppression of differentiation or maturation of a cell or tissue.

Many pathological conditions involve dysregulation of expression of important effector proteins. In certain classes of pathologies the dysregulation is manifested as elevated or excessive synthesis and secretion of protein effectors. In a clinical setting a subject may be suspected of suffering from a condition brought on by elevated or excessive levels of a protein effector of interest. Antibodies are multichain proteins that bind specifically to a given antigen, and bind poorly, or not at all, to substances deemed not to be cognate antigens. Antibodies are comprised of two short chains termed light chains and two long chains termed heavy chains. These chains are constituted of immunoglobulin domains, of which generally there are two classes: one variable domain per chain, one constant domain in light chains, and three or more constant domains in heavy chains. The antigen-specific portion of the immunoglobulin molecules resides in the variable domains; the variable domains of one light chain and one heavy chain associate with each other to generate the antigen-binding moiety. Antibodies that bind immunospecifically to a cognate or target antigen bind with high affinities. Accordingly, they are useful in assaying specifically for the presence of the antigen in a sample. In addition, they have the potential of inactivating the activity of the antigen.

Therefore there is a need to assay for the level of a protein effector of interest in a biological sample from such a subject, and to compare this level with that characteristic of a nonpathological condition. In particular, there is a need for such an assay based on the use of an antibody that binds immunospecifically to the antigen. There further is a need to inhibit the activity of the protein effector in cases where a pathological condition arises from elevated or excessive levels of the effector based on the use of an antibody that binds immunospecifically to the effector. Thus, there is a need for the antibody as a product of manufacture. There further is a need for a method of treatment of a pathological condition brought on by an elevated or excessive level of the protein effector of interest based on administering the antibody to the subject.

SUMMARY OF THE INVENTION The invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides. The novel nucleic acids and polypeptides are referred to herein as NO X, or NOV1, NOV2, NOV3, etc., nucleic acids and polypeptides. These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as "NOVX" nucleic acid or polypeptide sequences.

In one aspect, the invention provides an isolated polypeptide comprising a mature form of a NOVX amino acid. The polypeptide can be, for example, a NOVX amino acid sequence or a variant of a NOVX amino acid sequence, wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changeα. the invention also includes fragments of any of NOVX polypeptides. In another aspect, the invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof. Also included in the invention is a NOVX polypeptide that is a naturally occurring variant of a NOVX sequence. In one embodiment, the variant includes an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a NOVX nucleic acid sequence. In another embodiment, the NOVX polypeptide is a variant polypeptide described therein, wherein any amino acid specified in the chosen sequence is changed to provide a conservative substitution.

In another aspect, invention provides a method for determining the presence or amount of the NOVX polypeptide in a sample by providing a sample; introducing the sample to an antibody that binds immunospecifically to the polypeptide; and determining the presence or amount of antibody bound to the NOVX polypeptide, thereby determining the presence or amount of the NOVX polypeptide in the sample.

In yet another aspect, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide in a mammalian subject by measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and comparing the amount of the polypeptide in the sample of the first step to the amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, the disease. An alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

In another aspect, the invention includes pharmaceutical compositions that include therapeutically- or prophylactically-effective amounts of a therapeutic and a pharmaceutically-acceptable carrier. The therapeutic can be, e.g., a NOVX nucleic acid, a NOVX polypeptide, or an antibody specific for a NOVX polypeptide. In a further aspect, the invention includes, in one or more containers, a therapeutically- or prophylactically- effective amount of this pharmaceutical composition. In still another aspect, the invention provides the use of a therapeutic in the manxrfacture of a medicament for treating a syndrome associated with a human disease that is associated with a NOVX polypeptide.

In a further aspect, the invention provides a method for modulating the activity of a NOVX polypeptide by contacting a cell sample expressing the NOVX polypeptide with antibody that binds the NOVX polypeptide in an amount sumcϊent to modulate toe activity of the polypeptide.

The invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof. In a preferred embodiment, the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant. In another embodiment, the nucleic acid encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant. In another embodiment, the nucleic acid molecule differs by a single nucleotide from a NOVX nucleic acid sequence. In one embodiment, the NOVX nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 73, or a complement of the nucleotide sequence. In one embodiment, the invention provides a nucleic acid molecule wherein the nucleic acid includes the nucleotide sequence of a naturally occurring allelic nucleic acid variant. Also included in the invention is a vector containing one or more of the nucleic acids described herein, and a cell containing the vectors or nucleic acids described herein. The invention is also directed to host cells transformed with a vector comprising any of the nucleic acid molecules described above.

In yet another aspect, the invention provides for a method for determining the presence or amount of a nucleic acid molecule in a sample by contacting a sample with a probe that binds a NOVX nucleic acid and determining the amount of the probe that is bound to the NOVX nucleic acid. For example the NOVX nucleic may be a marker for cell or tissue type such as a cell or tissue type that is cancerous.

In yet a further aspect, the invention provides a method for determining the presence of or predisposition to a disease associated with altered levels of a nucleic acid molecule in a first mammalian subject, wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

The invention further provides an antibody that binds immunospecifically to a NOVX polypeptide. The NOVX antibody may be monoclonal, humanized, or a fully human antibody. Preferably, the antibody has a dissociation constant for the binding of the NOVX polypeptide to the antibody less than 1 x 10^"9 M. More preferably, the NOVX antibody neutralizes the activity of the NOVX polypeptide. In a further aspect, the invention provides for tlie use ot a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, associated with a NOVX polypeptide. Preferably the therapeutic is a NOVX antibody.

In yet a further aspect, the invention provides a method of treating or preventing a NOVX-associated disorder, a method of treating a pathological state in a mammal, and a method of treating or preventing a pathology associated with a polypeptide by administering a NOVX antibody to a subject in an amount sufficient to treat or prevent the disorder.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel nucleotides and polypeptides encoded thereby. Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compunds. The sequences are collectively referred to herein as "NOVX nucleic acids" or "NOVX polynucleotides" and the corresponding encoded polypeptides are referred to as "NOVX polypeptides" or "NOVX proteins." Unless indicated otherwise, "NOVX" is meant to refer to any of the novel sequences disclosed herein. Table 1 provides a summary of the NOVX nucleic acids and their encoded polypeptides. TABLE 1. NOVX Polynucleotide and Polypeptide Sequences and Corresponding SEQ ID Numbers

Table 1 indicates the homology of NOVX polypeptides to known protein families. Thus, the nucleic acids and polypeptides, antibodies and related compounds according to the invention corresponding to a NOVX as identified in column 1 of Table 1 will be useful in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table 1.

NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

Consistent with other known members of the family of proteins, identified in column 5 of Table 1, the NOVX polypeptides of the present invention show homology to, and contain domains that are characteristic of, other members of such protein families. Details of the sequence relatedness and domain analysis for each NOVX are presented in Example A.

The NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function. Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table 1.

The NOVX nucleic acids and polypeptides are also useful for detecting specific cell types. Details of the expression analysis for each NOVX are presented in Example C. Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection of a variety of diseases with differential expression in normal vs. diseased tissues, e.g. detection of a variety of cancers.

Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein.

NOVX clones

NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally,

NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy.

Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are described for each of the NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders.

The NOVX nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as research tools. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) a biological defense weapon. In one specific embodiment, the invention includes an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 73; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 73, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 73; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 73 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; and (e) a fragment of any of (a) through (d).

In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a)"a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 73; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 73 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 73; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 73, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 73 or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules.

In yet another specific embodiment, the invention includes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 73; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 73 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; (c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 73; and (d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 73 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed. NOVX Nucleic Acids and Polypeptides

One aspect of the invention pertains to isolated nucleic acid molecules that encode NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify NOVX- encoding nucleic acids (e.g., NOVX mRNA's) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA.

A NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a "mature" form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product "mature" form arises, again by way of nonlimiting example, as a result of one or more naturally occurring processing steps as they may take place within the cell, or host cell, in which the gene product arises. Examples of such processing steps leading to a "mature" form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of an ORF, or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+l to residue N remaining. Further as used herein, a "mature" form of a polypeptide or protein may arise from a step of post- translational modification other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them. The term "probes", as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.

The term "isolated" nucleic acid molecule, as utilized herein, is one, which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5'- and 3'-termini of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material or culture medium when produced by recombinant techniques, or of chemical precursors or other chemicals when chemically synthesized.

A nucleic acid molecule of the invention, e.g., a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:2«-l, wherein n is an integer between 1-73, or a complement of this aforementioned nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence of SEQ ID NO:2o-l, wherein n is an integer between 1-73, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et αl., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2^nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausubel, et αl., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993.)

A nucleic acid of the invention can be amplified using cDNA, mRNA or alternatively, genomic DNA, as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX^'hucieotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.

As used herein, the term "oligonucleotide" refers to a series of linked nucleotide residues, which oligonucleotide has a sufficient number of nucleotide bases to be used in a PCR reaction. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise portions of a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides of SEQ ID NO:2rø-l, wherein n is an integer between 1-73, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes.

In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide sequence SEQ ID NO:2«-l, wherein n is an integer between 1-73, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of a NOVX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence of SEQ ID NO:2«-l, wherein n is an integer between 1-73, is one that is sufficiently complementary to the nucleotide sequence of SEQ ID NO:2«-l, wherein n is an integer between 1-73, that it can hydrogen bond with little or no mismatches to the nucleotide sequence of SEQ ID NO:2n-l, wherein n is an integer between 1-73, thereby forming a stable duplex.

As used herein, the term "complementary" refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term "binding" means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates.

Fragments provided herein are defined as sequences of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, respectively,^" and are at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice. Derivatives are nucleic acid sequences or amino acid sequences formed from the native compounds either directly or by modification or partial substitution. Analogs are nucleic acid sequences or amino acid sequences that have a structure similar to, but not identical to, the native compound but differs from it in respect to certain components or side chains. Analogs may be synthetic or from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type. Homologs are nucleic acid sequences or amino acid sequences of a particular gene that are derived from different species.

A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 5 ' direction of the disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 3 ' direction of the disclosed sequence. Derivatives and analogs may be full length or other than full length, if the derivative or analog contains a modified nucleic acid or amino acid, as described below. Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 70%, 80%, or 95% identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement of a sequence encoding the aforementioned proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993, and below.

A "homologous nucleic acid sequence" or "homologous amino acid sequence," or variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences encode those sequences coding for isoforms of NOVX polypeptides. Tsofofms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, homologous nucleotide sequences include nucleotide sequences encoding for a NOVX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations of the nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human NOVX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NO:2/z-l, wherein n is an integer between 1-73, as well as a polypeptide possessing NOVX biological activity. Various biological activities of the NOVX proteins are described below. A NOVX polypeptide is encoded by the open reading frame ("ORF") of a NOVX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG "start" codon and terminates with one of the three "stop" codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bonafide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more. The nucleotide sequences determined from the cloning of the human NOVX genes allows for the generation of probes and primers designed for use in identifying and/or cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID NO:2«- 1, wherein n is an integer between 1-73; or an anti-sense strand nucleotide sequence of SEQ ID NO:2n-l, wherein n is an integer between 1-73; or of a naturally occurring mutant of SEQ ID NO:2«-l, wherein n is an integer between 1-73. Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe further comprises a label group attached thereto, e.g. the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express a NOVX protein, such as by measuring a level of a NOVX-encoding nucleic acid in a sample of cells from a subject e.g., detecting NOVX mRNA levels or determining whether a genomic NOVX gene has been mutated or deleted.

"A polypeptide having a biologically-active portion of a NOVX polypeptide" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a "biologically- active portion of NOVX" can be prepared by isolating a portion of SEQ ID NO:2n-l, wherein n is an integer between 1 -73, that encodes a polypeptide having a NOVX biological activity (the biological activities of the NOVX proteins are described below), expressing the encoded portion of NOVX protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of NOVX.

NOVX Nucleic Acid and Polypeptide Variants

The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences of SEQ ID NO:2«-l, wherein n is an integer between 1-73, due to degeneracy of the genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences of SEQ ID NO:2«-l, wherein n is an integer between 1-73. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence of SEQ ID NO:2«, wherein n is an integer between 1-73.

In addition to the human NOVX nucleotide sequences of SEQ ID NO:2«-l, wherein n is an integer between 1-73, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of the NOVX polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame (ORF) encoding a NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity of the NOVX polypeptides, are intended to be within the scope of the invention. Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from any one of the human SEQ ID NO:2«-l, wherein n is an integer between 1-73, are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.

Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2rø-l , wherein n is an integer between 1-73. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding region. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% homologous to each other typically remain hybridized to each other.

Homologs (i.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.

As used herein, the phrase "stringent hybridization conditions" refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5 °C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% of the probes are occupied at equilibrium. ' Typically,^' stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30 °C for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60 °C for longer probes, primers and oligonucleotides.

Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide.

Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N. Y. (1989), 6.3.1 -6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6X SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65 °C, followed by one or more washes in 0.2X SSC, 0.01 % BSA at 50 °C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to any one of the sequences of SEQ ID NO:2rø-l, wherein n is an integer between 1-73, corresponds to a naturally-occurring nucleic acid molecule. As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-l, wherein n is an integer between 1-73, or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6X SSC, 5X Reinhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55 °C, followed by one or more washes in IX SSC, 0.1% SDS at 37 °C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Krieger, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY.

In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of SEQ ID NO:2rc-l, wherein n is an integer between 1-73, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5X SSC, 50 mM Tris-HCl^' (pH T.5J, 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg ml denatured salmon sperm DNA, 10% (wt/volt) dextran sulfate at 40 °C, followed by one or more washes in 2X SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50 °C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.

Conservative Mutations

In addition to naturally-occurring allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of SEQ ID NO:2τ?-l, wherein n is an integer between 1 -73, thereby leading to changes in the amino acid sequences of the encoded NOVX proteins, without altering the functional ability of said NOVX proteins. For example, nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues can be made in the sequence of SEQ ID NO:2/ , wherein n is an integer between 1-73. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequences of the NOVX proteins without altering their biological activity, whereas an "essential" amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins of the invention are particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art. Another aspect of the invention pertains to nucleic acid molecules encoding NOVX proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from any one of SEQ ID NO:2π-l, wherein n is an integer between 1-73, yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 45% homologous to the amino acid sequences of SEQ ID NO:2«, wherein n is an integer between 1-73. Preferably, the protein encoded by the nucleic acid molecule is at least about 60%> homologous to SEQ ID NO:2«, wherein n is an integer between 1-73; more preferably at least about 70% homologous to SEQ ID NO:2«, wherein n is an integer between 1-73; still more preferably at least about 80% homologous to SEQ ID NO:2/ι, whe ein w is an integer Between 1-73; even more preferably at least about 90% homologous to SEQ ID NO:2«, wherein n is an integer between 1-73; and most preferably at least about 95% homologous to SEQ ID NO:2rø, wherein n is an integer between 1-73. An isolated nucleic acid molecule encoding a NOVX protein homologous to the protein of SEQ ID NO:2«, wherein n is an integer between 1-73, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO:2rø-l, wherein n is an integer between 1-73, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein. Mutations can be introduced into any of SEQ ID NO:27 -l, wherein n is an integer between 1-73, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of a NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis of any one of SEQ ID NO:2«-l, wherein n is an integer between 1-73, the encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined. The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved "strong" residues or fully conserved "weak" residues. The "strong" group of conserved amino acid residues may be any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the "weak"^' group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, HFY, wherein the letters within each group represent the single letter amino acid code. In one embodiment, a mutant NOVX protein can be assayed for (i) the ability to form proteinφrotein interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant NOVX protein and a NOVX ligand; or (Hi) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins). In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release).

Antisense Nucleic Acids

Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2«-l , wherein n is an integer between 1 -73, or fragments, analogs or derivatives thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a protein (e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a NOVX protein of SEQ ID NO:2«, wherein n is an integer between 1 -73, or antisense nucleic acids complementary to a NOVX nucleic acid sequence of SEQ ID NO: 2n-l, wherein n is an integer between 1 -73, are additionally provided.

In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence encoding a NOVX protein. The term "coding region" refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence encoding the NOVX protein. The term "noncoding region" refers to 5' and 3' sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions). Given the coding strand sequences encoding the NOVX protein disclosed herein, antisense nucleic acids of the invention can'be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of NOVX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used).

Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1 -methyl guanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomefhyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudoxiracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methylxιracil, uracil-5-oxyacetic acid mefhylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection). The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a NOVX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (See, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See, e.g., Inoue, et al, 1987. FEBSLett. 215: 327-330.

Ribozymes and PNA Moieties

Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.

In one embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave NOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for a NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of a NOVX cDNA disclosed herein (i. e. , any one of SEQ ID NO:2τ?-l , wherein n is an integer between 1-73). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a NOVX-encoding mRNA. See, e.g., U.S. Patent 4,987,071 to Cech, et al. and U.S. Patent 5,116,742 to Cech, et al. NOVX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al, (1993) Science 261:1411-1418.

Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the NOVX nucleic acid (e.g., the NOVX promoter and/or enhancers) to form triple helical structures that prevent transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15.

In various embodiments, the NOVX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al, 1996. Bioorg Med Chem 4: 5-23. As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleotide bases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomer can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al, 1996. supra; Perry-O'Keefe, et al, 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.

PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directedTPCR clamping; as artiiiciai restriction enzymes when used in combination with other enzymes, e.g., Sj nucleases (See, Hyrup, et al, 1996.supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al, 1996, supra; Perry-O'Keefe, et al, 1996. supra). In another embodiment, PNAs of NOVX can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of NOVX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleotide bases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al, 996. supra and Finn, et al, 1996. Nucl Acids Res 24: 3357-3363. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5' end of DNA. See, e.g., Mag, et al., 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment. See, e.g., Finn, et al, 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment. See, e.g., Petersen, et al, 1915. Bioorg. Med. Chem. Lett. 5: 1119-11124.

In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g. , for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al, 1989. Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556; Lemaitre, et al, 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g. , PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al, 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g.,

Zon, 1988. Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like. NOVX Polypeptides

A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in any one of SEQ ID NO:2«, wherein n is an integer between 1-73. The invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residues shown in any one of SEQ ID NO:2«, wherein n is an integer between 1-73, while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof.

In general, a NOVX variant that preserves NOVX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.

One aspect of the invention pertains to isolated NOVX proteins, and biologically- active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-NOVX antibodies. In one embodiment, native NOVX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, NOVX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, a NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.

An "isolated" or "purified" polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of NOVX proteins in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly-produced. In one embodiment, the language "substantially free of cellular material" includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a "contaminating protein"), more preferably less than about 20% of non-NOVX proteins, still more preferably less than about 10% of non-NOVX proteins, and most preferably less than about 5% of non-NOVX proteins. When the NOVX protein or biologically-active portion thereof is recombinantly- produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the NOVX protein preparation.

The language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20% chemical precursors or non-NOVX chemicals, still more preferably less than about 10% chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals. Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the NOVX proteins (e.g., the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1-73) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of a NOVX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity of the NOVX protein. A biologically- active portion of a NOVX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length.

Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native NOVX protein.

In an embodiment, the NOVX protein has an amino acid sequence of SEQ ID NO:2rø, wherein n is an integer between 1-73. In other embodiments, the NOVX protein is substantially homologous to SEQ ID NO:2rc, wherein n is an integer between 1-73, and retains the functional activity of the protein of SEQ ID NO:2rc, wherein n is an integer between 1-73, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence of SEQ ID NO:2rc, wherein n is an integer between 1-73, and retains the functional activity of the NOVX proteins of SEQ^'ΪE) NO:2«, wherein n is an integer between 1-73.

Determining Homology Between Two or More Sequences To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid "homology" is equivalent to amino acid or nucleic acid "identity").

The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. J Mol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA sequence of SEQ ID NO:2«-l, wherein n is an integer between 1-73.

The term "sequence identity" refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term "substantial identity" as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more Usually aϊ least 99 percent sequence identity as compared to a reference sequence over a comparison region.

Chimeric and Fusion Proteins The invention also provides NOVX chimeric or fusion proteins. As used herein, a

NOVX "chimeric protein" or "fusion protein" comprises a NOVX polypeptide operatively- linked to a non-NOVX polypeptide. An "NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a NOVX protein of SEQ ID NO:2π, wherein n is an integer between 1-73, whereas a "non-NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the NOVX protein, e.g., a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within a NOVX fusion protein the NOVX polypeptide can correspond to all or a portion of a NOVX protein. In one embodiment, a NOVX fusion protein comprises at least one biologically- active portion of a NOVX protein. In another embodiment, a NOVX fusion protein comprises at least two biologically-active portions of a NOVX protein. In yet another embodiment, a NOVX fusion protein comprises at least three biologically-active portions of a NOVX protein. Within the fusion protein, the term "operatively-linked" is intended to indicate that the NOVX polypeptide and the non-NOVX polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or C-terminus of the NOVX polypeptide.

In one embodiment, the fusion protein is a GST-NOVX fusion protein in which the NOVX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX polypeptides.

In another embodiment, the fusion protein is a NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of NOVX can be increased through use of a heterologous signal sequence. In yet another embodiment, the fusion protein is a NOVX-immunoglobulin fusion protein in which the NOVX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a NOVX ligand and a NOVX protein on the surface of a cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX-immunoglobulin fusion proteins can be used to affect the bioavailability of a NOVX cognate ligand. Inhibition of the NOVX ligand/NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the

NOVX-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with a NOVX ligand. A NOVX chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different pol peptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A NOVX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein.

NOVX Agonists and Antagonists

The invention also pertains to variants of the NOVX proteins that function as either NOVX agonists ( . e., mimetics) or as NOVX antagonists. Variants of the NOVX protein can be generated by mutagenesis (e.g., discrete point mutation or truncation of the NOVX protein). An agonist of the NOVX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurring form of the NOVX protein. An antagonist of the NOVX protein can inhibit one or more of the activities of the naturally occurring form of the NOVX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject" with a^" variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins. Variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) of the NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential NOVX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of NOVX sequences therein. There are a variety of methods which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential NOVX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al, 1984. Annu. Rev. Biochem. 53: 323; Itakura, et al, 1984. Science 198: 1056; Ike, et al, 1983. Nucl. Acids Res. 11 : 477.

Polypeptide Libraries In addition, libraries of fragments of the NOVX protein coding sequences can be used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of a NOVX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of a NOVX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double- stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with Sj nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-termmal and internal fragments of various sizes of the NOVX proteins.

Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of NOVX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants. See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, et al, 1993. Protein Engineering 6:327-331.

NOVX Antibodies

The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immxmoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, F_ab, F_ab' and F_(ab')2 fragments, and an F_ab expression library. In general, antibody molecules obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgGj, IgG₂, and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.

An isolated protein of the invention intended to serve as an antigen, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid"resϊdues of the ammo acid sequence of the full length protein, such as an amino acid sequence of SEQ ID NO:2«, wherein n is an integer between 1-73, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions. In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a region of NOVX that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824- 3828; Kyte and Doolittle 1982, J Mol. Biol. 157: 105-142, each incorporated herein by reference in their entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

The term "epitope" includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. A NOVX polyppeptide or a fragment thereof comprises at least one antigenic epitope. An anti-NOVX antibody of the present invention is said to specifically bind to antigen NOVX when the equilibrium binding constant (KD) is <1 μM, preferably < 100 nM, more preferably < 10 nM, and most preferably < 100 pM to about 1 pM, as measured by assays such as radioligand binding assays or similar assays known to those skilled in the art. A protein of the invention, or a derivative, fragment, analog, nomolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.

Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference). Some of these antibodies are discussed below. Polyclonal Antibodies

For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecifhin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).

The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is disctϊssecl,"ιor example,^' by^'D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No. 8 (April 17, 2000), pp. 25-28).

Monoclonal Antibodies

The term "monoclonal antibody" (MAb) or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.

Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.

The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59- 103). Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells. Preferred immortalized cell lines are those that rase^" efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63). The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen. After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding,1986). Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI- 1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal. The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host celts such as simian CO^'S^'cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Patent No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.

Humanized Antibodies

The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immxmoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321 :522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Patent No. 5,225,539.) In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et at.^', 1988; and Presϊa, Curr. Op. Struct. Biol., 2:593-596 (1992)).

Human Antibodies Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies", or "fully human antibodies" herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al, 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).

In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol, 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technology 10, 779- 783 (1992)); Lonberg et al. (Nature 368 856-859 (1994)); Morrison ( Nature 368, 812-13 (1994)); Fishwild et al,( Nature Biotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)). Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT publication WO94/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's ' genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.

An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Patent No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker. A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Patent No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.

In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049. Fa_b Fragments and Single Chain Antibodies

According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Patent No. 4,946,778). In addition, methods can be adapted for the construction of F_a expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal F_ab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F_(ab')2 fragment produced by pepsin digestion of an antibody molecule; (ii) an F_ab fragment generated by reducing the disulfide bridges of an F_{(a ')2} fragment; (iii) an F_ab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) F_v fragments.

Bispecific Antibodies

Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.

Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture often different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).

Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CHI) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-cήam fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121 :210 (1986). According to another approach described in WO 96/27011 , the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers. Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab') bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab')₂ fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.

Additionally, Fab' fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab')₂ molecule. Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets. Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5): 1547-1553

(1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers.

The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA

90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (V_L) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and V domains of one fragment are forced to pair with the complementary V_L and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al, J. Immunol. 152:5368 (1994).

Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRLII (CD 16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).

Heteroconjugate Antibodies

Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Patent No. 4,676,980), and for treatment of HIV nfectidh (WO ^'9T/00360; WO^' 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No. 4,676,980.

Effector Function Engineering It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement- mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560- 2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).

Immunoconjugates

The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).

Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricofhecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include ²¹²Bi, ^{13 I}I, ^I31In, ⁹⁰Y, and ' ⁶Re.

Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3 -(2 -pyridyl dithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as l,5-difluoro-2,4-dinitrobenzene). For example, aricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14- labeled l-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026. In another embodiment, the antibody can be conjugated to a "receptor" (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) that is in turn conjugated to a cytotoxic agent.

Immunoliposomes

The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556.

Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG- derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al .,_J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst, 81(19): 1484 (1989). Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention

Antibodies directed against a protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of the protein (e.g., for use in measuring levels of the protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies against the proteins, or derivatives, fragments, analogs or homologs thereof, that contain the antigen binding domain, are utilized as pharmacologically-active compounds (see below).

An antibody specific for a protein of the invention can be used to isolate the protein by standard techniques, such as immunoaffinity chromatography or immunoprecipitation. Such an antibody can facilitate the purification of the natural protein antigen from cells and of recombinantly produced antigen expressed in host cells. Moreover, such an antibody can be used to detect the antigenic protein (e.g. , in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic protein. Antibodies directed against the protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i. e. , physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ^{1 5}1, ¹³¹1, ³⁵S or ³H.

Antibody Therapeutics Antibodies of the invention, including polyclonal;' mohdclonal,^"humanizecTand fully human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect may be one of two kinds, depending on the specific nature of the interaction between the given antibody molecule and the target antigen in question. In the first instance, administration of the antibody may abrogate or inhibit the binding of the target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, wherein the ligand serves as an effector molecule. Thus the receptor mediates a signal transduction pathway for which ligand is responsible.

Alternatively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the disease or pathology, binds the antibody as a surrogate effector ligand, initiating a receptor- based signal transduction event by the receptor.

A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target, and in other cases, promotes a physiological response. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered. Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.

Pharmaceutical Compositions of Antibodies

Antibodies specifically binding a protein of the invention, as well as other molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington ^": TEe Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa. : 1995; Drug Absorption Enhancement : Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug ^' Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York.

If the antigenic protein is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.

The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

Sustained-release preparations can be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ ethyl-L-glutamate, non- degradable ethyl ene-vinyl acetate, degradable lactic

the LUPRON DEPOT ™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethyl ene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.

ELISA Assay

An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof

(e.g. , F_ab or F(_ab)2) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term "biological sample", therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in "ELISA: Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, NJ, 1995; "Immunoassay", E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and "Practice and Thory of Enzyme Immunoassays", P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. For example, the antibody can be labeled with a radioactive marKer whose presence and location in a subject can be detected by standard imaging techniques.

NOVX Recombinant Expression Vectors and Host Cells Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a NOVX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g. , non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.

Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably- linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., NOVX proteins, mutant forms of NOVX proteins, fusion proteins, etc.).

The recombinant expression vectors of the invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (Hi) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, NJ.) that fuse glutathione S-transferase (GS 1), maltose E binding protein, or protein A, respectively, to the target recombinant protein.

Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al, (1988) Gene 69:301-315) and pET l id (Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89).

One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al, 1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques. In another embodiment, the NOVX expression vector is a yeast expression vector.

Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSecl (Baldari, et al., 1987. EMBOJ. 6: 229-234), pMFa (Kurjan and Herskowifz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al, 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif), and picZ (InVitrogen Corp, San Diego, Calif). Alternatively, NOVX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al, 1983. Mol. Cell. Biol. 3: 2156-21 5) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).

In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al, 1987. EMBOJ. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al, MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989. In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al, 1987. Genes Dev. 1 : 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, et al, 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al, 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Grass, 1990. Science 249: 374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3 : 537-546).

The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub, et al, "Antisense RNA as a molecular tool for genetic analysis," Reviews-Trends in Genetics, Vol. 1(1) 1986.

Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell" and "recombinant host cell" are used interchangeably hereim If ϊs understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art. Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DΕAΕ-dextran-mediated transfection, lipofection, or eleetroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.

For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die). A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method further comprises isolating NOVX protein from the medium or the host cell.

Transgenic NOVX Animals

The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

A transgenic animal of the invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retro viral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human NOVX cDNA sequences, i.e., any one of SEQ ID NO:2n-l, wherein n is an integer between 1-73, can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue of the human NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the NOVX transgene to direct expressϊoffbf NOVX jjrδteϊή tό^' partϊcuϊar ^" cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866; 4,870,009; and 4,873,191; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the NOVX transgene in its genome and/or expression of NOVX mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene- encoding NOVX protein can further be bred to other transgenic animals carrying other transgenes.

To create a homologous recombinant animal, a vector is prepared which contains at least a portion of a NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g. , functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g., the cDNA of any one of SEQ ID NO:2 -l, wherein n is an integer between 1-73), but more preferably, is a non-human homologue of a human NOVX gene. For example, a mouse homologue of human NOVX gene of SEQ ID NO:2π-l, wherein n is an integer between 1-73, can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous NOVX gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a "knock out" vector).

Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion of the NOVX gene is flanked at its 5'- and 3'-termini by additional nucleic acid of the NOVX gene to allow for homologous recombination to occur between the exogenous NOVX gene carried by the vector and an endogenous NOVX gene in an embryonic stem cell. The additional flanking NOVX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5'- and 3'-termini) are included in the vector. See, e.g., Thomas, et al, 1987. Cell 51 : 503 for a description of homologous recombination vectors. The vector is ten introduced intd¹ ari"'emb^'ryδhϊc^"stefrrceiriihe (e.g. , by eleetroporation) and cells in which the introduced NOVX gene has homologously- recombined with the endogenous NOVX gene are selected. See, e.g., Li, et al, 1992. Cell 69: 915. The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously- recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169.

In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage PI . For a description of the cre/loxP recombinase system, See, e.g., Lakso, et al, 1992. Proc. Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al, 1991. Science 251:1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al, 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G₀ phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a one of the animal from which the cell (e.g., the somatic cell) is isolated.

Pharmaceutical Compositions

The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as "active compounds") of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound

(e.g., a NOVX protein or anti-NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al, 1994. Proc. Natl. Acad. Sci. USA 91 : 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g. , retro viral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

Screening and Detection Methods

The isolated nucleic acid molecules of the invention can be used to express NOVX protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect NOVX mRNA (e.g. , in a biological sample) or a genetic lesion in a NOVX gene, and to modulate NOVX activity, as described further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g. ; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies of the invention can be used to detect and isolate NOVX proteins and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion.

The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra.

Screening Assays

The invention provides a method (also referred to herein as a "screening assay") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX protein activity. The invention also includes compounds identified in the screening assays described herein.

In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of a

NOVX protein or polypeptide or biologically-active portion thereof. The test compounds of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145. A "small molecule" as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention.

Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al, 1993. Proc. Natl. Acad. Sci. U.S.A. 90: 6909; Erb, et al, 1994. Proc. Natl. Acad. Sci. U.S.A. 91: 11422; Zuckermann, et al, 1994. J Med. Chem. 37: 2678; Cho, et al, 1993. Science 261: 1303; Carrell, et al, 1994. Angew. Chem. Int. Ed. Engl. 33: 2059; Carell, et al, 1994. Angew. Chem. Int. Ed. Engl. 33: 2061; and Gallop, et al, 1994. J. Med. Chem. 37: 1233.

Libraries of compounds may be presented in solution (e.g., Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Patent No. 5,223,409), spores (Ladner, U.S. Patent 5,233,409), plasmids (Cull, et al, 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al, 1990. Proc. Natl Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol. 222: 301-310; Ladner, U.S. Patent No. 5,233,409.). In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface is contacted with a test compound and the ability of the test compound to bind to a NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the NOVX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with ¹²⁵1, ³⁵S, ¹⁴C, or ³H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX protein or a biologically-active portion thereof as compared to the known compound.

In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX or a biologically-active portion thereof can be accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule. As used herein, a "target molecule" is a molecule with which a NOVX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses a NOVX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. A NOVX target molecule can be a non-NOVX molecule or a NOVX protein or polypeptide of the invention. In one embodiment, a NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound NOVX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX.

Determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by detecting induction of a cellular second messenger of the target (i.e. intracellular Ca²⁺, diacylglycerol, IP₃, etc.), detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising a NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.

In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting a NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the NOVX protein or biologically- active portion thereof. Binding of the test compound to the NOVX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability ot the test compound to interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound. In still another embodiment, an assay is a cell-free assay comprising contacting NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g. stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability of the NOVX protein to bind to a NOVX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of NOVX protein can be accomplished by determining the ability of the NOVX protein further modulate a NOVX target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as described, supra. In yet another embodiment, the cell-free assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the activity of a NOVX target molecule.

The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound form of NOVX protein. In the case of cell-free assays comprising the membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton^® X-100, Triton^® X-l 14, Thesit^®, Isotridecypoly(ethylene glycol ether)_n, N-dodecyl~N,N-dimethyl-3-ammonio-l -propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1 -propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-l-ρropane sulfonate (CHAPSO).

In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a tesf compouhdtό NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST- NO VX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity determined using standard techniques.

Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated NOVX protein or target molecules can be prepared from biotin-NHS

(N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, 111.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding of the NOVX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or NOVX protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the NOVX protein or target molecule.

In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of NOVX mRNA or protein in the cell is determined. The level of expression of NOVX mRNA or protein in the presence of the candidate compound is compared to the level of expression of NOVX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of NOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of

NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of NOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein.

In yet another aspect of the invention, the NOVX proteins can be used as "bait proteins" in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Patent No. 5,283,317; Zervos, et al, 1993. Cell 72: 223-232; Madura, et al, 1993. J Biol. Chem. 268: 12046-12054; Bartel, et al, 1993. Biotechniques 14: 920-924; Iwabuchi, et al, 1993. Oncogene 8 : 1693 - 1696; and Brent WO 94/ 10300), to identify other proteins that bind to or interact with NOVX ("NOVX-binding proteins" or "NOVX-bp") and modulate NOVX activity. Such NOVX-binding proteins are also involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements of the NOVX pathway. The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for NOVX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g. , GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming a NOVX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with NOVX.

The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein. Detection Assays

Portions or fragments of the cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (z) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); and (Hi) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below.

Chromosome Mapping

Once the sequence (or a portion of the sequence) of a gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of the NOVX sequences of SEQ ID NO:2«-l, wherein n is an integer between 1-73, or fragments or derivatives thereof, can be used to map the location of the NOVX genes, respectively, on a chromosome. The mapping of the NOVX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.

Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the NOVX sequences. Computer analysis of the NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the NOVX sequences will yield an amplified fragment. Somatic cell hybrids are prepared by fusing somatic cells from different mammals

(e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al, 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions.

PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the NOVX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes.

Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al, HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988). Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al, 1987. Nature, 325: 783-787. Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the NOVX gene, can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.

Tissue Typing

The NOVX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA markers for RFLP ("restriction fragment length polymorphisms," described in U.S. Patent No. 5,272,057).

Furthermore, the sequences of the invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5'- and 3'-termini of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.

Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used to obtain such identification sequences from individuals and from tissue. The NOVX sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs).

Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If coding sequences, such as those of SEQ ID NO:2n-l, wherein n is an integer between 1-73, are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

Predictive Medicine

The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmaco genomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining NOVX protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant NOVX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in a NOVX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity.

Another aspect of the invention provides methods for determining NOVX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as "pharmacogenomics"). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent.) Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX in clinical trials.

These and other agents are described in further detail in the following sections.

Diagnostic Assays

An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NO:2«-l, wherein n is an integer between 1-73, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to NOVX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.

An agent for detecting NOVX protein is an antibody capable of binding to NOVX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g. , Fab or

F(ab')₂) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect NOVX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of NOVX protein include introducing into a subject a labeled anti-NOVX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.

In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the test sample. The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect NOVX protein or nucleic acid.

Prognostic Assays

The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression or activity in which a test sample is obtained from a subject and NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.

Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX expression or activity). The methods of the invention can also be used to detect genetic lesions in a NOVX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding a NOVX-protein, or the misexpression of the NOVX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of: (i) a deletion of one or more nucleotides from a NOVX gene; (ii) an addition of one or more nucleotides to a NOVX gene; (Hi) a substitution of one or more nucleotides of a NOVX gene, (iv) a chromosomal rearrangement of a NOVX gene; (v) an alteration in the level of a messenger RNA transcript of a NOVX gene, (vi) aberrant modification of a

NOVX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non- wild-type splicing pattern of a messenger RNA transcript of a NOVX gene, (viii) a non- wild-type level of a NOVX protein, (ix) allelic loss of a NOVX gene, and (x) inappropriate post-translational modification of a NOVX protein. As described herein, there are a large number of assay techniques known in the art which can be used for detecting lesions in a NOVX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells. In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Patent Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al, 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994. Proc. Natl Acad. Sci. USA 91 : 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al, 1995. Nucl. Acids Res. 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to a NOVX gene under conditions such that hybridization and amplification of the NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.

Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al, 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al, 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); Qβ Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low " numbers.

In an alternative embodiment, mutations in a NOVX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Patent No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

In other embodiments, genetic mutations in NOVX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density arrays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al, 1996. Human Mutation 1: 244-255; Kozal, et al, 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NOVX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al, supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence of the sample NOVX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al, 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen, et al, 1996. Adv. Chromatography 36: 127-162; and Griffin, et al, 1993. Appl. Biochem. Biotechnol. 38: 147-159).

Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al, 1985. Science 230: 1242. In general, the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with Si nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, et al, 1988. Proc. Natl. Acad. Sci USA 85: 4397; Saleeba, et al, 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection. In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al, 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on a NOVX sequence, e.g., a wild-type NOVX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Patent No. 5,459,039.

In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in NOVX genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et αl., 1989. Proc. Nαtl Acαd. Sci. USA: 86: 2766; Cotton, 1993. Mutαt. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79. Single-stranded DNA fragments of sample and control NOVX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al, 1991. Trends Genet. 1: 5. In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGΕ). See, e.g., Myers, et al, 1985. Nature 313: 495. When DGGΕ is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753. Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al, 1986. Nature 324: 163; Saiki, et al, 1989. Proc. Natl. Acad. Sci USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.

Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al, 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3'-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11 : 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparini, et al, 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3'-terminus of the 5' sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.

The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a NOVX gene.

Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which NOVX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

Pharmacogenomics Agents, or modulators that have a stimulatory or inhibitory effect on NOVX activity

(e.g., NOVX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders (The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.) In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.

Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drag disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol, 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome pregnancy zone protein precursor enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drag response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification. Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a NOVX modulator, such as a modulator identified by one of the exemplary screening assays described herein.

Monitoring of Effects During Clinical Trials

Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease NOVX gene expression, protein levels, or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting increased NOVX gene expression, protein levels, or upregulated NOVX activity. In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a "read out" or markers of the immune responsiveness of a particular cell. By way of example, and not of limitation, genes, including NOVX, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates NOVX activity (e.g., identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of NOVX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of NOVX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.

In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of ( ) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a NOVX protein, mRNA, or genomic DNA in the preadministration sample; (Hi) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX protein, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of NOVX to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of NOVX to lower levels than detected, i.e., to decrease the effectiveness of the agent.

Methods of Treatment

The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant NOVX expression or activity. The disorders include cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright Hereditary Ostoeodystrophy, and other diseases, disorders and conditions of the like.

These methods of treatment will be discussed more fully, below.

Disease and Disorders

Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: (i) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (Hi) nucleic acids encoding an aforementioned peptide; (fv) administration of antisense nucleic acid and nucleic acids that are "dysfunctional" (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to "knockout" endogenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators ( i.e., inhibitors, agonists and antagonists, including additional peptide mimetic of the invention or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner.

Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability.

Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like).

Prophylactic Methods

In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to the subject an agent that modulates NOVX expression or at least one NOVX activity. Subjects at risk for a disease that is caused or contributed to by aberrant NOVX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the NOVX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of NOVX aberrancy, for example, a NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections.

Therapeutic Methods

Another aspect of the invention pertains to methods of modulating NOVX expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of NOVX protein activity associated with the cell. An agent that modulates NOVX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of a NOVX protein, a peptide, a NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more NOVX protein activity. Examples of such stimulatory agents include active NOVX protein and a nucleic acid molecule encoding NOVX that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of a NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another embodiment, the method involves administering a NOVX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX expression or activity.

Stimulation of NOVX activity is desirable in sftwations in which NOVX is abnormally downregulated and/or in which increased NOVX activity has a beneficial effect. One example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia).

Determination of the Biological Effect of the Therapeutic

In various embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue.

In various specific embodiments, in vitro assays may be performed with representative cells of the type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to administration to human subjects.

Prophylactic and Therapeutic Uses of the Compositions of the Invention

The NOVX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders including, but not limited to: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer- associated cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.

As an example, a cDNA encoding the NOVX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions of the invention will have efficacy for treatment of patients suffering from: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immxxne disorders, hematopoietic disorders, and the various dyslipidemias.

Both the novel nucleic acid encoding the NOVX protein, and the NOVX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A further use could be as an anti-bacterial molecule (i.e., some peptides have been found to possess antibacterial properties). These materials are further useful in the generation of antibodies, which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods.

EXAMPLES

Example A: Polynucleotide and Polypeptide Sequences, and Homology Data

Example 1.

The NOVl clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 1 A.

Table 1A. NOVl Sequence Analysis

SEQ ID NO: 1 3430 bp

NOVl a, GGGCTGCAGGAATTCCCCCACAGAGGGAGCATGACTTCGGCAACTTCACCTATCATTC CG100653-01 TGAAΆTGGGACCCCAAAAGTTTGGAAATCCGGACGCTAACAGTGGAAAGGCTGTTGGA GCCACTTGTTACACAGGTGACTACACTTGTCAACACAAGCAACAAAGGCCCATCTGGT DNA Sequence AAAAAGAAAGGGAGGTCAAΆGAAAGCCCATGTACTAGCTGCCTCTGTAGAGCAAGCCA CTCAGAATTTCCTGGAAAAGGGTGAACAGATCGCTAAGGAGAGTCAAGATCTCAAAGA GAGTTGGTGGCTGCTGTAGAGGATGTGCGCAAACAAGGTGAGACGATGCGGATCGCC TCCTCCGAGTTTGCAGATGACCCTTGCTCGTCGGTAAAGCGCGGCACCATGGTACGGG CGGCAAGGGCTTTGCTCTCCGCGGTGACACGCTTACTCATCCTGGCGGACATGGCAGA TGTCATGAGACTTTTATCCCATCTGAAAATTGTGGAAGAGGCCCTGGAAGCTGTCAAA AATGCTACAAATGAGCAAGACCTTGCAAACCGTTTTAAAGAGTTTGGGAAAAAGATGG TGAAACTTAACTATGTAGCAGCAAGAAGACAACAGGAGCTGAAGGATCCTCACTGTCG GGATGAGATGGCAGCCGCCCGAGGGGCTCTGAAGAAGAATGCCACAATGCTGTACACG GCCTCTCAAGCATTTCTCCGCCACCCAGATGTCGCCGCTACGAGAGCCAACCGAGATT ATGTGTTCAAACAAGTCCAGGAGGCCATCGCCGGCATCTCCAATGCTGCTCAAGCTAC CTCGCCCACTGACGAAGCCAAGGGCCACACGGGCATCGGCGAGCTGGCTGCGGCTCTT AATGAGTTTGACAATAAGATTATCCTGGACCCCATGACGTTCAGCGAGGCCAGGTTCC GGCCGTCCCTGGAGGAGAGGCTGGAGAGCATCATCAGCGGCGCAGCGCTGATGGCCGA CTCCTCCTGCACGCGAGACGACCGGCGCGAGAGGATCGTGGCGGAGTGCAACGCCGTG CGGCAGGCGCTCCAGGACCTGCTCAGCGAGTACATGAATAATACTGGAAGGAAAGAAA AGGAGATCCTCTCAACATTGCGATTGATAAGATGACTAAGAAAACAAGAGATCTAAG GAGACAGCTTCGGAAAGCAGTGATGGATCACATATCTGACTCTTTCCTGGAAACCAAT GTTCCTTTGCTAGTTCTCATTGAGGCTGCAAAGAGCGGAAATGAAAAGGAAGTGAAAG AATATGCCCAΆGTTTTCCGTGAGCATGCCAACAAΆCTGGTAGAGGTTGCCAATTTGGC CTGTTCCATCTCCAACAATGAAGAAGGGGTGAAATTAGTTCGGATGGCAGCCACCCAG ATTGACAGCCTGTGTCCCCAGGTCATCAATGCCGCTCTGACACTGGCTGCCCGGCCAC AGAGCAAAGTTGCTCAGGATAACATGGACGTCTTCAAAGACCAGTGGGAGAAGCAGGT CCGAGTGTTGACAGAGGCCGTGGATGACATCACCTCAGTGGATGACTTCCTCTCTGTC TCAGAAAATCACATCTTGGAGGATGTGAACAAGTGTGTGATAGCCCTCCAAGAGGGCG ATGTGGACACTCTGGACCGGACTGCAGGGGCCATCAGGGGCCGGGCAGCTCGAGTCAT ACACATCATCAATGCTGAGATGGAGAACTATGAAGCTGGGGTTTATACTGAGAAGGTG TTGGAAGCTACAAAATTGCTTTCTGAAACAGTGATGCCACGCTTCGCTGAACAAGTAG AGGTTGCCATTGAAGCCCTGAGTGCCAACGTTCCTCAACCGTTTGAGGAGAATGAGTT CATCGATGCCTCTCGCCTGGTGTATGATGGCGTTCGGGACATCAGAAAGGCTGTGCTG ATGATCAGGACCCCAGAAGAACTAGAGGATGATTCTGACTTTGAGCAGGAAGATTATG ATGTGCGTAGAGGGACAAGTGTTCAGACTGAGGATGACCAGCTCATTGCAGGGCAGAG CGCACGGGCCATCATGGCGCAACTACCGCAGGAGGAGAAGGCAAAAATAGCTGAGCAG GTGGAGATATTCCATCAAGAGAAAAGCAAGCTGGATGCAGAAGTGGCCAAATGGGACG ACAGCGGCAATGATATCATTGTACTGGCCAAGCAGATGTGTATGATCATGATGGAAAT GACAGACTTCACAAGAGGCAAAGGCCCATTGAAAAATACATCTGATGTCATTAATGC GCCAAGAAAATTGCCGAAGCAGGTTCTCGAATGGACAAATTAGCTCGTGCTGTGGCTG ATCAGCTGGACAGTGCCACATCGCTTATCCAGGCAGCTAAAAACCTGATGAATGCTGT TGTCCTCACGGTGAAAGCATCCTATGTGGCCTCAACCAAATACCAGAAGGTCTATGGG: ACAGCAGCTGTCAACTCACCTGTTGTGTCTTGGAAGATGAAGGCTCCAGAGAAGAAGC CCCTTGTGAAGAGAGAAAAGCCTGAAGAATTCCAGACACGAGTTCGACGAGGTTCTCA GAAGAAACACATTTCGCCTGTACAGGCTTTAAGTGAATTCAAAGCAATGGATTCCTTC TAGGACGATAGGTTTTAACAAGAAAGCTTTTTCTTTCTTTTCTTTCTTTCTTTTTCTT

TTTAATTCCATTTTTGTATGCATACCTGCCAGCTCGTATGCCTCTGGCATGGGGAAAT

TAAGGGAACAGTGTCTGTTTGCATGTAAGATGAGATGAGATCAATACTACTGATCCAT CTGTAGCCTGGGAAGGAGACAGGACATTCCTGTACTAAGGTGGCACAGAGCTGTCCTT

TGCAACATTCTCATAAAATTGGGCACAGAGTTCGCATTGGCGCAATATTTATGGGAGT

GGGAGGGATGGGGAAAATAAACTTAACTCTACAAAAGCAAACTCTAATGCATGCAAGA

ATCATTAGGTTGGCAGGTATATGCATAAGTGAAAAATCTGGAAGTGTAATGGTAGAAC

ATAAAACTTGTATTGCTTCTGTTTCAGTGCAAAAATGTACTAGCCAATACGCTTAAGT

GTGTGGCCCATGAATTGAACAATTTAACCTTGAAGTCTATATCCGTGATATTATGTCG

ATTTTTAACTGAGGGGAAATTAACTAGTCCAGCCTAAAATGCTTCTTTTAATCTGCAT

TCTGTTTCCTCTTCTAGTTGTGCCATTACTAGTGATCATGTTTTTTTCCCCCCTTTAA

TGAAAACAATAAACATCTATTTGAGACAATTAAAATCCTTCTGGGGGCACTGGAAGCA

CAATACGGTGACCAATCTTGCTTTCATTTTTTTTTCTTTTTAATTTGAACCATGATTT

TGCTAGAAATAGAAGGCCCAGTGGTGGAATATTAGAGGGAAGGAAACTGACAACGTGT

GAAAGTTA

ORF Start: ATG at 31 ORF Stop: TAG at 2611

SEQ ID NO: 2 860 aa MW at 95525.9kD

NOVla, MTSATSPIILK DPKSLEIRTLTVERLLEPLVTQVTTLVNTSNKGPSGKKKGRSKKAH CG100653-01 V AASVEQATQNFLE GEQIAKESQDLKEELVAAVEDVR QGΞTMRIASSEFADDPCS SVKRGTMVRAARALLSAVTRLLILADMADVMR LSH KIVEEALEAVKNATNEQD AN Protein Sequence RFKEFGKK VKLlΛTVAARRQQEL DPHCRDE AAARGALK ATMLYTASQAFLRHPD VAATRANRDYVFKQVQEAIAGISNAAQATSPTDEAKGHTGIGE AAALNEFDNKII D PMTFSEARFRPSLEERLESIISGAA MADSSCTRDDRRERIVAECNAVRQA QD LSE Y NNTGRKEKGDP NIAIDK TKKTRD RRQLRKAVMDHISDSFLETNVPLLVLIEAA KSGNEKEVKEYAQVFREHANK VEVANLACSISrøEEGVRLVRMAATQIDS CPQVIN AA T AARPQSKVAQDNMDVFKDQWEKQVRV TEAVDDITSVDDFLSVSENHI EDVN KCVIALQEGDVDTLDRTAGAIRGRAARVIHIINAEMENYEAGVYTEKV EATKLLSET VMPRFAEQVEVAIEA SANVPQPFEENEFIDASRLVYDGVRDIRKAVMIRTPEELED DSDFEQEDYDVRRGTSVQTEDDQLIAGQSARAIMAQLPQΞEKAKIAEQVEIFHQEKSK LDAEVAKWDDSGNDIIV AKQMCMI ME TDFTRGKGP KNTSDVINAAKKIAEAGSR ^mKLARAVADQLDS TS IQAAKNLM AVVLTV ASYVAS KYQKVYGT AVNSPV S WKMKAPEKKPLV REKPEEFQTRVRRGSQ KHISPVQA SΞF AMDSF

Further analysis of the NOVla protein yielded the following properties shown in Table IB.

Table IB. Protein Sequence Properties NOVla

PSort 0.3600 probability located in mitochondrial matrix space; 0.3000 probability analysis: located in microbody (peroxisome); 0.1000 probability located in lysosome (lumen); 0.0000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOVla protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table lC.

In a BLAST search of public sequence databases, the NOVla protein was found to have homology to the proteins shown in the BLASTP data in Table ID.

PFam analysis predicts that the NOVla protein contains the domains shown in the Table IE.

Example 2.

The NOV2 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 2A.

DNA Sequence AGAATATATGCAGGAATGCTTAACTTTGTGGGTTTTCTCTCCTCTTGCCCTCACTGAC

TCAGGATACACAAAGACCTATCAAGCTCACGCAAAGCAGAAATTCAGCCGCTTATGGT CCAGCAAGTCTGTCACTGAGATTCACCTATACTTTGAGGAGGAAGTCAAGCAAGAAGA ATGTGACCATTTGGACCGCCTTTTTGCTCCCAAGGAAGCTGGGAAACAGCCACGTACA GTGATCATTCAAGGACCACAAGGAATTGGAAAAACGACACTCCTGATGAAGCTGATGA TGGCCTGGTCGGACAACAAGATCTTTCGGGATAGGTTCCTGTACACGTTCTATTTCTG CTGCAGAGAACTGAGGGAGTTGCCGCCAACGAGTTTGGCTGACTTGATTTCCAGAGAG TGGCCTGACCCCGCTGCTCCTATAACAGAGATCGTGTCTCAACCGGAGAGACTCTTGT TCGTCATCGACAGCTTCGAAGAGCTGCAGGGCGGCTTGAACGAACCCGATTCGGATCT GTGTGGTGACTTGATGGAGAAACGGCCGGTGCAGGTGCTTCTGAGCAGTTTGCTGAGG AAGAAGATGCTCCCGGAGGCCTCCCTGCTCATCGCTATCAAACCCGTGTGCCCGAAGG AGCTCCGGGATCAGGTGACGATCTCAGAAATCTACCAGCCCCGGGGATTCAACGAGAG TGATAGGTTAGTGTATTTCTGCTGTTTCTTCAAAGACCCGAAAAGAGCCATGGAAGCC TTCAATCTTGTAAGAGAAAGTGAACAGCTGTTTTCCATATGCCAAATCCCGCTCCTCT GCTGGATCCTGTGTACCAGTCTGAAGCAAGAGATGCAGAAAGGAAAAGACCTGGCCCT GACCTGCCAGAGCACTACCTCTGTGTACTCCTCTTTCGTCTTTAACCTGTTCACACCT GAGGGTGCCGAGGGCCCGACTCCGCAAACCCAGCACCAGCTGAAGGCCCTGTGCTCCC TGGCTGCAGAGGGTATGTGGACAGACACATTTGAGTTTTGTGAAGACGACCTCCGGAG AAATGGGGTTGTTGACGCTGACATCCCTGCGCTGCTGGGCACCAAGATACTTCTGAAG TACGGGGAGCGTGAGAGCTCCTACGTGTTCCTCCACGTGTGTATCCAGGAGTTCTGTG CCGCCTTGTTCTATTTGCTCAAGAGCCACCTTGATCATCCTCACCCAGCTGTGAGATG TGTACAGGAATTGCTAGTTGCCAATTTTGAAAAAGCAAGGAGAGCACATTGGATTTTT TTGGGGTGTTTTCTAACTGGCCTTTTAAATAAAAAGGAACAAGAAAAACTGGATGCGT TTTTTGGCTTCCAACTGTCCCAAGAGATAAAGCAGCAAATTCACCAGTGCCTGAAGAG CTTAGGGGAGCGTGGCAATCCTCAGGGACAGGTGGATTCCTTGGCGATATTTTACTGT CTCTTTGAAATGCAGGATCCTGCCTTTGTGAAGCAGGCAGTGAACCTCCTCCAAGAAG CTAACTTTCATATTATTGACAACGTGGACTTGGTGGTTTCTGCCTACTGCTTAAAATA CTGCTCCAGCTTGAGGAAACTCTGTTTTTCCGTTCAAAATGTCTTTAAGAAAGAGGAT GAACACAGCTCTACGTCGGATTACAGCCTCATCTGTTGGCATCACATCTGCTCTGTGC TCACCACCAGCGGGCACCTCAGAGAGCTCCAGGTGCAGGACAGCACCCTCAGCGAGTC GACCTTTGTGACCTGGTGTAACCAGCTGAGGCATCCCAGCTGTCGCCTTCAGAAGCTT GGAATAAATAACGTTTCCTTTTCTGGCCAGAGTGTTCTGCTCTTTGAGGTGCTCTTTT ATCAGCCAGACTTGAAATACCTGAGCTTCACCCTCACGAAACTCTCTCGTGATGACAT CAGGTCCCTCTGTGATGCCTTGAACTACCCAGCAGGCAACGTCAAAGAGCTAGCGCTG GTAAATTGTCACCTCTCACCCATTGATTGTGAAGTCCTTGCTGGCCTTCTAACCAACA ACAAGAAGCTGACGTATCTGAATGTATCCTGCAACCAGTTAGACACAGGCGTGCCCCT TTTGTGTGAAGCCCTGTGCAGCCCAGACACGGTCCTGGTATACCTGATGTTGGCTTTC TGCCACCTCAGCGAGCAGTGCTGCGAATACATCTCTGAAATGCTTCTGCGTAACAAGA GCGTGCGCTATCTAGACCTCAGTGCCAATGTCCTGAAGGACGAAGGACTGAAAACTCT CTGCGAGGCCTTGAAACATCCGGACTGCTGCCTGGATTCACTGTGTTTGGTAAAATGT TTTATCACTGCTGCTGGCTGTGAAGACCTCGCCTCTGCTCTCATCAGCAATCAAAACC TGAAGATTCTGCAAATTGGGTGCAATGAAATCGGAGATGTGGGTGTGCAGCTGTTGTG TCGGGCTCTGACGCATACGGATTGCCGCTTAGAGATTCTTGGGTTGGAAGAATGTGGG TTAACGAGCACCTGCTGTAAGGATCTCGCGTCTGTTCTCACCTGCAGTAAGACCCTGC AGCAGCTCAACCTGACCTTGAACACCTTGGACCACACAGGGGTGGTTGTACTCTGTGA GGCCCTGAGACACCCAGAGTGTGCCCTGCAGGTGCTCGGGCTGAGAAAAACTGATTTT GATGAGGAAACCCAGGCACTTCTGACGGCTGAGGAAGAGAGAAATCCTAACCTGACCA TCACAGACGACTGTGACACAATCACAAGGGTAGAGATCTGA

ORF Start: ATG at 124 ORF Stop: TGA at 2881

SEQ ID NO: 4 919 aa MW at l03966.7kD

NOV2a, MQECLTLWVFSP ALTDSGYTKTYQAHAKQ FSRLWSSKSVTEIHLYFEEEVKQEECD CGI 00689-01 H DR FAP EAGKQPRTVIIQGPQGIG TT LMKLMMAWSDNKIFRDRF YTFYFCCR ELRE PPTSLADLISREWPDPAAPITEIVSQPERLLFVIDSFEE QGGLNEPDSDLCG Protein Sequence DLMEKRPVQVL SS LRKKMLPEASLLIAIKPVCPKE RDQVTISEIYQPRGFNESDR LVYFCCFFKDPKRAMΞAFN VRESEQ FSICQIPLLC I CTS QEMQKGKDLA TC QSTTSVYSSFVFN FTPEGAEGPTPQTQHQLKA CSLAAEGM TDTFEFCΞDDLRRNG WDADIPALLGTKI KYGΞRESSYVF HVCIQEFCAALFY KSH DHPHPAVRCVQ ELLVANFΞKARRAHWIFLGCFLTG LNKKEQEKLDAFFGFQLSQEI QQIHQCLKS G ERGNPQGQΛ SIAIFYCLFE QDPAFVKQAVNLLQEA FHIIDNVDLVVSAYCLKYCS SLRKLCFSVQNVFK EDEHSSTSDYSLICWHHICSV TTSGHLRE QVQDSTLSESTF VTWCNQLRHPSCR QKLGINNVSFSGQSVLLFEV FYQPD KYLSFTLTKLSRDDIRS CDAL YPAGNVKE ALVWCH SPIDCEVLAGLLTNNKKLTYLNVSCWQLDTGVPLLC EA CSPDTVL.VY MLAFCH SEQCCEYISEMLLRNKSVRY DLSANV KDEG KTLCE ALKHPDCCLDSLC VKCFITAAGCΞDLASALISNQN I QIGCNEIGDVGVQ CRA LTHTDCRLEI G EECGLTSTCCKD ASV TCSKTLQQ NLTLNTLDHTGVWLCEAL RHPECALQV G RKTDFDEETQALLTAEEERNPNLTI DDCD ITRVEI

Further analysis of the NOV2a protein yielded the following properties shown in Table 2B.

Table 2B. Protein Sequence Properties NOV2a

PSort 0.6000 probability located in nucleus; 0.3000 probability located in microbody analysis: (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

SignalP Cleavage site between residues 17 and 18 analysis:

A search of the NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2C.

In a BLAST search of public sequence databases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2D.

PFam analysis predicts that the NOV2a protein contains the domains shown in the Table

2E.

Table 2E. Domain Analysis of NO 2a

Identities/

Pfam Domain NOV2a Match Region Similarities Expect Value for the Matched Region

SRP54 71..93 11/23 (48%) 0.18 17/23 (74%) Example 3.

The NOV3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 3A.

Table 3A. NOV3 Sequence Analysis

SEQ ID NO: 5 2142 bp

NOV3a, TATTATTCAGCAAACAATCTCAATGTGTTCCTGATGGGAGAGAGAGCATCTGGAAAAA CG100760-01 CTATTGTTATAAATCTGGCTGTGTTGAGGTGGATCAAGGGTGAGATGTGGCAGAACAT GATCTCGTACGTCGTTCACCTCACTGCTCACGAAATAAACCAGATGACCAACAGCAGC DNA Sequence TTGGCTGAGCTAATCGCCAAGGACTGGCCTGACGGCCAGGCTCCCATTGCAGACATCC TGTCTGATCCCAAGAAACTCCTTTTCATCCTCGAGGACTTGGACAACATAAGATTCGA GTTAAATGTCAATGAAAGTGCTTTGTGTAGTAACAGCACCCAGAAAGTTCCCATTCCA GTTCTCCTGGTCAGTTTGCTGAAGAGAAAAATGGCTCCAGGCTGCTGGTTCCTCATCT CCTCAAGGCCCACACGTGGGAATAATGTAAAAACGTTCTTGAAAGAGGTAGATTGCTG CACGACCTTGCAGCTGTCGAATGGGAAGAGGGAGATATATTTTAACTCTTTCTTTAAA GACCGCCAGAGGGCGTCGGCAGCCCTCCAGCTTGTACATGAGGATGAAATACTCGTGG GTCTGTGCCGAGTCGCCATCTTATGCTGGATCACGTGTACTGTCCTGAAGCGGCAGAT GGACAAGGGGCGTGACTTCCAGCTCTGCTGCCAAACACCCACTGATCTACATGCCCAC TTTCTTGCTGATGCGTTGACATCAGAGGCTGGACTTACTGCCAATCAGTATCACCTAG GTCTCCTAAAACGTCTGTGTTTGCTGGCTGCAGGAGGACTGTTTCTGAGCACCCTGAA TTTCAGTGGTGAAGACCTCAGATGTGTTGGGTTTACTGAGGCTGATGTCTCTGTGTTG CAGGCCGCGAATATTCTTTTGCCGAGCAACACTCATAAAGACCGTTACAAGTTCATAC ACTTGAACGTCCAGGAGTTTTGTACAGCCATTGCATTTCTGATGGCAGTACCCAACTA TCTGATCCCCTCAGGCAGCAGAGAGTATAAAGAGAAGAGAGAACAATACTCTGACTTT AATCAΆGTGTTTACTTTCATTTTTGGTCTTCTAAΆTGCAAACAGGAGAAAGATTCTTG AGACATCCTTTGGATACCAGCTACCGATGGTAGACAGCTTCAAGTGGTACTCGGTGGG ATACATGAAACATTTGGACCGTGACCCGGAAAAGTTGACGCACCATATGCCTTTGTTT TACTGTCTCTATGAGAATCGGGAAGAAGAATTTGTGAAGACGATTGTGGATGCTCTCA TGGAGGTTACAGTTTACCTTCAATCAGACAAGGATATGATGGTCTCATTATACTGTCT GGATTACTGCTGTCACCTGAGGACACTTAAGTTGAGTGTTCAGCGCATCTTTCAAAAC AAACTGGAGAAATGCAACTTGTCGGCAGCCAGCTGTCAGGACCTAGCCTTGTTTCTCA CCAGCATCCAACACGTAACTCGATTGTGCCTGGGATTTAATCGGCTCCAAGATGATGG CATAAAGCTATTGTGTGCGGCCCTGACTCACCCCAAGTGTGCCTTAGAGAGACTGGAG CTCTGGTTTTGCCAGCTGGCAGCACCCGCTTGCAAGCACTTGTCAGATGCTCTCCTGC AGAACAGGAGCCTGACACACCTGAATCTGAGCAAGAACAGCCTGAGAGACGAGGGAGT CAAGTTCCTGTGTGAGGCCTTGGGTCGCCCAGATGGTAACCTGCAGAGCCTGAGTTTG TCAGGTTGTTCTTTCACAAGAGAGGGCTGTGGAGAGCTGGCTAATGCCCTCAGCCATA ATCATAATGTGAAAATCTTGGATTTGGGAGAAAATGATCTTCAGGATGATGGAGTGAA GCTACTGTGTGAGGCTCTGAAACCACATCGTGCATTGCACACACTTGGGTTGGCGAAA TGCAATCTGACAACTGCTTGCTGCCAGCATCTCTTCTCTGTTCTCAGCAGCAGTAAGA GCCTGGTCAATCTGAACCTTCTAGGCAATGAATTGGATACTGATGGTGTCAAGATGCT ATGTAAGGCTTTGAAAAAGTCGACATGCAGGCTGCAGAAACTCGGGTAAACCTCACTG

ACTTTTCTGCAGGGGAGAACATACAGGGACAAGGCTAGATTGACTAGGCTTCTA

ORF Start: ATG at 34 ORF Stop: TAA at 2077

SEQ ID NO: 6 681 aa MW at 76724. IkD

NOV3a, MGERASGKTIVINLAVLR IKGEM QNMISYWHLTAHEINQ TNSSLAELIAKD PD CGI 00760-01 GQAPIADILSDPKKL FI ΞDLDNIRFELNVNESALCSNSTQKVPIPV LVSLI-KRKM APGCWFL.ISSRPTRGN1 KTFLKEVDCCTTLQLSNGKREI FNSFFKDRQRASAALQL Protein Sequence VHEDEI VGLCRVAILC ITCTV KRQMD GRDFQLCCQTPTDLHAHFLADALTSEAG TA QYH GL KRLC AAGGLF STLNFSGEDLRCVGFTEADVSVLQAANI LPSNT HKDRYKFIHLNVQEFCTAIAF MAVPNYLIPSGΞREYKE REQYSDFNQVFTFIFGLL NARRKILETSFGYQ PMVDSFK YSVGYMKH DRDPΞKLTHHMPLFYC YEWREEEF VKTIVDALMEVTVYLQSDKDMMVS YCLDYCCHLRTLK SVQRIFQNK EKCNLSAAS CQDLALFLTSIQHVTR CLGFNRLQDDGIKL CAALTHPKCA ERLEL FCQLAAPAC KHLSDALLQNRSLTHLN SK SLRDΞGVKFLCEALGRPDGW QSLSLSGCSFTREGCG E ANALSH αsWKILDLGENDLQDDGVKLLCEA KPHRAl.HTLGLAKCNLTTACCQHIi FSVLSSSKSLVNLNLLGNELDTDGVKM CKAL KSTCR QK G

Further analysis of the NOV3a protein yielded the following properties shown in Table 3B.

Table 3B. Protein Sequence Properties NO 3a

PSort 0.8200 probability located in endoplasmic reticulum (membrane); 0.1900 analysis: probability located in plasma membrane; 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP Cleavage site between residues 23 and 24 analysis:

A search of the NOV3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3C.

In a BLAST search of public sequence databases, the NOV3a protein was found to have homology to the proteins shown in the BLASTP data in Table 3D.

Example 4.

The NO 4 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 4A.

Further analysis of the NOV4a protein yielded the following properties shown in Table 4B.

Table 4B. Protein Sequence Properties NOVla

PSort 0.6400 probability located in plasma membrane; 0.4600 probability located in analysis: Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 32 and 33 analysis:

A search of the NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4C.

In a BLAST search of public sequence databases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4D.

Table 4D. Public BLASTP Results for NOV4a

NOV4a Identities/

Protein Residues/ Similarities for Expect

Accession Protein/Organism/Length

Match the Matched Value

Number Residues Portion

PI 9397 Leukocyte surface antigen CD53 1..206 205/219 (93%) e-115 (Cell surface glycoprotein CD53) 1..219 205/219 (93%) Homo sapiens (Human), 219 aa.

AAH21310 CD53 ANTIGEN - Mus musculus 1..206 168/219 (76%) 6e-95 (Mouse), 219 aa. 1..219 183/219 (82%)

Q61451 Leukocyte surface antigen CD 53 2..206 167/218 (76%) 2e-94 (Cell surface glycoprotein CD53) 1..218 182/218 (82%) Mus musculus (Mouse), 218 aa.

A39574 leukocyte antigen OX-44 - rat, 219 1..206 164/219 (74%) 7e-94 aa. 1..219 183/219 (82%)

P24485 Leukocyte surface antigen CD53 2..206 163/218 (74%) 3e-93 (Cell surface glycoprotein CD53) 1..218 182/218 (82%) (Leukocyte antigen MRC OX-44) Rattus norvegicus (Rat), 218 aa.

PFam analysis predicts that the NOV4a protein contains the domains shown in the Table 4E.

Example 5.

The NOV5 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 5A. Table 5A. NOV5 Sequence Analysis

SEQ ID NO: 9 1719 bp

NOV5a, ATGCGGACGCCGGTGGTGATGACGCTGGGCATGGTGTTGGCGCCCTGCGGGCTCCTGC CG101068-01 TCAACCTGACCGGCACCCTGGCGCCCGGCTGGCGGCTGGTGAAGGGCTTCCTGAACCA GCCAGTGGACGTGGAGTTGTACCAGGGCCTGTGGGACATGTGTCGCGAGCAGAGCAGC DNA Sequence CGCGAGCGCGAGTGCGGCCAGACGGACCAGTGGGGCTACTTCGAGGCCCAGCCCGTGC TGGTGGCGCGGGCACTCATGGTCACCTCGCTGGCCGCCACGGTCCTGGGGCTTCTGCT GGCGTCGCTGGGCGTGCGCTGCTGGCAGGACGAGCCCAACTTCGTGCTGGCAGGGCTC TCGGGCGTCGTGCTCTTCGTCGCTGGCCTCCTCGGCCTCATCCCGGTGTCCTGGTACA ACCACTTCTTGGGGGACCGCGACGTGCTGCCCGCCCCGGCCAGCCCGGTCACGGTGCA GGTCAGCTACAGCCTGGTCCTGGGCTACCTGGGCAGCTGCCTCCTGCTGCTGGGCGGC TTCTCGCTGGCGCTCAGCTTCGCGCCCTGGTGCGACGAGCGTTGTCGCCGCCGCCGCA AGGGACCCTCCGCCGGGCCTCGCCGCAGCAGCGTCAGCACCATCCAAGTGGAGTGGCC CGAGCCCGACCTGGCGCCCGCCATCAAGTACTACAGCGACGGCCAGCACCGACCGCCG CCTGCCCAGCACCGCAAGCCCAAGCCCAAGCCCAAGGTCGGCTTCCCCATGCCGCGGC CGCGGCCCAAGGCCTACACCAACTCGGTGGACGTCCTCGACGGGGAGGGGTGGGAGTC CCAGGACGCTCCCTCGTGCAGCACCCACCCCTGCGACAGCTCGCTGCCCTGCGACTCC GACCTCTAGACGCTTGTAGAGCCTGGGGGGCGCCGGGTGGCAAAGGACTCACCCCCGC

ACAGGCCCGCCTGGCTTCGAGTTGGAACCCGGACACTTGCCCCTCACTGGTGTGGATG

GAAATCTGCCTTTCGTGGGACCAAACAGGACTCCTTGGACGATTAGTTCAGGTTGGGT

TTGGTTTTCTTCTTAAAGAGTTTAGTTTTCCTCTCCAGAGGGATCAGGGTCCTCTTAG

GGAGTGACGGGCTTTTCATATATTTTTGCTGAAGAATATATGGAAAGGGTGGCATTTG

CGTCACGTGGACCAGGGACAGTGCTGAAATCAGCAGTGCTCAGAAACAATTTAACATG

TTGAAACGACAATATTCTAAAATACTGATGAATCTTGCATCAATATAATTATTGGGTT

TTTTTTCTTTTTCCTGCTGTATAACTCCTTGCCATGCAAACTCTCAAGAGGCCAATAT

ATTCCTGGCCATGTTTGAATGAGCCTCTTAAAATAAACTTAGAGCCATGCAAATGCCA

GCAGCTTAATGGATTTCATGGAATGAAATACCGTGATTAACTCATAGCTACATATCAT

TGCATAAATGGGATTTATCTTTTTTCTCACTTATTTTTGCGGTGAAAGTCGAGGGCAT

GCAAGAGTTTCTCTTCCAGAAGCCAAGAGGAGAACAAAGGTCCTAATGCTGTACTATT

CCACCCTTTGGACGCCTCATCCAGGACGCAGAGGACTCTAGGTTTAACATTTTGTACA

AAATGGAACCTGTTAATCATATTAAAGCACATATGTATATATCTTTTATTTATAAATA

AAATTTTAAAACAATAGTTTCAGTATAGCCACAAAAA

ORF Start: ATG at 1 ORF Stop: TAG at 877

SEQ ID NO: 10 292 aa MW at 31914.5kD

NOV5a, MRTPWMT GMVLAPCGLL NLTGTLAPG R VKGFLNQPVPVE YQG DMCREQSS CGI 01068-01 RERECGQTDQ GYFEAQPVLVARALMVTS AATVLGL ASIiGVRC QDEPNFVLAG SGWLFVAG GLIPVSWYNHF GDRDV PAPASPVTVQVSYS VLGYLGSCLLLLGG Protein Sequence FSLA SFAP CDERCRRRRKGPSAGPRRSSVSTIQVE PEPD APAIKYYSDGQHRPP PAQHRKPKPKPKVGFPMPRPRPKAYTNSVDV DGEGWESQDAPSCSTHPCDSSLPCDS D

Further analysis of the NOV5a protein yielded the following properties shown in Table 5B.

Table 5B. Protein Sequence Properties NOV5a

PSort 0.6400 probability located in plasma membrane; 0.4600 probability located in analysis: Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 28 and 29 analysis: A search of the NOV5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 5C.

In a BLAST search of public sequence databases, the NOV5a protein was found to have homology to the proteins shown in the BLASTP data in Table 5D.

PFam analysis predicts that the NOV5a protein contains the domains shown in the Table 5E.

Table 5E. Domain Analysis of NOV5a

Identities/

Pfam Domain NOV5a Match Region Similarities Expect Value for the Matched Region

PMP22 Claudi 3..177 40/194 (21%) 0.00018 108/194 (56%)

Example 6.

The NOV6 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 6A.

TTTGCTTTGGATGGTATGCCTTACACTTTCTTGTACAAAGTGGAATTTCCTACTGTAT CATGATCATCATAGGAGTGGAGAACATGCACAATTACTGCTTTGTGTTTGCTCTGGGA TACCTCACAGTGTGCCAAGTTACTCGAGTCTATATCTTTGACTATGGACAATATTCTG CTGATTTTTCAGGCCCAATGATGATCATTACTCAGAAGATCACTAGTTTGGCTTGCGA AATTCATGATGGGATGTTTCGGAAGGATGAAGAACTGACTTCCTCACAGAGGGATTTA GCTGTAAGGCGCATGCCAAGCTTACTGGAGTATTTGAGTTACAACTGTAACTTCATGG GGATCCTGGCAGGCCCACTTTGCTCTTACAAAGACTACATTACTTTCATTGAAGGCAG ATCATACCATATCACACAATCTGGTGAAAATGGAAAAGAAGAGACACAGTATGAAAGA ACAGAGCCATCTCCAAATAGTGCGGTTGTTCAGAAGCTCTTAGTTTGTGGGCTGTCCT TGTTATTTCACTTGACCATCTGTACAACATTACCTGTGGAGTACAACATTGATGAGCA TTTTCAAGCTACAGCTTCGTGGCCAACAAAGATTATCTATCTGTATATCTCTCTTTTG GCTGCCAGACCCAAATACTATTTTGCATGGACGCTAGCTGATGCCATTAATAΆTGCTG CAGGCTTTGGTTTCAGAGGGTATGACGAAAATGGAGCAGCTCGCTGGGACTTAATTTC CAATTTGAGAATTCAACAAATAGAGATGTCAACAAGTTTCAAGATGTTTCTTGATAAT GGAATATTCAGACAGCTCTTTGGCTCAAAAGGGTGTGTTATGAACGAACCTCCTTCA GTCCAΆCTATCCAGACGTTCATTCTCTCTGCCATTTGGCACGGGGTATACCCAGGATA TTATCTAACGTTTCTAACAGGGGTGTTAATGACATTAGCAGCAAGAGCTGTAΆGAAAT AACTTTAGACATTATTTCATTGAACCTTCCCAACTGAAATTATTTTATGATGTTATAA CATGGATAGTAACTCAAGTAGCAATAAGTTACACAGTTGTGCCATTTGTGCTTCTTTC TATAAΆΆCCATCACTCACGTTTTACAGCTCCTGGTATTATTGCCTGCACATTCTTGGT TCTTAGTATTATTGTTGTTGCCAGTAAAAAAAACTCAAAGAAGAAAGAATACACATG AAAACATTCAGCTCTCACAATCCAAAAAGTTTGATGAAGGAGAAAATTCTTTGGGACA GAACAGTTTTTCTACAACAAACAATGTTTGCAATCAGAATCAAGAAATAGCCTCGAGA CATTCATCACTAAAGCAGTGATCGGGAAGGCTCTGAGGGCTGTTTTTTTTTTTTGATG TAACAGAAACCAATCTTAGCACCTTTTCAΆGGGGTTTGAGTTTGTTGGAAAAGCAGT

TAACTGGGGGGAAATGGACAGTTATAGATAAGGAATTTCCTGTΆCACCAGATTGGAAA GGAGTGAAACAAGCCCTCCCATGCCATGTCCCCGTGGGCCACGCCTTATGTAAGAAT

ATTTCCATATTTCAGTGGGCACTCCCAACCTCAGCACTTGTCCGTAGGGTCACACGCG

TGCCCTGTTGCTGAATGTATGTTGCGTATCCCAAGGCACTGAAGAGGTGGAAAAATAA

TCGTGTCAATCTGGATGATAGAGAGAAATTAACTTTTCCAAATGAATGTCTTGCCTTA

AACCCTCTATTTCCTAAAATATTGTTCCTAAATGGTATTTTCAAGTGTAATATTGTGA

GAACGCTACTGCAGTAGTTGATGTTGTGTGCTGTAAAGGATTTTAGGAGGAATTTGAA

ACAGGATATTTAAGAGTGTGGATATTTTTAAAATGCAATAAACATCTCAGTATTTGAA

GGGTTTTCTTAAAGTATGTCAAATGACTACAATCCATAGTGAAACTGTAAACAGTAAT

GGACGCCAAATTATAGGTAGCTGATTTTGCTGGAGAGTTTAATTACCTTGTGCAGTCA

AAGAGCGCTTCCAGAAGGAATCTCTTAAAACATAATGAGAGGTTTGGTAATGTGATAT

TTTAAGCTTACTCTTTTTCTTAAAAGAGAGAGGTGACGAAGGAAGGCAG

ORF Start: ATG at 25 ORF Stop: TGA at 1585

SEQ ID NO: 12 520 aa MW at 59480.0kD

NOV6a, MATTSTTGST LQPLSNAVQLPIDQVNFWCQLFALLAAI FRTY HSS TSSFIRHV CG101231-01 VATLLG YLALFCFG YAHFLVQSGISYCIMIIIGVENMHNYCFVFALGY TVCQVT RVYIFDYGQYSADFSGPMMIITQKITSLACEIHDGMFRKDEE TSSQRDLAVRRMPSL Protein Sequence LEYLSY CNFMGILAGPLCSYKDYITFIEGRSYHITQSGΞNGKEETQYERTEPSPNSA WQ L VCGLSLLFHLTICTTLPVEYNIDEHFQATAS PTKIIYLYISL AARPKYYF A TLADAIN AAGFGFRGYDENGAARWDLISNLRIQQIEMSTSFKMF DN NIQTALW KRVCYERTSFSPTIQTFILSAIWHGVYPGYYLTFLTGV MT AARAVRlsTNFRHYFIE PSQ KLFYDVIT IVTQVAISYTVVPFVLLSIKPSLTFYSS YYC HILGILVLL LP VKKTQRRKNTHENIQLSQSKKFDEGENS GQNSFSTTN VCNQNQEIASRHSSLKQ

SEQ ID NO: 13 2270 bp

NOV6b, CGGCCGGAGCGCCGAGGCCCGGCCATGGCCACCACCAGCACCACGGGCTCCACCCTGC CG101231-02 TGCAGCCCCTCAGCAACGCCGTGCAGCTGCCCATCGACCAGGTCAACTTTGTAGTGTG CCAACTCTTTGCCTTGCTAGCAGCCATTTGGTTTCGAACTTATCTACATTCAAGCAAA DNA Sequence ACTAGCTCTTTTATAAGACATGTAGTTGCTACCCTTTTGGGCCTTTATCTTGCACTTT TTTGCTTTGGATGGTATGCCTTACACTTTCTTGTACAAAGTGGAATTTCCTACTGTAT CATGATCATCATAGGAGTGGAGAACATGCAGCCAATGATGATCATTACTCAGAAGATC ACTAGTTTGGCTTGCGAAATTCATGATGGGATGTTTCGGAAGGATGAAGAACTGACTT CCTCACAGAGGGATTTAGCTGTAAGGCGCATGCCAAGCTTACTGGAGTATTTGAGTTA CAACTGTAACTTCATGGGGATCCTGGCAGGCCCACTTTGCTCTTACAAAGACTACATT ACTTTCATTGAAGGCAGATCATACCATATCACACAATCTGGTGAAAATGGAAAAGAAG AGACACAGTATGAAAGAACAGAGCCATCTCCAAATAGTGCGGTTGTTCAGAAGCTCTT AGTTTGTGGGCTGTCCTTGTTATTTCACTTGACCATCTGTACAACATTACCTGTGGAG TACAACATTGATGAGCATTTTCAAGCTACAGCTTCGTGGCCAACAAAGATTATCTATC TGTATATCTCTCTTTTGGCTGCCAGACCCAAATACTATTTTGCATGGACGCTAGCTGA TGCCATTAATAATGCTGCAGGCTTTGGTTTCAGAGGGTATGACGAAAATGGAGCAGCT CGCTGGGACTTAATTTCCAATTTGAGAATTCAACAAATAGAGATGTCAACAAGTTTCA AGATGTTTCTTGATAATTGGAATATTCAGACAGCTCTTTGGCTCAAAAGGGTGTGTTA TGAACGAACCTCCTTCAGTCCAACTATCCAGACGTTCATTCTCTCTGCCATTTGGCAC GGGGTATACCCAGGATATTATCTAACGTTTCTAACAGGGGTGTTAATGACATTAGCAG CAAGAGCTGTAAGAAATAACTTTAGACATTATTTCATTGAACCTTCCCAACTGAAATT ATTTTATGATGTTATAACATGGATAGTAACTCAAGTAGCAATAAGTTACACAGTTGTG CCATTTGTGCTTCTTTCTATAAAACCATCACTCACGTTTTACAGCTCCTGGTATTATT GCCTGCACATTCTTGGTATCTTAGTATTATTGTTGTTGCCAGTAAAAAAAACTCAAAG AAGAAAGAATACACATGAAAACATTCAGCTCTCACAATCCAAAAAGTTTGATGAAGGA GAAAATTCTTTGGGACAGAACAGTTTTTCTACAACAAACAATGTTTGCAATCAGAATC AAGAAATAGCCTCGAGACATTCATCACTAAAGCAGTGATCGGGAAGGCTCTGAGGGCT

GTTTTTTTTTTTTGATGTTAACAGAAACCAATCTTAGCACCTTTTCAAGGGGTTTGAG

TTTGTTGGAAAAGCAGTTAACTGGGGGGAAATGGACAGTTATAGATAAGGAATTTCCT

GTACACCAGATTGGAAATGGAGTGAAACAAGCCCTCCCATGCCATGTCCCCGTGGGCC

ACGCCTTATGTAAGAATATTTCCATATTTCAGTGGGCACTCCCAACCTCAGCACTTGT

CCGTAGGGTCACACGCGTGCCCTGTTGCTGAATGTATGTTGCGTATCCCAAGGCACTG

AAGAGGTGGAAAAATAATCGTGTCAATCTGGATGATAGAGAGAAATTAACTTTTCCAA

ATGAATGTCTTGCCTTAAACCCTCTATTTCCTAAAATATTGTTCCTAAATGGTATTTT

CAAGTGTAATATTGTGAGAACGCTACTGCAGTAGTTGATGTTGTGTGCTGTAAAGGAT

TTTAGGAGGAATTTGAAACAGGATATTTAAGAGTGTGGATATTTTTAAAATGCAATAA

ACATCTCAGTATTTGAAGGGTTTTCTTAAAGTATGTCAAATGACTACAATCCATAGTG

AAACTGTAAACAGTAATGGACGCCAAATTATAGGTAGCTGATTTTGCTGGAGAGTTTA

ATTACCTTGTGCAGTCAAAGAGCGCTTCCAGAAGGAATCTCTTAAAACATAATGAGAG

GTTTGGTAATGTGATATTTTAAGCTTACTCTTTTTCTTAAAAGAGAGAGGTGACGAAG

GAAGGCAG

ORF Start: ATG at 25 ORF Stop: TGA at 1486

SEQ ID NO: 14 487 aa MW at 55677.7kD

NOV6b, MATTSTTGSTLLQP SNAVQLPIDQVNFWCQ FAL AAI FRTY HSSKTSSFIRHV CG101231-02 VATLLG YLA FCFG YA HFLVQSGISYCIMIIIGVEN QPMMIITQKITSLACEIH DGMFRKDEELTSSQRDLAVRRMPSLLEY SYNCNF GI AGP1.CSYKDYITFIEGRSY Protein Sequence HITQSGENGKEETQYERTEPSPNSAWQKLLVCGLSLLFHLTICTT PVEYNIDEHFQ ATAS PTKIIY YIS AARPKYYFA T ADAINNAAGFGFRGYDENGAAR DLISN RIQQIΞMSTSF MF DN NIQTALW KRVCYΞRTSFSPTIQTFI SAIWHGVYPGYYL TF TGV MTLAARAVR NFRHYFIEPSQLKLFYDVITWIVTQVAISYTVVPFVLLSIK PSLTFYSS YYCLHI GI VLL LPVKKTQRRKNTHENIQ SQSKKFDEGENSLGQNS FSTTN VCNQNQEIASRHSSLKQ

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 6B.

Further analysis of the NOV6a protein yielded the following properties shown in Table 6C. Table 6C. Protein Sequence Properties NOVόa

PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3406 probability located in mitochondrial intermembrane space; 0.3384 probability located in mitochondrial inner membrane

SignalP Cleavage site between residues 44 and 45 analysis:

A search of the NOV6a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6D.

In a BLAST search of public sequence databases, the NOV6a protein was found to have homology to the proteins shown in the BLASTP data in Table 6E.

PFam analysis predicts that the NOV6a protein contains the domains shown in the Table 6F.

Example 7.

The NOV7 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 7A.

Further analysis of the NOV7a protein yielded the following properties shown in Table 7B.

Table 7B. Protein Sequence Properties NOV7a

PSort 0.6400 probability located in microbody (peroxisome); 0.4500 probability analysis: 1 located in cytoplasm; 0.2288 probability located in lysosome (lumen); 0.1000 j probability located in mitochondrial matrix space

SignalP j No Known Signal Sequence Predicted analysis:

A search of the NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7C.

In a BLAST search of public sequence databases, the NOV7a protein was found to have homology to the proteins shown in the BLASTP data in Table 7D.

Example 8.

The NOV8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 8A.

CCTGGGAGAGTTTGACCAGCACTTGAAGGGAAGAACAGATTTCATTAAAGGGATGAAG AAGAAGAGCAGAGCAGAGCGGAAGACAGAAATCATTCGAAAACGCCTCCACAAAGACA TTCCCCACCACTCCGTCATCATGCTCAACTTCTGTCCCGACCTCCAGTCAGTCCAGCC GTGCCTGAGAAAGGCCCACGGGGAGTTCATCTTCCTCATTGACAGGAGCAGCAGCATG AGCGGGATCAGCATGCACCGAGTCAAGGATGCCATGTTGGTGGCCCTTAAGAGCCTCA TGCCAGCCTGCCTCTTCAATATCATTGGGTTTGGATCCACATTTAAGAGCCTTTTTCC TTCCAGCCAGACCTACAGTGAGGACAGCTTGGCCATGGCTTGTGATGACATCCAGAGA ATGAAGGCCGACATGGGTGGGACCAACATCCTTTCCCCTCTCAAGTGGGTCATCAGGC AGCCAGTGCACCGAGGCCACCCGCGGCTCCTCTTCGTGATCACAGATGGCGCTGTCAA CAACACAGGGAAGGTGCTGGAGCTGGTGCGAAATCACGCCTTCTCCACCAGGTGCTAT AGCTTTGGAATTGGACCCAACGTCTGCCACAGACTGGTGAAAGGACTGGCATCTGTGT CCGAGGGCAGTGCTGAGCTCCTGATGGAGGGGGAGCGGCTGCAACCCAAGATGGTCAA ATCCTTGAAGAAGGCCATGGCCCCAGTCCTGAGCGATGTGACTGTGGAGTGGATCTTC CCTGAGACCACTGAGGTCCTGGTCTCACCCGTCAGCGCCAGCTCCCTCTTCCCTGGAG AACGGCTGGTGGGGTATGGCATTGTATGTGATGCTTCTTTGCACATCTCCAATCCCAG ATCTGACAAGAGGCGCCGGTACAGCATGCTGCACTCTCAGGAGTCTGGCAGCTCTGTC TTCTACCACTCTCAGGATGACGGACCCGGGCTGGAAGGTGGAGACTGTGCCAAGAACT CGGGGGCACCCTTCATCCTAGGGCAGGCCAAAAATGCCCGGCTAGCCAGCGGAGACTC TACCACCAAGCACGGTCTGAACCTCTCTCAGCGACGGAGGGCATACAGCACCAACCAG ATCACCAATCACAAGCCCCTCCCAAGAGCCACCATGGCAAGTGACCCCATGCCAGCTG CCAAGAGATACCCACTGCGGAAAGCCAGGCTGCAGGACCTCACCAACCAGACCAGCCT GGATGTCCAGCGGTGGCAGATTGATTTGCAGGTATTGCTGAACAGTGGTCAGGACCTG AACCAGGGCCCCAAACTCCGTGGCCCAGGGGCCCGAAGGCCCTCTCTGCTGCCCCAAG GCTGCCAGCCCTTCCTGCCCTGGGGCCAGGAGACCCAGGCCTGGAGCCCTGTGAGAGA GCGGACTTCTGACAGCCGAAGCCCTGGAGATCTGCCCGCAGAGCCGTCCCACCATCCC TCTGCCTTCGAGACAGAGACGTCCTCGGACTGGGACCCCCCAGCCGAGTCCCAGGAGC GAGCCAGTCCCAGCAGGCCCGCCACCCCGGCCCCGGTGCTGGGCAAGGCCCTGGTCAA AGGCCTGCACGACAGCCAACGCCTGCAGTGGGAGGTGAGCTTCGAGCTGGGGACCCCT GGACCGGAGCGGGGCGGCGCGCAGGATGCCGACCTATGGAGCGAGACCTTCCACCACC TGGCGGCCCGCGCCATCATCCGCGACTTCGAGCAGCTGGCGGAGCGCGAGGGCGAGAT CGAGCAGGGTTCCAACCGCCGCTACCAAGTGAGCGCCTTGCACACCAGCAAGGCCTGC AACATCATTAGCAAATACACAGCCTTCGTGCCTGTGGACGTGAGCAAGAGCCGGTACC TGCCCACCGTGGTGGAGTACCCCAACTCTGGTCGTATGCTTGGCTCTCGGGCCCTGGC CCAACAGTGGAGGGGCACCTCTTCTGGCTTTGGAAGGCCGCAGACGATGCTTGGAGAA GATTCGGCACCAGGAAATGGTAAATTTCAGGTCCTAGACATGGAGGCAAGTCCCACTG CTCTCTTCAGCGAGGCCAGGTCCCCCGGCCGCGAGAAGCACGGTGCTTCTGAAGGTCC CCAGCGCAGCCTGGCTACAAATACTCTTTCTTCCATGAAGGCCTCAGAGAATCTCTTT GGATCCAGGCTAAATCTCAACAAGTCCAGGCTACTGACGCGAGCAGCCAAGGGCTTCC TGAGCAAGCCACTGATCAAAGCTGTGGAGTCGACCTCCGGGAACCAGAGCTTCGACTA CATACCTCTGGTGTCTCTGCAGCTGGCCTCCGGAGCCTTCCTGCTCAACGAAGCCTTC TGTGAGGCCACGCACATCCCCATGGAGAAGCTCAAGTGGACGTCCCCCTTCACCTGCC ATCGAGTGTCCCTCACCACCCGCCCGTCTGAGTCCAAGACCCCGAGTCCCCAGCTGTG CACCAGCTCCCCGCCTAGGCACCCGTCCTGTGACAGCTTCTCCCTGGAGCCTCTGGCC AAGGGCAAGCTGGGCCTGGAGCCGAGGGCAGTGGTGGAGCACACTGGGAAGCTGTGGG CCACGGTGGTGGGGCTGGCATGGCTGGAGCACAGTTCGGCCTCCTACTTCACTGAGTG GGAGTTGGTGGCTGCCAAGGCCAACTCATGGCTGGAGCAGCAGGAAGTACCCGAGGGC CGCACGCAGGGCACACTCAAGGCCGCTGCCCGCCAGCTGTTTGTGCTTCTGCGGCACT GGGATGAGAATCTCGAGTTCAATATGCTCTGCTATAACCCGAATTATGTGTAGTTGA

ORF Start: ATG at 5 ORF Stop: TAG at 3647

SEQ ID NO: 18 1214 aa MW at l33118.0kD

NOV8a, PG NWITGAALPLTASDVTSCVSGYALGLTAS TYGNLEAQPFQGLFVYPLDECT CG101458-01 VIGFEAVIADRWTVQIKDKAK ESGHFDASHVRSPTVTGKBTRRAAAGPGKVTLDED ERILFVAN GTIAPMENVTIFISTSSELPTLPSGAVRVLLPAVCAPTVPQFCTKSTG Protein Sequence TSNQQAQGKDRHCFGAWAPGS NK CLAT NTEVSNP EYEFNFQ EIRGPCL AGV ESPTHEIRADAAPSARSAKSIIITLANKHTFDRPVEILIHPSEPHMPHVLIE GDMTL GEFDQH KGRTDF I KGMKKKSRAERKTE I IRKRLHKD I PHHS VI LNFCPDLQS VQPC LRKAHGEF IFLIDRSSSMSGI SMHRVKDA L-VALKS MPACLFNI IGFGSTFKS FPS SQTYSEDS AMACDDIQRMKADMGGTNILSP K VIRQPVHRGHPRLLFVITDGAVlsTN TGKV ELVTINHAFSTRCYSFGIGPNVCHRLVKGLASVSEGSAELLMEGER QPKMVKS LKKAMAPVLSDVTVEWIFPETTEVLVSPVSASS FPGERLVGYGIVCDASLHISNPRS DKRRRYSMLHSQESGSSVFYHSQDDGPGLEGGDCAKNSGAPFILGQAKNARLASGDST TKHGLN SQRRRAYSTNQIT HKPLPRATMASDPMPAAKRYPLR ARLQD TNQTSLD VQR QIDLQVL SGQD NQGPK RGPGARRPS PQGCQPFLP GQETQAWSPVRER TSDSRSPGD PAEPSHHPSAFETETSSDWDPPAESQERASPSRPATPAPV GKALVKG LHDSQR QWEVSFELGTPGPERGGAQDADLWSETFHHLAARAIIRDFEQ AEREGEIE QGSNRRYQVSALHTSKACNIISKYTAFVPVDVSKSRYLPTVVEYPNSGRMLGSRALAQ Q RGTSSGFGRPQTM GEDSAPGNG FQV DMEASPTALFSEARSPGREKHGASEGPQ RSLATNT SSMKASEN FGSRLN NKSRLLTRAAKGFLS PLI AVESTSGNQSFDYI PLVS QLASGAFL NΞAFCEATHIPMEK KWTSPFTCHRVS TTRPSESKTPSPQLCT SSPPRHPSCDSFS EPLAKGKLGLEPRAλArEHTGKL ATWGLA LEHSSASYFTEWE LVAAKANS LEQQEVPEGRTQGTLIOAARQLFVL RHWDENLEFISMLCYlsTPlrYV

Further analysis of the NOV8a protein yielded the following properties shown in Table 8B.

Table 8B. Protein Sequence Properties NOV8a

PSort 0.8700 probability located in nucleus; 0.8500 probability located in analysis: endoplasmic reticulum (membrane); 0.7900 probability located in plasma membrane; 0.3325 probability located in microbody (peroxisome)

SignalP Cleavage site between residues 19 and 20 analysis:

A search of the NOV8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 8C.

Table 8C. Geneseq Results for NO 8a

NOV8a Identities/

Geneseq Protein/Organism/Length [Patent Residues/ Similarities for Expect Identifier #, Date] Match the Matched Value Residues Region

AAB82047 Human mast cell surface antigen - 13..565 168/565 (29%) 2e-59 Homo sapiens, 786 aa. 15..500 269/565 (46%) [JP2001025388-A, 30-JAN-2001]

AAY82530 Human neurotransmitter associated 1034..1211 82/194 (42%) le-32 protein sequence SEQ ID NO: 6 - 16..207 105/194 (53%) Homo sapiens, 210 aa. [WO200012685-A2, 09-MAR- 2000]

AAU33242 Novel human secreted protein 36..568 120/537 (22%) 4e-23 #3733 - Homo sapiens, 1730 aa. 650..1096 214/537 (39%) [WO200179449-A2, 25-OCT-2001] i

AAB51022 Human minor vault protein pi 93 36..568 120/537 (22%) 6e-23 Homo sapiens, 1724 aa. 644..1090 214/537 (39%) [US6156879-A, 05-DEC-2000]

AAY54373 cDNA sequence encoding the 36-568 120/537 (22%) 6e-23 human minor vault protein pi 93 - 644..1090 214/537 (39%) Homo sapiens, 1724 aa. [WO9962547-A1, 09-DEC-1999]

In a BLAST search of public sequence databases, the NOVδa protein was found to have homology to the proteins shown in the BLASTP data in Table 8D.

PFam analysis predicts that the NOV8a protein contains the domains shown in the Table 8E.

Table 8E. Domain Analysis of NOV8a

Identities/

Pfam Domain NOV8a Match Region Similarities Expect Value for the Matched Region vwa 355..523 37/203 (18%) 0.021 107/203 (53%)

Example 9.

The NOV9 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 9A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 9B. Table 9B. Comparison of NO 9a against NO 9b.

NOV9a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV9b 9..275 241/268 (89%) 1..268 241/268 (89%)

Further analysis of the NOV9a protein yielded the following properties shown in Table 9C.

Table 9C. Protein Sequence Properties NO 9a

PSort j 0.7900 probability located in plasma membrane; 0.3000 probability located in analysis: Golgi body; 0.2000 probability located in endoplasmic reticulum (membrane); j 0.1000 probability located in mitochondrial inner membrane

SignalP [ Cleavage site between residues 62 and 63 analysis:

A search of the NOV9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 9D.

In a BLAST search of public sequence databases, the NOV9a protein was found to have homology to the proteins shown in the BLASTP data in Table 9E.

PFam analysis predicts that the NOV9a protein contains the domains shown in the Table 9F.

Example 10.

The NOV10 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 10A.

Further analysis of the NOVlOa protein yielded the following properties shown in Table 10B.

Table 10B. Protein Sequence Properties NOVlOa

PSort 0.9190 probability located in plasma membrane; 0.2000 probability located in analysis: lysosome (membrane); 0.1021 probability located in microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOVl 0a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table IOC.

In a BLAST search of public sequence databases, the NOVlOa protein was found to have homology to the proteins shown in the BLASTP data in Table 10D.

Example 11.

The NOVl 1 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 11 A.

Protein Sequence DRQVPLWGQ LLFLVFVIV FFIYHFMQAEEGNPF

Further analysis of the NOVl la protein yielded the following properties shown in Table 11B.

Table 11B. Protein Sequence Properties NOVlla

PSort 0.8500 probability located in endoplasmic reticulum (membrane); 0.6000 analysis: probability located in nucleus; 0.4400 probability located in plasma membrane; 0.2323 probability located in microbody (peroxisome)

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOVl la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 11 C.

In a BLAST search of public sequence databases, the NOVl 1 a protein was found to have homology to the proteins shown in the BLASTP data in Table 1 ID.

PFam analysis predicts that the NOVl la protein contains the domains shown in the Table HE.

Table HE. Domain Analysis of NOVlla

Identities/

Pfam Domain NOVlla Match Region Similarities Expect Value for the Matched Region

LEM 1..44 22/47 (47%) 4.4e-24 43/47 (91%)

Example 12.

The NOVl 2 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 12 A.

TGGTTGTATCCTGAGAAAACTAGATGGCAAGATTGTTTTACCAGGCAACTTTCTGTAT TGTACATTCTATGGACGACCGTACAAGCTGCAAGTATTGCGAGTGAAAGGGGCAGATG GCATGATATTGGGAGGGCCTCAGAGTGACTCTGACACTGATGCCCAAAGAATGGCCTT TGAACAGTCCAGCATGGAAACCAGTAGCCTGGAGTTATCCTTACAGCTAAGCCAGTTA GATCTGGAGGATACCCAGATCCCAACATCAAGAAGTACTCCTTATAAACCAATTGATG ACAGAATTACAAATAAAGCCAGTGATGTTTTGCTGGATGTTACACAGAGCCCTGGAGA TGGCAGTGGACTTATGCTAGAGGAAGTCACAGGTCTTAAATGTAATTTTGAATCTGCC AGAGAAGGAAATGAGCAACTTACTGAAGAAGAGAGACTGCTAAAGTTCAGCATAGGAG CAAAGTGCAATACTGATACTTTTTATTTTATTTCTTCAACAACAAGAGTCAATTTTAC AGAGATTGATAAAAATTCAAAAGAGCAAGACAGTGATGTTAAAAGTAACTATGACCAT GATAGAGGATTAAGTAGCCAGCTGAAAGCAATTAGAGAAATAATTGAATTGCCCCTCA AAATTCCTGCCCCTAGAGGATTGTTACTTTATGGTCCTCCATGTACTGGAAAAACAAT GATCGCCAGGGCTGTTGCTAATGAATTTGGAGCCTATGTTTCTGTAATTAATGGTCCT GAAATTATAAGCAAGTTCTATGGTGAGACTGAAGCAAAGTTACGTCAGATATTTGCTG AAGCCACTCTAAGACACCCATCAATTATTTTTATTGATGAGCTGGATGCACTTTGTCC GAAAAGAGAGGGGGCCCAGAATGAAGTGGAAAAAAGAGTTGTGGCTTCACTCTTAACA CTGATGGATGGCATTGGTTCAGAAGTAAGTGAAGGACAAGTGTTGGTTCTTGGGGCCA CAAATCGCCCTCATGCCTTGGATGCTGCTCTCCGAAGACCTGGGCGATTTGATAAAGA GATTGAGATTGGAGTTCCCAATGCTCAGGACCGGCTAGATATTCTCCAGAAACTGCTT CGAAGGGTACCCCATTTGCTCACTGAGGCTGAGCTGCTGCAGCTGGCAAATAGTGCTC ATGGATACGTTGGAGCAGACTTGAAAGTCTTGTGTAATGAAGCAGGTCTCTGTGCCTT GCGGAGAATCCTGAAAAAACAGCCTAACCTCCCTGATGTCAAGGTGGCTGGACTGGTG AAGATTACTCTGAAGGATTTCTTGCAGGCAATGAATGATATCAGACCCAGTGCCATGA GGGAAATAGCAATTGATGTCCCAAATGTAAGTTATGATGATGTTGGTGGAGTTAGAAA GCAAATGGCCCAAATCAGAGAGCTTGTTGAGCTTCCACTACGCCATCCTCAACTTTTC AAATCTATTGGTATTCCTGCCCCTAGAGGATTGTTACTTTATGGTCCTCCATGTACTG GAAAAACAATGATCGCCAGGGCTGTTGCTAATGAATTTGGAGCCTATGTTTCTGTAAT TAATGGTCCTGAAATTATAAGCAAGTATGTTGGTGAGAGTGAACGTGCTGTGCGACAA GTTTTTCAACGAGCCAAGAACTCAGCACCATCAATTATTTTTATTGATGAGCTGGATG CACTTTGTCCGAAAAGAGAGGGGGCCCAGAATGAAGTGGAAAAAAGAGTTGTGGCTTC ACTCTTAACACTGATGGATGGCATTGGTTCAGTAAGTATAGTGTTGGTTCTTGGGGCC ACAAATCGCCCTCATGCCTTGGATGCTGCTCTCCGAAGACCTGGGCGATTTGATAAAG AGATTGAGATTGGAGTTCCCAATGCTCAGGACCGGCTAGATATTCTCCAGAAACTGCT TCGAAGGGTACCCCATTTGCTCACTGAGGCTGAGCTGCTGCAGCTGGCAAATAGTGCT CATGGATACGTTGGAGCAGACTTGAAAGTCTTGTGTAATGAAGCAGGTGAGTGTGGTT TGCTATGGGACATTCAAGCCAATCTCATCATGAAAAGACATTTCACTCAGGCCTTGAG CACTGTGACACCTAGAATTCCTGAGTCATTGAGACGTTTTTATGAAGATTATCAAGAG AAGAGTGGGCTGCATACACTCTGAGAAAATATATATATTCAAGATGCTGAAAATCCTT

TCCAGAGAAAATTGTTTCTTTTTAAAATTTTTGAGAGTGTTAAAAAAAATTTTACTAG

GCAAAATGTTTGAAGTATGTTCAGTAGA

ORF Start: ATG at 47 ORF Stop: TGA at 2690

SEQ ID NO: 28 881 aa MW at 96419.5kD

^!NOV12a, MSSKKNRKR NQSAENGSSLPSAASSCAEARAPSAGSDFAATSGT TVTNL EKGKIP CG102575-01 KTFQNSLIHLGLNTMKSANICIGRPV LTSLNGKQEVYTA PMAGFPGGKVG SE AQ KNVGVRPGDAIQVQP VGAV QAEEMDVALSDKDMEINEEE TGCILRK DGKIVLPG Protein Sequence NF YCTFYGRPYKLQVLRVKGADGMILGGPQSDSDTDAQR AFEQSSMETSS ELS Q LSQLDLEDTQIPTSRSTPY PIDDRITNKASDVL DVTQSPGDGSGL EEVTGL CN FESAREGNEQLTEEERLLKFSIGAKCNTDTFYFISSTTRVNFTEIDKNS EQDSDVKS NYDHDRGLSSQ KAIREIIELP KIPAPRG LLYGPPCTGKTMIARAVANEFGAYVSV INGPEIISKFYGETEAKLRQIFAEATLRHPS11FIDE DA CPKREGAQNEVEKRWA S T MDGIGSEVSEGQVLV GAT RPHA DAALRRPGRFDKEIEIGVPNAQDR DI QKLLRRVPH TEAE Q A SAHGYVGADLKVLCNEAG CA RRILKKQPNLPDV V AGLVKITLKDF QAMHDIRPSAMREIAIDVPNVSYDDVGGVRKQMAQIREL.VE PLRH PQ FKSIGIPAPRGL LYGPPCTGKTMIARAVANEFGAYVSVINGPEIISKYVGESER; AVRQVFQRAKNSAPSIIFIDELDALCPKREGAQNEVEKRWASL TLMDGIGSVSIV V GATNRPHA DAALRRPGRFDKEIEIGVPNAQDRLDILQKL RRVPHLLTEAE LQL ANSAHGYVGAD KVLCNEAGECGLL DIQANLIMKRHFTQAI.STVTPRIPESLRRFYE DYQEKSG HT SEQ ID NO: 29 2789 bp

NOVl 2b, CAGAGTTCGCCCTTCATTGAGTCGGCTTTTCTACTGCTTCGGCTAGGGTACCTTGTGA CGI 02575-02 CCATGTCTTCCAAGAAGAATAGAAAGCGGTTGAACCAAAGCGCGGAAAATGGTTCGTC CTTGCCCTCTGCTGCTTCCTCTTGTGTGGAGGCACGGGCTCCTTCTGCTGGATCAGAC DNA Sequence TTCGCGGCAACCTCCGGGACTCTGACGGTGACCAACTTATTAGAAAAGGTAGATGACA AAATTCCTAAAACATTCCAGAATTCCCTTATTCATCTTGGACTCAACACTATGAAGTC TGCAAATATATGTATAGGTCGACCAGTGTTGCTTACTAGTTTGAACGGAAAGCAAGAG GTGTATACAGCCTGGCCTATGGCAGGATTTCCTGGAGGCAAGGTCGGCCTGAGTGAAA TGGCACAGAAAAATGTGGGTGTGAGGCCTGGTGATGCCATCCAGGTCCAGCCTCTTGT GGGTGCTGTGCTACAGGCTGAGGAAATGGATGTGGCACTGAGTGACAAAGATATGGAA ATTAATGAAGAAGAACTGACTGGTTGTATCCTGAGAAAACTAGATGGCAAGATTGTTT TACCAGGCAACTTTCTGTATTGTACATTCTATGGACGACCGTACAAGCTGCAAGTATT GCGAGTGAAAGGGGCAGATGGCATGATATTGGGAGGGCCTCAGAGTGACTCTGACACT GATGCCCAAAGAATGGCCTTTGAACAGTCCAGCATGGAAACCAGTAGCCTGGAGTTAT CCTTACAGCTAAGCCAGTTAGATCTGGAGGATACCCAGATCCCAACATCAAGAAGTAC TCCTTATAAACCAATTGATGACAGAATTACAAATAAAGCCAGTGATGTTTTGCTGGAT GTTACACAGAGCCCTGGAGATGGCAGTGGACTTATGCTAGAGGAAGTCACAGGTCTTA AATGTAATTTTGAATCTGCCAGAGAAGGAAATGAGCAACTTACTGAAGAAGAGAGACT GCTAAAGTTCAGCATAGGAGCAAAGTGCAATACTGATACTTTTTATTTTATTTCTTCA ACAACAAGAGTCAATTTTACAGAGATTGATAAAAATTCAAAAGAGCAAGACAACCAAT TTAAAGTAACTTATGACATGATAGGAGGATTAAGTAGCCAGCTGAAAGCAATTAGAGA AATAATTGAATTGCCCCTCAAACAGCCTGAGCTTTTCAAGAGTTATGGAATTCCTGCC CCTAGAGGAGTGTTACTTTATGGTCCTCCAGGTACTGGAAAAACAATGATCGCCAGGG CTGTTGCTAATGAAGTTGGAGCCTATGTTTCTGTAATTAATGGTCCTGAAATTATAAG CAAATTCTATGGTGAGACTGAAGCAAAGTTACGTCAGATATTTGCTGAAGCCACTCTA CGACACCCATCAATTATTTTTATTGATGAGCTGGATGCACTTTGTCCGAAAAGAGAGG GGGCCCAGAATGAAGTGGAAAAAAGAGTTGTGGCTTCACTCTTAACACTGATGGATGG CATTGGTTCAGAAGTAAGTGAAGGACAAGTGTTGGTTCTTGGGGCCACAAATCGCCCT CATGCCTTGGATGCTGCTCTCCGAAGACCTGGGCGATTTGATAAAGAGATTGAGATTG GAGTTCCCAATGCTCAGGACCGGCTAGATATTCTCCAGAAACTGCTTCGAAGGGTACC CCATTTGCTCACTGAGGCTGAGCTGCTGCAGCTGGCAAATAGTGCTCATGGATACGTT GGAGCAGACTTGAAAGTCTTGTGTAATGAAGCAGGTCTCTGTGCCTTGCGGAGAATCC TGAAAAAACAGCCTAACCTCCCTGATGTCAAGGTGGCTGGACTGGTGAAGATTACTCT GAAGGATTTCTTGCAGGCAATGAATGATATCAGACCCAGTGCCATGAGGGAAATAGCA ATTGATGTCCCAAATGTATCCTGGTCAGATATAGGAGGACTGGAAAGTATCAAACTGA AGTTGGAACAGGCTGTGGAATGGCCCTTAAAACATCCAGAGTCTTTCATTCGAATGGG TATTCAGCCACCTAAAGGAGTTCTTCTCTATGGGCCACCTGGGTGCTCTAAAACAATG ATAGCAAAGGCTTTGGCCAATGAGAGTGGACTGAATTTTCTAGCTATAAAGGGGCCTG AATTAATGAATAAATATGTTGGTGAATCTGAAAGAGCAGTTAGAGAGACCTTCCGAAA AGCAAGAGCAGTGGCGCCTTCCATTATTTTCTTTGATGAACTGGATGCCTTAGCAGTT GAAAGGGGCAGTTCTTTAGGTGCTGGGAATGTAGCCGATCGTGTTTTGGCTCAGCTCT TAACAGAAATGGATGGGATTGAACAGCTAAAGGATGTGACCATTTTGGCAGCTACTAA CCGTCCAGATAGGATAGACAAGGCTTTGATGCGGCCTGGAAGAATTGATAGAATCATC TATGTGCCTTTACCGGATGCAGCAACAAGAAGGGAAATATTTAAGCTGCAGTTTCACT CCATGCCTGTCAGTAATGAAGTTGACCTGGATGAACTCATCCTTCAAACCGACGCATA CTCAGGAGCAGAGATTGTAGCTGTCTGCAGAGAGGCAGCTCTTCTGGCTCTGGAAGAA GACATTCAAGCCAATCTCATCATGAAAAGACATTTCACTCAGGCCTTGAGCACTGTGA CACCTAGAATTCCTGAGTCATTGAGACGTTTTTATGAAGATTATCAAGAGAAGAGTGG GCTGCATACACTCTGAGAAAATATATATATTCAAGATGCTGAAAATCCTTTCCAGAGA AAATT

ORF Start: ATG at 61 ORF Stop: TGA at 2740

SEQ ID NO: 30 893 aa MW at 97931.2kD

NOV12b, SSKKNRKRLNQSAENGSS PSAASSCVEARAPSAGSDFAATSGT TVTNLLE VDDK CGI 02575-02 IPKTFQNSLIHLGLNTMKSANICIGRPVLLTSLNGKQEVYTAWPMAGFPGGKVG SEM AQKNVGVRPGDAIQVQPLVGAVLQAEEMDVALSDKDMEINEEE TGCILRKLDGKIV Protein Sequence PGNF YCTFYGRPYKLQV RVKGADGMILGGPQSDSDTDAQRMAFEQSSMETSSLELS LQ SQ DLEDTQIPTSRSTPYKPIDDRITNKASDVLLDVTQSPGDGSGLMLEEVTGLK CNFESAREGNEQLTEEΞRL KFSIGAKCNTDTFYFISSTTRV FTEIDKNSKEQDNQF KVTYDMIGGLSSQLKAIREIIELPLKQPE FKSYGIPAPRGVL YGPPGTGKTMIARA VA EVGAYVSVINGPEIISKFYGETEAKLRQIFAEATIiRHPSIIFIDELDALCPKREG AQNΞVEKRWASLLTLMDGIGSEVSΞGQVLVLGATNRPHALDAA RRPGRFDKEIEIG VPNAQDR DILQK LRRVPHL TEAΞLLQ A SAHGYVGADLKV CNEAG CALRRI QPN PDVKVAG VKIT KDF QAMKDIRPSA REIAIDVPNVSWSDIGG ESIK EQAVEWP KHPESFIRMGIQPPKGV LYGPPGCSKTMIAIALANESGL FLAIKGPE MN YVGESΞRAVRETFRKARAVAPSIIFFDELDA AVERGSS GAGNVADRVLiAQLL TEMDGIEQ KDVTILAATNRPDRIDKA RPGRIDRIIYVP PDAATRREIFKLQFHS PVSNEVDLDΞLILQTDAYSGAEIVAVCREAALLA EEDIQAN IMKRHFTQA STVT PRIPESLRRFYEDYQEKSG HTL

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 12B.

Further analysis of the NOVl 2a protein yielded the following properties shown in Table 12C.

Table 12C. Protein Sequence Properties NOV12a

PSort 0.7000 probability located in plasma membrane; 0.3000 probability located in analysis: microbody (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOVl 2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 12D.

In a BLAST search of public sequence databases, the NOVl 2a protein was found to have homology to the proteins shown in the BLASTP data in Table 12E.

PFam analysis predicts that the NOVl 2a protein contains the domains shown in the Table 12F.

Example 13.

The NOVl 3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 13 A.

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 13B.

Table 13B. Comparison of NOV13a against NO V13b.

NOV13a Residues/ Identities/

Protein Sequence

Match Residues Similarities for the Matched Region

NOVl 3b 1..86 86/86 (100%) 31..116 86/86 (100%)

Further analysis of the NOVl 3a protein yielded the following properties shown in Table 13C.

Table 13C. Protein Sequence Properties NOV13a

PSort 0.4600 probability located in plasma membrane; 0.2000 probability located in analysis: lysosome (membrane); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 20 and 21 analysis: A search of the NOVl 3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 13D.

In a BLAST search of public sequence databases, the NOVl 3a protein was found to have homology to the proteins shown in the BLASTP data in Table 13E.

PFam analysis predicts that the NOVl 3a protein contains the domains shown in the Table 13F.

Example 14.

The NOVl 4 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 14A.

Table 14A. NOV14 Sequence Analysis

SEQ ID NO: 35 1638 bp

NOVl 4a, TTATCTAATATGTTTGTTTTAGCTACATCTTTATCAAGCCAAGTGAATCCTGACTGGC CGI 02646-01 GAACATATATCATGCTTGCAGTATATTTTCTAATTTTACTTGTTATTGGATATTATGG TTATAAGCAAGCAACCGGAGATTTAAGTGAATATATGCTTGGCGAAAGAAATATTGGT DNA Sequence CCATATGTCACTGCCTTATCTGCCGGAGCTTCAGATATGAGCGGTTGGATGATTATGG GATTACCTGGAGAAGTTTATACTACAGGTTTATCAGCAGCATGGTTAGCTATTGGGTT AACTATCGGAGCTTATGTTAACTACATACTTGTAGCACCAAGACTTCGTGTGTACACT GAAAAAGCCAATGACTCAATTACATTGCCTAATTACTTTACACATCGTCTTAATGATA ATTCCAATATTATTAAAATTATCTCTGGTGGTATCATTGTTGTATTTTTTACACTCTA TACTCATTCAGGTATGGTATCAGGTGGTAAATTATTTGATAGTGCTTTTGGTTTAGAC TATCATATTGGACTTATTTTAATCTCTGTCATTGTAATTTTATATACTTTTTTTGGTG GCTATTTAGCAGTGTCGTTAACTGACTTTTTCCAAGGGGTTGTCATGTTAATTGCGAT GGTTATGGTACCTATTGTAGCCATGATGCAGCTCGGAGGTATGGATGCTTTTTCACAA GCAGCAACATTAAAACCTACTAATTTAGATTTATTTAAAGGAACAACTATTATAGGCA TCATTTCATTCTTTGCTTGGGGATTAGGCTATTTTGGCCAGCCTCATATCATTGTACG ATTTATGTCTATCAAATCCGTACGACAATTAAAAACGTCTAGAAGATTTGGTATTAGT TGGATGGCTATTAGTTTAATCGGTGCAGTATGTGTTGGATTAATTGGCATTTCGTTTG TACAAGATAAAGGTGTTGAATTAAAAGATCCAGAAACACTATTTATTTTAATGGGACA AATTTTATTCCATCCTCTTGTAGGTGGGTTCCTACTTGCAGCCATTTTGGCAGCAATT ATGAGTACGATTTCTTCCCAATTACTTGTGACTTCAAGTTCACTTACAGAAGATTTTT ACAAGTTAATTCGTGGTGAAGAAGCAGCAAAGCAACATAAGAAAGAATTTTTATTAGT GGGTCGATTATCTGTTGTAGTCGTTGCGATTATCTCCATCCTCATTGCATGGACGCCA AATGACACTATCTTAAATCTTGTTGGTAACGCTTGGGCTGGATTCGGTGCAGCATTTG GTCCACTGGTATTATTATCTCTCTATTCGAAAGGTTTAAGTCGTACTGGAGCTATTTC TGGAATGTTATCAGGAGCAATTGTCGTCATTCTTTGGATTGTGTTTGTTAAACCATTA GGAGCATATAATGATTTCTTTAATTTATATGAAATTATTCCTGGTTTCTTAACAAGTC_: TTATTGTGACATATGTAGTGAGTCTTGTAACTAAAAAGCCAGATCTCAATGTTCAAAAi AGATTTAGAAGACGTCAAACGTATTGTAAAAGGACAATAAATTAATAATATTCAACGA^

TGCTTAATGTCAATATTATTTCAATTAGTGCATTACTCTTATAATATGAAACACAAAT

AAATTTTTATACAT

ORF Start: ATG at 10 ORF Stop: TAA at 1546

SEQ ID NO: 36 512 aa MW at 55813.4kD

NOV14a, MFVLATS SSQVNPDWRTYIM AVYFLI VIGYYGY QATGD SEYMLGER IGPYV CGI 02646-01 TALSAGASD SG MI G PGEVYTTG SAAWLAIGLTIGAYVNYI VAPRLRVYTEKA NDSITLPNYFTHR NDNSNIIKIISGGIIVVFFTLYTHSGMVSGG LFDSAFGLDYHI Protein Sequence GLI ISVIVILYTFFGGY AVSLTDFFQGWM IAMVMVPIVAMMQLGGMDAFSQAAT LKPTNLD FKGTTIIGIISFFA G GYFGQPHIIVRF SIKSVRQ KTSRRFGIS MA ISLIGAVCVGLIGISFVQDKGVELKDPETLFILMGQI FHPLVGGF IJAAI AAIMST ISSQ LVTSSSLTEDFYKLIRGEEAAKQHK EFLLVGRLSWλ/VAIISILIA TPNDT IL VGNA AGFGAAFGPLVLLS YSKG SRTGAISG SGAIWIL IVFVKPLGAY NDFFNLYEIIPGFLTS IVTYWS VTKKPDLlsTVQKDLEDVKRIVKGQ

Further analysis of the NOVl 4a protein yielded the following properties shown in Table 14B.

Table 14B. Protein Sequence Properties NOV14a

PSort 0.8200 probability located in plasma membrane; 0.4600 probability located in analysis: Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 37 and 38 analysis:

A search of the NOVl 4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 14C.

In a BLAST search of public sequence databases, the NOVl 4a protein was found to have homology to the proteins shown in the BLASTP data in Table 14D.

PFam analysis predicts that the NOVl 4a protein contains the domains shown in the Table 14E.

Table 14E. Domain Analysis of NOV14a

Identities/

Pfam Domain NOV14a Match Region J Similarities Expect Value for the Matched Region

SSF 47..447 134/449 (30%) 5.7e-121 318/449 (71%)

Example 15.

The NOVl 5 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 15 A.

CRARFC LDVCTVR

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 15B.

Table 15B. Comparison of NOV15a against NOV15b.

NOV15a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOVl 5b 1..362 361/362 (99%) 1..362 361/362 (99%)

Further analysis of the NOVl 5a protein yielded the following properties shown in Table 15C.

Table 15C. Protein Sequence Properties NOVl 5a

PSort 0.6760 probability located in plasma membrane; 0.1000 probability located in analysis: endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP Cleavage site between residues 29 and 30 analysis:

A search of the NOVl 5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 15D.

In a BLAST search of public sequence databases, the NOVl 5a protein was found to have homology to the proteins shown in the BLASTP data in Table 15E.

Example 16.

The NOVl 6 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 16A.

GAAGAGGATCGCCGTGGGCATGTTCTTTGTCATGTGCTCAGCCTTTGCTGCAGGAATT TTGGAGAGTAAAAGGCTGAACCTTGTTAAAGAGAAAACCATTAATCAGACCATCGGCA ACGTCGTCTACCATGCTGCCGATCTGTCGCTGTGGTGGCAGGTGCCGCAGTACTTGCT GATTGGGATCAGCGAGATCTTTGCAAGTATCGCAGGCCTGGAATTTGCATACTCAGCT GCCCCCAAGTCCATGCAGAGTGCCATAATGGGCTTGTTCTTTTTCTTCTCTGGCGTCG GGTCGTTCGTGGGTTCTGGACTGCTGGCACTGGTGTCTATCAAAGCCATCGGATGGAT GAGCAGTCACACAGACTTTGGTAATATTAACGGCTGCTATTTGAACTATTACTTTTTT CTTCTGGCTGCTATTCAAGGAGCTACCCTCCTGCTTTTCCTCATTATTTCTGTGAAAT ATGACCATCATCGAGACCATCAGCGATCAAGAGCCAATGGCGTGCCCACCAGCAGGAG GGCCTGACCTTCCTGAGGCCATGTGCGGTTTCTGAGGCTGACATGTCAGTAACTGACT

GGGGTGCACTGAGAACAGGCAAGACTTTAAATTCCCATAAAATGTCTGACTTCACTGA

AACTTGCATGTTGCCTGGATTGATTTCTTCTTTCCCTCTATCCAAAGGAGCTTGGTAA

GTGCCTTACTGCAGCGTGTCTCCTGGCACGCTGGGCCCTCCGGGAGGAGAGCTGCAGA

TTTCGAGTATGTCGCTTGTCATTCAAGGTCTCTGTGAATCCTCTAGCTGGGTTCCCTT

TTTTACAGAAACTCACAAATGGAGATTGCAAAGTCTTGGGGAACTCCACGTGTTAGTT

GGCATCCCAGTTTCTTAAACAAATAGTATCACCTGCTTCCCATAGCCATATCTCACTG

TAAAAAAAAAAATTAATAAACTGTTACTTATATTTAAGAAAGTGAGGATTTTTTTTTT

TTAAAGATAAAAGCATGGTCAGATGCTGCAAGGATTTTACATAAATGCCATATTTATG

GTTTCCTTCCTGAGAACAATCTTGCTCTTGCCATGTTCTTTGATTTAGGCTGGTAGTA

AACACATTTCATCTGCTGCTTCAAAAAGTACTTACTTTTTAAACCATCAACATTACTT

TTCTTTCTTAAGGCAAGGCATGCATAAGAGTCATTTGAGACCATGTGTCCCATCTCAA

GCCACAGAGCAACTCACGGGGTACTTCACACCTTACCTAGTCAGAGTGCTTATATATA

GCTTTATTTTGGTACGATTGAGACTAAAGACTGATCATGGTTGTATGTAAGGAAAACA

TTCTTTTGAACAGAAATAGTGTAATTAAAAATAATTGAAAGTGTTAAATGTGAACTTG

AGCTGTTTGACCAGTCACATTTTTGTATTGTTACTGTACGTGTATCTGGGGCTTCTCC

GTTTGTTAATACTTTTTCTGTATTTGTTGCTGTATTTTTGGCATAACTTTATTATAAA

AAGCATCTCAAATGCGAAAAAAAAAAAAAAAAAAAAAAA

ORF Start: ATG at 14 ORF Stop: TGA at 1745

SEQ ID NO: 42 577 aa MW at 62004.6kD

NOVl 6a, MEGSGGGAGERAPL GARRAAAAAAAAGAFAGRRAACGAVL TELLERAAFYGITSN CGI 03459-01 V FLNGAPFC EGAQASEALLLFMG TY GSPFGG LADARLGRARAIL SLALYL G l-AFP LAAPATRAALCGSAR LNCTAPGPDAAARCCSPATFAGLV VGLGVATVKAN Protein Sequence ITPFGADQVKDRGPEATRRFFN FYWSINLGAILSLGGIAYIQQNVSFVTGYAIPTVC VGLAFVAF CGQSVFITKPPDGSAFTDMFKILTYSCCSQKRSGERQSNGΞGIGVFQQS SKQSLFDSCKMSHGGPFTEEKVEDVKA VKIVPVFLALIPY TVYFQMQTTYVLQS H RIPEISNITTTPHT PAA LTMFDAVLILLLIP KDKLVDPILRRHG LPSS KRIA VGMFFVMCSAFAAGILES R N VKEKTINQTIGrrvΛnfHAAD S QVPQYL IGIS ElFASIAGLEFAYSAAPKSMQSAIMGLFFFFSGVGSFVGSG ALVSIKAIGWMSSHT DFGNINGCYLNYYFFL AAIQGAT LF IISVKYDHHRDHQRSRANGVPTSRRA

Further analysis of the NOVl 6a protein yielded the following properties shown in Table 16B.

Table 16B. Protein Sequence Properties NOVlόa

PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOVl 6a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 16C.

In a BLAST search of public sequence databases, the NOVl 6a protein was found to have homology to the proteins shown in the BLASTP data in Table 16D.

PFam analysis predicts that the NOVl 6a protein contains the domains shown in the Table 16E.

Table 16E. Domain Analysis of NOVlβa

Identities/

Pfam Domain NOV16a Match Region Similarities Expect Value for the Matched Region I

PTR2 103-496 109/448 (24%) 6.7e-103 310/448 (69%)

Example 17.

The NOVl 7 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 17A.

GGGAGCAGTGCCGGCCAGAGGAGCCAGGTCACTGTGTGGCCCAATCTGAGGTGGTCAA GGAAGGTTGCTCCATCTACAACCGCTCAGAGGCATGTCCAGCTGCTCACCACCACCCC ACCTATGAACCGAAGACAGTCACAACAGGTAGCCCCCCAGTCCCTGAGGCCCACAGCC CTGGATTTGACGGGGCCAGCTTTATCGGAGGTGTCGTGCTGGTGTTGAGCCTACAGGC GGTGGCTTTCTTTGTGCTGCACTTCCTCAAGGCCAAGGACAGCACCTACCAGACGCTG TGAGTACCTGGCCAGCAGCAAGTACCTGAGTCCCAGCTCACCTCCTGGTTCCTGCCCC

ACCGTTCCCCTTCAGTACCCAGGGTGCTGTCTTCTCCACTGGCAAGCCCTCAGGACGG

TGACAGCGTGCTCCATGTGAGCCACACCCCTTTTGTCTCCTCCAGTTGGGGTGTTTCC

TTTGTCAGATGTTGGCTGGGACCAGGACTCAGCCTGGGCCAGTCTAGGAGCCCAGCTG

AGCCCTCCTGTGTCTTTTCCCTTCATGCTGCCAGCAGGGAAGAGAACCAGTAGGTGCC

AGCCCAGCAACCTGTGGCCCGCGTTTCTGTGGCTGTGGGCAGGAGCTGGGCCTTGTGT

CTAGTTGGGTTTTGCTCTGAGAAGGGGAGCTGTGCTGAGGCCCTCTGTGTGCCGTGTG

TGCTGTGGGGCGGGTCGCCACAGCCTGTGTTAAAGTGTTTGCTCTTCCTCTGCTGCCT

CCTCTCGAGGCAGGGGGTCCTTGGCTGGCTGAGGCAGTGTCACCTTCCTGAGTGTCCT

CTTTGGCCTCTGCAGAATCTGACCCCTTTGGGCCTGGACTCCATCCTGAGGGGAAAGG

AGGATGCAGAGGGTGGCCTCTGGGCACCCTTGTGGGTAAGCGGGGGGCGGGGGCGGGA

AAAACTCTGGCCGCCAGTTTTTGGCTCCTGCGGGCACCAAGCAGGCTCAGTGTCTGAT

GCTTGACATCTCCTCCTGTCCTGGGCCTGGAACCTGCAGCTGAGAAAATCCCTCAACC

ACCTCGTCTCCTCCATCGCCCCTGCTGGGCCCCCCAGCCTGACAGTGGGTTGTATGCC

TGCCTCTTTCCACCAACTGGCCTGGGCACTGCCCCCAAATAAAGGAACTCTGCACTGC

ORF Start: ATG at 4 ORF Stop: TGA at 523

SEQ ID NO: 44 173 aa MW at l8421.0kD

NOV17a, MEAPGPRALRTALCGGCCC CAQ AVAG GARGFGRGALIRLNI PAVQGACKQLE CGI 04210-01 VCEHCVEGDRARNLSSCM ΞQCRPEEPGHCVAQSEWKEGCSIYNRSEACPAAHHHPT YEPKTVTTGSPPVPEAHSPGFDGASFIGGWLVLS QAVAFFVLHFLKAKDSTYQTL Protein Sequence

SEQ ID NO: 45 561 bp

NOV17b, CCCATGGAGGCTCCGGGACCCCGCGCCTTGCGGACTGCGCTCTGTGGCGGCTGTTGCT CGI 04210-02 GCCTCCTCCTATGTGCCCAGCTGGCTGTGGCTGGTAAAGGAGCTCGAGGCTTTGGGAG GGGAGCCCTGATCCGCCTGAATATCTGGCCGGCGGTCCAAGGGGCCTGCAAACAGCTG DNA Sequence GAGGTCTGTGAGCACTGCGTGGAGGGAGACAGAGCGCGCAATCTCTCCAGCTGCGTGT GGGAGCAGTGCCGGCCAGAGGAGCCAGGACACTGTGTGGCCCAATCTGAGGTGGTCAA GGAAGGTTGCTCCATCTACAACCGCTCAGAGGCATGTCCAGCTGCTCACCACCACCCC ACCTATGAACCGAAGACAGTCACAACAGGGAGCCCCCCAGTCCCTGAGGCCCACAGCC CTGGATTTGACGGGGCCAGCTTTATCGGAGGTGTCGTGCTGGTGTTGAGCCTACAGGC GGTGGCTTTCTTTGTGCTGCACTTCCTCAAGGCCAAGGACAGCACCTACCAGACGCTG TGAGTACCTGGCCAGCAGCAAGTACCTGAGTCCCAGCTC

ORF Start: ATG at 4 ORF Stop: TGA at 523

SEQ ID NO: 46 173 aa MW at l8389.0kD

NOVl 7b, MEAPGPRALRTALCGGCCCLLLCAQ AVAGKGARGFGRGALIRLNI PAVQGACKQLE CG104210-02 VCEHCVEGDRARN SSCV EQCRPEEPGHCVAQSEWKEGCSIYNRSEACPAAHHHPT YEPKTVTTGSPPVPEAHSPGFDGASFIGGW VIJSLQAVAFFV HFLKAKDSTYQTL Protein Sequence

SEQ ID NO: 47 1349 bp

NOV17c, CACCGGATCCGGTAAAGGAGCTCGAGGCTTTGGGAGGGGAGCCCTGATCCGCCTGAAT 272249075 DNA ATCTGGCCGGCGGTCCAAGGGGCCTGCAAACAGCTGGAGGTCTGTGAGCACTGCGTGG AGGGAGACAGAGCGCGCAATCTCTCCAGCTGCATGTGGGAGCAGTGCCGGCCAGAGGA Sequence GCCAGGACACTGTGTGGCCCAATCTGAGGTGGTCAAGGAAGGTTGCTCCATCTACAAC CGCTCAGAGGCATGTCCAGCTGCTCACCACCACCCCACCTATGAACCGAAGACAGTCA CAACAGGGAGCCCCCCAGTCCCTGAGGCCCACAGCCCTGGATTTGACGGGGTCGACGG C

ORF Start: at 2 ORF Stop: end of sequence

SEQ ID NO: 48 116 aa |MW at l2383.7kD

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 17B.

Further analysis of the NOVl 7a protein yielded the following properties shown in Table 17C.

Table 17C Protein Sequence Properties NOVl 7a

PSort 0.6850 probability located in endoplasmic reticulum (membrane); 0.6400 analysis: probability located in plasma membrane; 0.4600 probability located in Golgi body; 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 30 and 31 analysis:

A search of the NOVl 7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 17D.

In a BLAST search of public sequence databases, the NOVl 7a protein was found to have homology to the proteins shown in the BLASTP data in Table 17E.

Example 18.

The NOVl 8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 18A.

Table 18A. NOV18 Sequence Analysis

SEQ ID NO: 49 788 bp

NOVl 8a, CTTTTGCCTTTATGCAACCAACATGGAGATTTTGTACCATGTCCTGTTCTTAGTGCTT CG104251-01 GAATGTCCTAACCTGAAGCTGAAGAAGCCGCCCTGGCTGCACATGCTGTCGGCCATGA CTGTATGCTCTGGTGGTGGTGTCTTCCTCATTACCGGAGGAATCATTTATGATGTTAT DNA Sequence TGTTGAACCTCCAAGTGTTGGCTCTATGACTGATGAACATGGGCATCAGAGGCCAGTA GCTTTCTTTGCCTATAGAGTAAATGGACAATATATTATGGAAGGACTTGCATCCAGCT TCCTGTTTACAATGGGAGGTTTAGGTTTCATAATCCTGGACCAATTGAATGCACCAAA TATCCCAAAACTCAATAGATTTCTTCTTCTATTCATTGGATTTGTCTGTGTTCTATTG AGTATTTTCATGGCTAGAGTATTCATGAGAATGAAACTGCCGAGCTATCTGATGGGTT AGAGTGCCTTTGAGAAGAAATCAGTGGATACTGGATTTTTTCTTGTCAATGAAGTTTT

AAAGGCTGTACCAATCCTCTAATATGAAATGTGGAAAAGAATGAAGAGCAGCAGTAAA

AGAAATATCTAGTGAAAAAACAGGAAGCGTATTGAAGCTTGGACTAGAATTTCTTCTT

GGTATTAAAGAGACAAGTTTATCACAGAATTTTTTTTCCTGCTGGCCTATTGCTATAC

CAATGATGTTGAGTGGCATTTTCTTTTTAGTTTTTCATTAAAATATATTCCATATCTA

CAΆCTATAATATCAAATAAΆGTGATTATTTTTTΆ

ORF Start: ATG at 23 ORF Stop: TAG at 464

SEQ ID NO: 50 147 aa MW at l6447.7kD

NOVl 8a, MEIL.YHVLFLVLECPN KKPP HMLSAMTVCSGGGVFLITGGIIYDVIVEPPSVG CG104251-01 SMTDEHGHQRPVAFFAYRV GQYIMEGLASSFLFT GG GFIILDQ NAPNIPKLNRF L FI GFVCVLi S I FMARVFMR KLPS YL.MG Protein Sequence Further analysis of the NOVl 8a protein yielded the following properties snown in Table 18B.

Table 18B. Protein Sequence Properties NOVl 8a

PSort 0.6400 probability located in plasma membrane; 0.4600 probability located in analysis: Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 42 and 43 analysis:

A search of the NOVl 8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 18C.

In a BLAST search of public sequence databases, the NOVl 8a protein was found to have homology to the proteins shown in the BLASTP data in Table 18D.

Example 19.

The NOVl 9 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 19A.

TATAATCAGAAAACGGAGTCGGAAAGGCAGAGGAATCTGTTCCTCAAGGCATTCACGG ACTTCCTGGCCTTCATGGTCCTCTTTAACTACATCATCCCTGTGTCCATGTACGTCAC GGTCGAGATGCAGAAGTTCCTCGGCTCTTACTTCATCACCTGGGACGAAGACATGTTT GACGAGGAGACTGGCGAGGGGCCTCTGGTGAACACGTCGGACCTCAATGAAGAGCTGG GACAGGTGGAGTACATCTTCACAGACAAGACCGGCACCCTCACGGAAAACAACATGGA GTTCAAGGAGTGCTGCATCGAAGGCCATGTCTACGTGCCCCACGTCATCTGCAACGGG CAGGTCCTCCCAGAGTCGTCAGGAATCGACATGATTGACTCGTCCCCCAGCGTCAACG GGAGGGAGCGCGAGGAGCTGTTTTTCCGGGCCCTCTGTCTCTGCCACACCGTCCAGGT GAAAGACGATGACAGCGTAGACGGCCCCAGGAAATCGCCGGACGGGGGGAAATCCTGT GTGTACATCTCATCCTCGCCCGACGAGGTGGCGCTGGTCGAAGGTGTCCAGAGACTTG GCTTTACCTACCTAAGGCTGAAGGACAATTACATGGAGATATTAAACAGGGAGAACCA CATCGAAAGGTTTGAATTGCTGGAAATTTTGAGTTTTGACTCAGTCAGAAGGAGAATG AGTGTAATTGTAAAATCTGCTACAGGAGAAATTTATCTGTTTTGCAAAGGAGCAGATT CTTCGATATTCCCCCGAGTGATAGAAGGCAAAGTTGACCAGATCCGAGCCAGAGTGGA GCGTAACGCAGTGGAGGGGCTCCGAACTTTGTGTGTTGCTTATAAAAGGCTGATCCAA GAAGAATATGAAGGCATTTGTAAGCTGCTGCAGGCTGCCAAAGTGGCCCTTCAAGATC GAGAGAAAAAGTTAGCAGAAGCCTATGAGCAAATAGAGAAAGATCTTACTCTGCTTGG TGCTACAGCTGTTGAGGACCGGCTGCAGGAGAAAGCTGCAGACACCATCGAGGCCCTG CAGAAGGCCGGGATCAAAGTCTGGGTTCTCACGGGAGACAAGATGGAGACGGCCGCGG CCACGTGCTACGCCTGCAAGCTCTTCCGCAGGAACACGCAGCTGCTGGAGCTGACCAC CAAGAGGATCGAGGAGCAGAGCCTGCACGACGTCCTGTTCGAGCTGAGCAAGACGGTC CTGCGCCACAGCGGGAGCCTGACCAGAGACAACCTGTCCGGACTTTCAGCAGATATGC AGGACTACGGTTTAATTATCGACGGAGCTGCACTGTCTCTGATAATGAAGCCTCGAGA AGACGGGAGTTCCGGCAACTACAGGGAGCTCTTCCTGGAAATCTGCCGGAGCTGCAGC GCGGTGCTCTGCTGCCGCATGGCGCCCTTGCAGAAGGCTCAGATTGTTAAATTAATCA AATTTTCAAAAGAGCACCCAATCACGTTAGCAATTGGCGATGGTGCAAATGATGTCAG CATGATTCTGGAAGCGCACGTGGGCATAGGTGTCATCGGCAAGGAAGGCCGCCAGGCT GCCAGGAACAGCGACTATGCAATCCCAAAGTTTAAGCATTTGAAGAAGATGCTGCTTG TTCACGGGCATTTTTATTACATTAGGATCTCTGAGCTCGTGCAGTACTTCTTCTATAA GAACGTCTGCTTCATCTTCCCTCAGTTTTTATACCAGTTCTTCTGTGGGTTTTCACAA CAGACTTTGTACGACACCGCGTATCTGACCCTCTACAACATCAGCTTCACCTCCCTCC CCATCCTCCTGTACAGCCTCATGGAGCAGCATGTTGGCATTGACGTGCTCAAGAGAGA CCCGACCCTGTACAGGGACGTCGCCAAGAATGCCCTGCTGCGCTGGCGCGTGTTCATC TACTGGACGCTCCTGGGACTGTTTGACGCACTGGTGTTCTTCTTTGGTGCTTATTTCG GTTTGAAAATACAACTGTGACAAGCAACGGGCAGATATTTGGAAACTGGACGTTTGG AACGCTGGTATTCACCGTGATGGTGTTCACAGTTACACTAAAGCTTGCATTGGACACA CACTACTGGACTTGGATCAACCATTTTGTCATCTGGGGGTCGCTGCTGTTCTACGTTG TCTTTTCGCTTCTCTGGGGAGGAGTGATCTGGCCGTTCCTCAACTACCAGAGGATGTA CTACGTGTTCATCCAGATGCTGTCCAGCGGGCCCGCCTGGCTGGCCATCGTGCTGCTG GTGACCATCAGCCTCCTTCCCGACGTCCTCAAGAAAGTCCTGTGCCGGCAGCTGTGGC CAACAGCAACAGAGAGAGTCCAGAATGGGTGCGCACAGCCTCGGGACCGCGACTCAGA ATTCACCCCTCTTGCCTCTCTGCAGAGCCCAGGCTACCAGAGCACCTGTCCCTCGGCC GCCTGGTACAGCTCCCACTCTCAGCAGGTGACACTCGCGGCCTGGAAGGAGAAGGTGT CCACGGAGCCCCCACCCATCCTCGGCGGTTCCCATCACCACTGCAGTTCCATCCCAAG TCACAGCTGCCCTAGGTCCCGTGTGGGAATGCTCGTGTGATGGATGGTCCTAAGCCTG

TGGAGACTGTGCACGTGCCTCTTCCTGGCCCCCAGCAGGCAAGGAGGGGGGTCACAGG

CCTTGCCCTCGAGCATGGCACCCTGGCCGCCTGGACCCAGCACTGTGGT

ORF Start: ATG at 61 ORF Stop: TGA at 3634

SEQ ID NO: 52 1191 aa MW at l35846.0kD

NOVl 9a, MDCS λTRTLVHRYCAGEΞN VDSRTIYVGHREPPPGAEAYIPQRYPDNRIVSSKYTF CGI 04934-01 NFIPKNLFEQFRRVANFYFLIIF VQLIIDTPTSPVTSGLPLFFVITVTAIKQGYED RHKADNAMNQCPVHFIQHGK VRKQSRKLRVGDIVMVKEDETFPCDLIFLSSNRGDG Protein Sequence TCHVTTASLDGESSHKTHYAVQDTKGFHTEEDIGGLHATIECEQPQPDLYKFVGRINV YSD ND WRPLGS ENLLLRGAT KNTEKI FGVAI TGMETKMALNYQS KSQKRS AVE KS^^TAFLIVYLCI ISK INT KYlWQSE FRDE ^^TQKTESERQRN FLKAFTD F AFMVLFNYIIPVSMYVTVEMQKFLGSYFIT DEDMFDEETGEGPLVNTSD NEE G QVEYI FTDKTGTLTENNMEFKECCIEGHVYVPHVI CNGQVLPES SGIDMIDS S PSV G REREE FFRALCLCHTVQVKDDDSVDGPRKSPDGGKSCVYISSSPDEVALVEGVQR G FTYLR ϊT)3SrYMEI NRENHIERFEL EILSFDSVRRRMSVIVKSATGEIYLFCKGADS SIFPRVIEGKVDQIRARVERNAVEGLRTLCVAYKRLIQEEYEGICK LQAAKVALQDR EKJ AEAYEQIEKDLTLLGATAVEDRLQEKAADTIEALQKAGI V VLTGDKMETAAA TCYACKLFRRNTQL ELTTKRIEEQS HDVLFELSKTVLRHSGSLTRDNLSGLSADMQ DYGLIIDGAALS IMKPREDGSSGNYRELF EICRSCSAV CCR AP Q AQIVKLI FSKEHPITtAIGDGANDVSMILEAHVG GVIGKEGRQAAR SDYAIPKF HLKK LV HGHFYYIRISELVQYFFYKNVCFIFPQF YQFFCGFSQQTLYDTAY TLYNISFTS P I YSL EQHVGIDV KRDPTLYRDVA NAL R RVFIYWT LGLFDALVFFFGAYFV FENTTVTSNGQIFGNWTFGTLVFTVIWFTVTLKLA DTHYJT INHFVI GS LFYVV FSLL GG I PF NYQRMYYVFIQMLSSGPA AI V ISLLPDV KKVLCRQLWP TATERVQNGCAQPRDRDSEFTPLASLQSPGYQSTCPSAAWYSSHSQQVTLAAWKEKVS TEPPPILGGSHHHCSSIPSHSCPRSRVGM V

Further analysis of the NOVl 9a protein yielded the following properties shown in Table 19B.

Table 19B. Protein Sequence Properties NOV19a

PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.0300 probability located in mitochondrial inner membrane

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOVl 9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 19C.

In a BLAST search of public sequence databases, the NOVl 9a protein was found to have homology to the proteins shown in the BLASTP data in Table 19D.

PFam analysis predicts that the NOVl 9a protein contains the domains shown in the Table 19E.

Example 20.

The NOV20 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 20A. Table 20A. NO 20 Sequence Analysis

SEQ ID NO: 53 2588 bp

NOV20a, AGTTCCGAACAGAAGGCTGTGTATTCTCTGCCGCTTATTGTGGCCTCGACAGGCCATG CG105463-01 GTTACTTTGGCCACTGCCAGAGCAGCCTTGGCACTATGGAGGAGCCTAGGGCTACCCC

TCAGCTGTACTTGGGGCTGGTCCTGCAGTTGCTACCCAGGGTTATGGCAGCACTGCCT DNA Sequence GAAGGTGTGAGACCAAATTCGAATCCTTATGGTTTTCCATGGGAATTGGTGATATGTG CAGCTGTCCTTGGATTTGTTGCTGTTCCCTTTTTTTTGTGGAGAAGTTTTAGATCGGT TAGGAGTCGGCTTTATGTGGGAAGAGAGAAAGAGCTTGCTATAGCGCTTTCTGGACTA ATTGAAGAAAAATGTAGACTACTTGAAAAATTTAGCCTTGTTCAAAAAGAGTATGAAG GCTATGAAGTAGAGTCATCTTTAGAGGATGCCAGCTTTGAGΆAGGAGGCAACAGAΆGC ACAAAGTCTGGAGGCAAACTGTGAAAAGCTGAACAGGTCCAATTCTGAACTGGAGCAT GAAATACTCTGTCTAGAAAAGGGGATAAAAGAAGAGAAATCTAAACATTCTGAACAΆG ATGAGGTGATGGCAGATATTTCCAAAAAGATACAGTCTCTAGAAGATGAGTCAAAATC CCTCAAATCACTACTAACTGAAGCCAAAATGACCTTCAAGGGATTTCAAATGAATGAA GAAAAACTGGAGATAGGAATACAAGATGCTTCGAGTGAAAATTGTCAACTTCAGGAAA GCCAGAAACAGCTTTTGCAAGAAGCTGAAGTATGGAAAGAACAΆGTGAGTGAACTTAA TAAACAGAAAATAACATTTGAAGACTCCAAAGTACACGCAGAACAAGTTCTAAATGAT AAAGAAAATCACATCGAGACTCTGACTGAACGCTTGCTAAAGATCAAAGATCAGGCTG CTGTGCTGGAAGAAGACATAACGGATGATGGTAACTTGGAATTAGAAATGAACAGTGA ATTGAAAGATGGTGCTTACTTAGATAATCCTCCAAAAGGAGCTTTGAAGAAACTGATT CATGCTGCTAAGTTAAATGCTTCTTTAACAACCTTAGAAGGAGAAAGAAACCAATTTA TATTCAGTTATCTGAAGTTGATAAAACCAAGGAAGAGCTTAGAGAGCATATTAAAAAT CTTCAGACGGAACAAGCATCTTTGCAGTCGGAAAACACACATTTTGAAAGTGAGAATC AGAAACTTCAACAGAAAGTTAATGACTGAGTTATATCAAGAAAATGAAATGAAACTCT ACAGGAAATTAATAGTAGAGGAAAATAACCGGTTAGAGAAAGAGAAACTTTCTAAAGT AGACGAAATGATCAGCCATGCCACTGAAGAGCTGGAGACCTGCAGAAAGCGAGCCAAA GATCTTGAAGAA'GAACTTGAGAGAACTATTCTTTTTTATCAAGGGAAGATTATATACC ATGAGAAAAAAGCACATGATAATTGTTTGGCAGCATGGACTGCTGAAAGAAACCTCAA TGATTTAAGGAAAGAAAATGCTCACAAAAGACAAAAΆTTAGCTGAAACAGAGTTTAAA ATTAAACTTTTAGAAAAAGATCCTTATGCACTTGATGTTCCAAATACAGCATTTGGCA GAGAGCATTCCTCATATGGTCCCTCACCATTGGGTCGGCCTTCATCTGAAACGAGAGC TTTTCTCTATCTTCCGACTTTGTTGGAGGGTCCACTGAGACTCTCACCTTTGCTTCCA GGGGGAGGAGGAAGAGACCCAAGAGGCCCAGGGAATCCTCTGGACCACCAGATTACCA AGGAAAGAGGAGAATCAAGCTGTGATAGGTTTACTGATCCTCACAAGGCTCCTTCTGA CACTGGGCCCCTGTCACCTCCGTGGGAACAGGACCGTAGGATGATGTTTCCTCCACCA GGACAATCATATCCTGATTCAGCTCTTCCTCCACAAAGGCAAGACAGATTTTATTCTA ATTCTGCTAGACGCTCTGGACTAGCAGAACTCAGAAGTTTTAATATACCTTCTTTGGA TAAAATGGATGGGTCAATGCCTTCAGAAATGGAATCCAGTGGAAATGATACCAAAGAT AATCTTGGTAATTTAAATGTGGCTGATTCATCTCTCCCTGCTGGAAATGAAGTGAGTG GCCCTGGCTTTGTTCCTCCACCTCTTGCTTCAATCAGAGGTCCATTGTTTCCAGTGGA TACGAGGGGCCCGTTCATGAGAAGAGGACCTCCTTTCCCTCCACCTCCTCCAGGAACC ATGTTTGGAGCTTCTCCAGATTATTTTCCACCAAGGGATGTCCCAGGTCCACCACGTG CTCCATTTGCAATGAGAAATGTCTGTCCACCGAGGGGTTTTCCTCCTTACCTTCCCCC AAGACCTGGATTTTGCCCCCACCCCCACCCCCACAGTGAGTTCCCTTTAGGGTTGAGT CTGCCTTCAAATGAGCCTGCTGCTGAAGATCCAGAACCACGGCAAGAAACCTGATAAT

ATTTTTGCTGTCTTCAAAAGTCATTTTGACTATTCTCATTTTCAGTTGAAGTAACTGC

TGTTACTTCAGTGATTACACTTTTGCTCAAATTGAA

ORF Start: ATG at 94 ORF Stop: TGA at 2488

SEQ ID NO: 54 798 aa MW at 90383.6kD

NOV20a, MEEPRATPQ YLGLV Q LPRVMAALPEG PNSNPYGFPWELVICAAVLGFVAVPFF CG105463-01 LWRSFRSVRSRLYVGREKELAIALSGLIEEKCR LEKFSLVQKEYEGYEVΞSSLEDAS FEKEATEAQSLΞANCEKLlTOSNSE EHEI CLEKGIIsΕE SKHSEQDEV ADISKKIQ Protein Sequence S EDESKSLKS TEAKMTFKGFQMNEEK EIGIQDASSENCQLQESQKQL QEAEVW KEQVSELNKQKITFEDSKΛ AEQVLNDKENHIET TERLLKIKDQAAV EEDITDDGN LELEMNSE KDGAYLDNPPKGALKKLIHAAKLNAS TTLEGERNQFIFSYLKLI PRK SLESILKIFRRNKHLCSRKTHILKVRIRNFNRK MTE YQENE K YRK IVEENNRL EKEKLS VDEMISHATEELΞTCRKRAKD EEELERTI FYQGKIIYHEKKAHDNCLAA WTAERNLNDLRKENAHKRQK AETEFKIKIiLEKDPYALDVPNTAFGREHSSYGPSPLG RPSSETRAF YLPTL EGP R SP LPGGGGRDPRGPGNPLDHQITKERGΞSSCDRFT DPH APSDTGP SPP EQDRRM FPPPGQSYPDSALPPQRQDRFYSNSARRSG AELR SFNIPSLDKMDGSMPSE ΞSSGNϋTKDNLGNLNVADSSLPAGNEVSGPGFVPPPLASI RGP FPVDTRGPFMRRGPPFPPPPPGTMFGASPDYFPPRDVPGPPRAPFAMRNVCPPR GFPPYLPPRPGFCPHPHPHSEFPLG SLPSNΞPAAEDPEPRQET

SEQ ID NO: 55 2483 bp

NOV20b, AGCTGGAATTCGCCCTTCTCGACAGGCCATGGTTACTTTGGCCACTGCCAGAGCAGCC CG105463-02 TTGGCACTATGGAGGAGCCTAGGGCTACCCCTCAGCTGTACTTGGGGCTGGTCCTGCA

GTTGCTACCCAGGGTTATGGCAGCACTGCCTGAAGGTGTGAGACCAAATTCGAATCCT DNA Sequence TATGGTTTTCCATGGGAATTGGTGATATGTGCAGCTGTCCTTGGATTTGTTGCTGTTC CCTTTTTTTTGTGGAGAAGTTTTAGATCGGTTAGGAGTCGGCTTTATGTGGGAAGAGA GAAAGAGCTTGCTATAGCGCTTTCTGGACTAATTGAAGAAAAATGTAGACTACTTGAA AAATTTAGCCTTGTTCAAAAAGAGTATGAAGGCTATGAAGTAGAGTCATCTTTAGAGG ATGCCAGCTTTGAGAAGGAGGCAACAGAAGCACAAAGTCTGGAGGCAAACTGTGAAAA GCTGAACAGGTCCAATTCTGAACTGGAGCATGAAATACTCTGTCTAGAAAAGGGGATA AAAGAAGAGAAATCTAAACATTCTGAACAAGATGAGGTGATGGCAGATATTTCCAAAA AGATACAGTCTCTAGAAGATGAGTCAAAATCCCTCAAATCACTACTAACTGAAGCTAA AATGACCTTCAAGGGATTTCAAATGAATGAAGAAAAACTGGAGATAGGAATACAAGAT GCTTCGAGTGAAAATTGTCAACTTCAGGAAAGCCAGAAACAGCTTTTGCAAGAAGCTG AAGTATGGAAAGAACAAGTGAGTGAΆCTTAATAAACAGAAAATAACATTTGAΆGACTC CAAAGTACACGCAGAACAAGTTCTAAATGATAAAGAAAΆTCACATCGAGACTCTGACT GAACGCTTGCTAAAGATCAAAGATCAGGCTGCTGTGCTGGAAGAAGACATAACGGATG ATGGTAACTTGGAATTAGAAATGAACAGTGAATTGAAAGATGGTGCTTACTTAGATAA TCCTCCAAΆAGGAGCTTTGAAGAAACTGATTCATGCTGCTAAGTTAAATGCTTCTTTA ACAACCTTAGAAGGAGAAAGAAACCAATTTATATTCAGTTATCTGAAGTTGATAAAAC CAAGGAAGAGCTTAGAGAGCATATTAAAAATCTTCAGACGGAACAAGCATCTTTGCAG TCGGAAAΆCACACATTTTGAΆAGTGAGAATCAGAAACTTCAACAGAAAGTTAΆTGACT GAGTTATATCAAGAAAATGAAATGAAACTCTACAGGAAATTAATAGTAGAGGAAAATA ACCGGTTAGAGAAAGAGAAACTTTCTAAAGTAGACGAAATGATCAGCCATGCCACTGA AGAGCTGGAGACCTGCAGAAAGCGAGCCAAAGATCTTGAΆGAAGAACTTGAGAGAACT ATTCTTTTTTATCAAGGGAAGATTATATACCATGAGAAAAAAGCACATGATAATTGTT TGGCAGCATGGACTGCTGAAAGAAACCTCAATGATTTAAGGAAAGAAAATGCTCACAA AAGACAAAAATTAGCTGAAACAGAGTTTAAAATTAAACTTTTAGAAAAAGATCCTTAT GCACTTGATGTTCCAAATACAGCATTTGGCAGAGAGCATTCCTCATATGGTCCCTCAC CATTGGGTCGGCCTTCATCTGAAACGAGAGCTTTTCTCTATCTTCCGACTTTGTTGGA GGGTCCACTGAGACTCTCACCTTTGCTTCCAGGGGGAGGAGGAAGAGGCCCAAGAGGC CCAGGGAATCCTCTGGACCACCAGATTACCAAGGAAAGAGGAGAATCAAGCTGTGATA GGTTTACTGATCCTCACAAGGCTCCTTCTGACACTGGGCCCCTGTCACCTCCGTGGGA ACAGGACCGTAGGATGATGTTTCCTCCACCAGGACAATCATATCCTGATTCAGCTCTT CCTCCACAAAGGCAAGACAGATTTTATTCTAATTCTGCTAGACGCTCTGGACTAGCAG AACTCAGAAGTTTTAATATACCTTCTTTGGATAAAATGGATGGGTCAATGCCTTCAGA AATGGAATCCAGTGGAAATGATACCAAAGATAATCTTGGTAATTTAAATGTGGCTGAT TCATCTCTCCCTGCTGGAAATGAAGTGAGTGGCCCTGGCTTTGTTCCTCCACCTCTTG CTCCAATCAGAGGTCCGTTGTTTCCAGTGGATACGAGGGGCCCGTTCATGAGAAGAGG ACCTCCTTTCCCTCCACCTCCTCCAGGAACCATGTTTGGAGCTTCTCCAGATTATTTT CCACCAAGGGATGTCCCAGGTCTACCACGTGCTCCATTTGCAATGAGAAATGTCTGTC CACCGAGGGGTTTTCCTCCTTACCTTCCCCCAAGACCTGGATTTTGCCCCCACCCCCA CCCCCACATTCTGAAGATAGAGTGAGTTCCCTTTAGGGTTGAGTGCCTTCAAATGAGC

CTGCTGCTGAAGATCCAGAACCACGGCAAGAAACCTGATAATATTTT

ORF Start: ATG at 67 ORF Stop: TGA at 2401

SEQ ID NO: 56 778 aa MW at 88255.5kD

NOV20b, MEEPRATPQ YLG V Q PRVMAA PEGVRPNSNPYGFP E VICAAV GFVAVPFF CGI 05463-02 L RSFRSVRSRLYVGRE ELAIA SGLIEEKCR LEKFSLVQKEYEGYEVESS EDAS FEKEATEAQSLEANCE NRSNSE EHEILC EKGIKEEKSKHSEQDEVMADISKKIQ Protein Sequence S EDESKSLKSLLTEAKMTFKGFQM EEK EIGIQDASSENCQLQESQKQL QEAEV KEQVSELNKQ ITFEDSKλ AEQVL DKΞNHIETLTER LKIKDQAAVLEEDITDDGN LE EMNSELKDGAY DNPPKGALKKLIHAAKLNASLTTLEGER QFIFSYLKLIKPRK S ESILKIFRRNKHLCSRKTHILKVRIRNFNRKLMTE YQENEMKLYRK IVEENNRL EKEKLSKVDEMISHATEE ETCRKRAKDLEEΞLERTI FYQGKIIYHE KAHDNCLAA TAERlsTLNDLRKENAH RQKLAETEFKI LLEKDPYALDVPNTAFGREHSSYGPSP G RPSSETRAFLYLPTLLEGPLRLSPLLPGGGGRGPRGPGNP DHQ TKERGESSCDRFT DPHKAPSDTGPLSPPWEQDRRMMFPPPGQSYPDSA PPQRQDRFYSNSARRSG AE R SFNIPSLDKMDGSMPSEMESSGNDTKDNLGN NVADSS PAGNEVSGPGFVPPP API RGPLFPVDTRGPFMRRGPPFPPPPPGT FGASPDYFPPRDVPGLPRAPFAMRNVCPPR GFPPY PPRPGFCPHPHPHI KIE

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 20B.

Further analysis of the NOV20a protein yielded the following properties shown in Table 20C.

Table 20C. Protein Sequence Properties NOV20a

PSort 0.4600 probability located in plasma membrane; 0.1000 probability located in analysis: endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP Cleavage site between residues 25 and 26 analysis:

A search of the NOV20a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 20D.

In a BLAST search of public sequence databases, the NOV20a protein was found to have homology to the proteins shown in the BLASTP data in Table 20E.

PFam analysis predicts that the NOV20a protein contains the domains shown in the Table 20F.

Table 20F. Domain Analysis of NOV20a

Identities/

Pfam Domain NOV20a Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 21.

The NOV21 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 21 A.

Further analysis of the NOV2 la protein yielded the following properties shown in Table 21B.

Table 21B. Protein Sequence Properties NOV21a

PSort 0.7900 probability located in plasma membrane; 0.3000 probability located in analysis: Golgi body; 0.2000 probability located in endoplasmic reticulum (membrane); 0.1007 probability located in microbody (peroxisome)

SignalP Cleavage site between residues 33 and 34 analysis:

A search of the NOV2 la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 21 C.

In a BLAST search of public sequence databases, the NOV2 la protein was found to have homology to the proteins shown in the BLASTP data in Table 2 ID. •

PFam analysis predicts that the NOV2 la protein contains the domains shown in the Table 21E.

Example 22.

The NOV22 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 22A.

DNA Sequence CGTGATAACATCCTGATTGAGTGTGAAGCAAAAGGGAACCCTGCCCCCAGCTTCCACT GGACACGAAACAGCAGATTCTTCAACATCGCCAAGGACCCCCGGGTGTCCATGAGGAG GAGGTCTGGGACCCTGGTGATTGACTTCCGCAGTGGCGGGCGGCCGGAGGAATATGAG GGGGAATATCAGTGCTTCGCCCGCAACAAATTTGGCACGGCCCTGTCCAATAGGATCC GCCTGCAGGTGTCTAAATCTCCTCTGTGGCCCAAGGAAAACCTAGACCCTGTCGTGGT CCAAGAGGGCGCTCCTTTGACGCTCCAGTGCAACCCCCCGCCTGGACTTCCATCCCCG GTCATCTTCTGGATGAGCAGCGCCATGGAGCCCATCACCCAAGACAAACGTGTCTCTC AGGGCCATAACGGAGACCTATACTTCTCCAACGTGATGCTGCAGGACATGCAGACCGA CTACAGTTGTAACGCCCGCTTCCACTTCACCCACACCATCCAGCAGAAGAACCCTTTC ACCCTCAAGGTCCTCACCAGTAAGCCTTATAATGACTCGTCCTTAAGAAACCACCCTG ACATGTACAGTGCCCGAGGAGTTGCAGAAAGAACACCAAGCTTCATGTATCCCCAGGG CACCGCGAGCAGCCAGATGGTGCTTCGTGGCATGGACCTCCTGCTGGAATGCATCGCC TCCGGGGTCCCAACACCAGACATCGCATGGTACAAGAAAGGTGGGGACCTCCCATCTG ATAAGGCCAAGTTTGAGAACTTTAATAAGGCCCTGCGTATCACAAATGTCTCTGAGGA AGACTCCGGGGAGTATTTCTGCCTGGCCTCCAACAAGATGGGCAGCATCCGGCACACG ATCTCGGTGAGAGTAAAGGCTGCTCCCTACTGGCTGGACGAACCCAAGAACCTTATTC TGGCTCCTGGCGAGGATGGGAGACTGGTGTGTCGAGCCAATGGAAACCCCAAACCCAC TGTCCAGTGGATGGTGAATGGGGAACCTTTGCAAGCGGCACCACCTAACCCAAACCGT GAGGTGGCCGGAGACACCATCATCTTCCGGGACACCCAGATCAGCAGCAGGGCTGTGT ACCAGTGCAACACCTCCAACGAGCATGGCTACCTGCTGGCCAACGCCTTTGTCAGTGT GCTGGATGTGCCGCCTCGGATGCTGTCGCCCCGGAACCAGCTCATTCGAGTGATTCTT TACAACCGGACGCGGCTGGACTGCCCTTTCTTTGGGTCTCCCATCCCCACACTGCGAT GGTTTAAGAATGGGCAAGGAAGCAACCTGGATGGTGGCAACTACCATGTTTATGAGAA CGGCAGTCTGGAAATTAAGATGATCCGCAAAGAGGACCAGGGCATCTACACCTGTGTC GCCACCAACATCCTGGGCAAAGCTGAAAACCAAGTCCGCCTGGAGGTAAAAGACCCCA CCAGGATCTACCGGATGCCCGAGGACCAGGTGGCCAGAAGGGGCACCACGGTGCAACT GGAGTGTCGGGTGAAGCACGACCCCTCCCTGAAACTCACCGTCTACTGGCTGAAGGAT GACGAGCCGCTCTATATTGGAAACAGGATGAAGAAGGAAGACGACTCCCTGACCATCT TTGGGGTGGCAGAGCGGGACCAGGGCAGTTACACGTGTGTCGCCAGCACCGAGCTAGA CCAAGACCTGGCCAAGGCCTACCTCACCGTGCTAGGACGGCCAGACCGGCCCCGGGAC CTGGAGCTGACCGACCTGGCCGAGAGGAGCGTGCGGCTGACCTGGATCCCCGGGGATG CTAACAACAGCCCCATCACAGACTACGTCGTCCAGTTTGAAGAAGACCAGTTCCAACC TGGGGTCTGGCATGACCATTCCAAGTACCCCGGCAGCGTTAACTCAGCCGTCCTCCGG CTGTCCCCGTATGTCAACTACCAGTTCCGTGTCATTGCCATCAACGAGGTTGGGAGCA GCCACCCCAGCCTCCCATCCGAGCGCTACCGAACCAGTGGAGCACCCCCCGAGTCCAA TCCTGGTGACGTGAAGGGAGAGGGGACCAGAAAGAACAACATGGAGATCACGTGGACG CCCATGAATGCCACCTCGGCCTTTGGCCCCAACCTGCGCTACATTGTCAAGTGGAGGC GGAGAGAGACTCGAGAGGCCTGGAACAACGTCACAGTGTGGGGCTCTCGCTACGTGGT GGGGCAGACCCCAGTCTACGTGCCCTATGAGATCCGAGTCCAGGCTGAAAATGACTTC GGGAAGGGCCCTGAGCCAGAGTCCGTCATCGGTTACTCCGGAGAAGATTATCCCAGGG CTGCGCCCACTGAAGTTAAAGTCCGAGTCATGAACAGCACAGCCATCAGCCTTCAGTG GAACCGCGTCTACTCCGACACGGTCCAGGGCCAGCTCAGAGAGTACCGAGCCTACTAC TGGAGGGAGAGCAGCTTGCTGAAGAACCTGTGGGTGTCTCAGAAGAGACAGCAAGCCA GCTTCCCTGGTGACCGCCTCCGTGGCGTGGTGTCCCGCCTCTTCCCCTACAGTAACTA CAAGCTGGAGATGGTTGTGGTCAATGGGAGAGGTGATGGGCCTCGCAGTGAGACCAAG GAGTTCACCACCCCGGAAGGAGTACCCAGTGCCCCTAGGCGTTTCCGAGTCCGGCAGC CCAACCTGGAGACAATCAACCTGGAATGGGATCATCCTGAGCATCCAAATGGGATCAT GATTGGATACACTCTCAAATATGTGGCCTGTACGTTCTCCCCAGTTAACGGGACCAAA GTAGGAAAGCAGATAGTGGAAAACTTCTCTCCCAATCAGACCAAGTTCACGGTGCAAA GAACGGACCCCGTGTCACGCTACCGCTTTACCCTCAGCGCCAGGACGCAGGTGGGCTC TGGGGAAGCCGTCACAGAGGAGTCACCAGCACCCCCGAATGAAGGTAGGTGCATGGCA GCAGCCCCTGGGGTAAAACCCCCGACTACCGTGGGTGCGACGGGCGCTGTGAGCAGTA CCGATGCTACTGCCATTGCTGCCACCACCGAAGCCACAACAGTCCCCATCATCCCAAC TGTCGCACCTACCACCATGGCCACCACCACCACCGTCGCCACAACTACTACAACCACT GCTGCCGCCACCACCACCACGGAGAGTCCTCCCACCACCACCTCCGGGACTAAGATAC ACGAATCCGGTACTGCGCATCGCCCATGCTCCCCAGCCCCTGATGAGCAGTCCATATG GAACGTCACGGTGCTCCCCAACAGTAAATGGGCCAACATCACCTGGAAGCACAATTTC GGGCCCGGAACTGACTTTGTGGTTGAGTACATCGACAGTAACCATACGAAAAAAACTG TCCCAGTTAAGGCCCAGGCTCAGCCTATACAGCTGACAGACCTCTATCCCGGGATGAC ATACACGTTGCGGGTTTATTCCCGGGACAACGAGGGCATCAGCAATCATTCACGGGTT TGCTTCCGGCCCTCCCCGCCAGCTTACACCAACAACCAAGCGGACATCGCCACCCAGG

Further analysis of the NOV22a protein yielded the following properties shown in Table 22B.

Table 22B. Protein Sequence Properties NOV22a

PSort 0.4600 probability located in plasma membrane; 0.1000 probability located in analysis: endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP Cleavage site between residues 25 and 26 analysis:

A search of the NOV22a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 22C.

In a BLAST search of public sequence databases, the NOV22a protein was found to have homology to the proteins shown in the BLASTP data in Table 22D.

PFam analysis predicts that the NOV22a protein contains the domains shown in the Table

22E.

Example 23.

The NOV23 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 23A.

Table 23A. NO 23 Sequence Analysis

SEQ ID NO: 61 2497 bp

NOV23a, GCCCCGATGGACGCCGCGTTCCTCCTCGTCCTCGGGCTGTTGGCCCAGAGCCTCTGCC CG105963-01 TGTCTTTGGGGGTTCCTGGATGGAGGAGGCCCACCACCCTGTACCCCTGGCGCCGGGC GCCTGCCCTGAGCCGCGTGCGGAGGGCCTGGGTCATCCCCCCGATCAGCGTATCCGAG DNA Sequence AACCACAAGCGTCTCCCCTACCCCCTGGTTCAGGTGAGCAGGTGGAAGCACCAGTTGG CCAGCGTCATCTCCAGCATCCAGGGCCCCGGCGTGGATGAGGAGCCCCGGGGCGTCTT CTCTATCGCCCAGTTCACAGGGAAGGTCTTCCTCAATGCCATGCTGGACCGCGAGAAG ACTGATCGCTTCAGGCTAAGAGGGTTTGCCCTGGACCTGGGAGGATCCACCCTGGAGG ACCCCACGGACCTGGAGATTGTAGTTGTGGATCAGAATGACAACCGGCCAGCCTTCCT GCAGGAGGCGTTCACTGGCCGCGTGCTGGAGGGTGCAGTCCCAGGTACCTATGTGACC AGGGCAGAGGCCACAGATGCCGACGACCCCGAGACGGACAACGCAGCGCTGCGGTTCT CCATCCTGCAGCAGGGCAGCCCCGAGCTCTTCAGCATCGACGAGCTCACAGGAGAGAT CCGCACAGTGCAAGTGGGGCTGGACCGCGAGGTGGTCGCGGTGTACAATCTGACCCTG CAGGTGGCGGACATGTCTGGAGACGGCCTCACAGCCACTGCTTCAGCCATCATCACCT TTGATGACATCAATGACAATGCCCCCGAGTTCACCAGGGATGAGTTCTTCATGGAGGC CATAGAGGCCGTCAGCGGAGTGGATGTGGGACGCCTGGAAGTGGAGGACAGGGACCTG CCAGGCTCCCCAAACTGGGTGGCCAGGTTCACCATCCTGGAAGGCGACCCCGATGGGC AGTTCACCATCCGCACGGACCCCAAGACCAACGAGGGTGTTCTGTCCATTGTGAAGGC CCTGGACTATGAAAGCTGTGAACACTACGAAACTAAAACACACGGGCAGGATAAGACA GAGAACGCACGGGCAGGGCTGAGGGCTGAGCGGGGCCAGGCCAAGGTCCGCGTGCATG TGCAGGACACCAACGAGCCCCCCGTGTTCCAGGAGAACCCACTTCGGACCAGCCTAGC AGAGGGGGCACCCCCAGGCACTCTGGTGGCCACCTTCTCTGCCCGGGACCCTGACACA GAGCAGCTGCAGAGGCTCAGCTACTCCAAGGACTACGACCCGGAAGACTGGCTGCAAG TGGACGCAGCCACTGGCCGGATCCAGACCCAGCACGTGCTCAGCCCGGCGTCCCCTTT CCTCAAGGGCGGCTGGTACAGAGCCATCGTCTTGGCCCAGGATGCCTCCCAGCCCCGC ACCGCCACCGGCACCCTGTCCATCGAGATCCTGGAGGTGAACGACCATGCACCTGTGC TGGCCCCGCCGCCGCCGGGCAGCCTGTGCAGCGAGCCACACCAAGGCCCAGGCCTCCT CCTGGGCGCCACGGATGAGGACCTGCCCCCCCACGGGGCCCCCTTCCACTTCCAGCTG AGCCCCAGGCTCCCAGAGCTCGGCCGGAACTGGAGCCTCAGCCAGGTCAACCCTCTCT CCCATCACCGTCTCCACCCAGACCCCCACCTGCCCCATGGCCCCCATTTCATGTCTGT GGCTCACCAGCTTTTCCCCAGACCCAGCTCCGGAGCCCACAGGCGTGGCCGATGCAGA AACCTCAGGAAGGTGTGTTGTGAATGTGGGAGGGAGGGTGTGGCGGTCGTGGGCTGTG CGGGAGTTCTGACTAGGGGAAGTGGGCTCAGCCTGGGCGCACTGGTCATCGTGCTGGC CAGCGCCCTCCTGCTGCTGGTGCTGGTCCTGCTCGTGGCACTCCGGGCGCGGTTCTGG AAGCAGTCTCGGGGCAAGGGGCTGCTGCACGGCCCCCAGGACGACCTTCGAGACAATG TCCTCAACTACGATGAGCAAGGAGGCGGGGAGGAGGACCAGGACGCCTACGACATCAG CCAGCTGCGTCACCCGACAGCGCTGAGCCTGCCTCTGGGACCGCCGCCACTTCGCAGA GATGCCCCGCAGGGCCGCCTGCACCCCCAGCCACCCCGAGTGCTGCCCACCAGCCCCC TGGACATCGCCGACTTCATCAATGATGGCTTGGAGGCTGCAGATAGTGACCCCAGTGT GCCGCCTTACGACACAGCCCTCATCTATGACTACGAGGGTGACGGCTCGGTGGCGGGG ACGCTGAGCTCCATCCTGTCCAGCCAGGGCGATGAGGACCAGGACTACGACTACCTCA GAGACTGGGGGCCCCGCTTCGCCCGGCTGGCAGACATGTATGGGCACCCGTGCGGGTT GGAGTACGGGGCCAGATGGGACCACCAGGCCAGGGAGGGTCTTTCTCCTGGGGCACTG CTACCCAGACACAGAGGCCGGACAGCCTGACCCTGGGGCGCAACTGGACATGCCACTC CCC

ORF Start: ATG at 7 ORF Stop: TGA at 2464

SEQ ID NO: 62 819 aa MW at 89687.6kD

NOV23a, MDAAF LVLGLLAQSLCLSLGVPG RRPTTLYP RRAPA SRVRRA VIPPISVSENH CGI 05963-01 KR PYP VQVSR KHQ ASVISSIQGPGVDEEPRGVFSIAQFTGKVF NAMLDREKTD RFRLRGFALDLGGSTLEDPTDLEIVWDQ3STDNRPAF QEAFTGRVI.EGAVPGTYVTRA Protein Sequence EATDADDPΞTDNAALRFSI QQGSPELFSIDE TGEIRTVQVGLDREWAVYNLTLQV ADMSGDGLTATASAIITFDDINDNAPEFTRDEFFMEAIEAVSGVDVGRLEVEDRDLPG SPNWVARFTILEGDPDGQFTIRTDPKTNEGV SIVKALDYESCEHYETKTHGQD TEN ARAGLRAERGQAKVRVHVQDTNEPPVFQENP RTSLAEGAPPGT VATFSARDPDTEQ LQRLSYSKDYDPED QVDAATGRIQTQHVLSPASPF KGGWYRAIVLAQDASQPRTA TGTLSIEILEVMDHAPVLAPPPPGSLCSEPHQGPGLLLGATDED PPHGAPFHFQ SP RLPE GRN SLSQV PLSHHR HPDPH PHGPHFMSVAHQLFPRPSSGAHRRGRCRNL RKVCCECGREGVAWGCAGV TRGSGLSLGA VIVLASAIiLL VLVL VALRARF Q SRG GLLHGPQDD RDNVLNYDEQGGGEEDQDAYDISQ RHPTALSLP GPPPLRRDA PQGRLHPQPPRVLPTSPLDIADFINDG EAADSDPSVPPYDTALIYDYEGDGSVAGTL SSILSSQGDEDQDYDY RD GPRFARLADMYGHPCGLEYGARWDHQAREG SPGA P RHRGRTA

Further analysis of the NOV23a protein yielded the following properties shown in Table 23B. Table 23B. Protein Sequence Properties NOV23a

PSort j 0.6850 probability located in endoplasmic reticulum (membrane); 0.6400 analysis: J probability located in plasma membrane; 0.4600 probability located in Golgi body; 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP , Cleavage site between residues 22 and 23 analysis:

A search of the NOV23a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 23C.

In a BLAST search of public sequence databases, the NOV23a protein was found to have homology to the proteins shown in the BLASTP data in Table 23D.

PFam analysis predicts that the NOV23a protein contains the domains shown in the Table 23E.

Example 24.

The NOV24 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 24A.

Table 24A. NOV24 Sequence Analysis

SEQ ID NO: 63 3617 bp

NOV24a, GAGATGGGACTGCAATAGAAATCCGGGCAGCCCGAAGAGGCACCCAGCGCTCCAGCCA CG105973-01 CCAGCTGGGCCGCCCGGGAGTCCCTGGCTCTAGACCAGCCGCGAGGAGGCGCCGCGAG

AGAGCTGGTCCCTGCCCGCGGCCGGAGGAGGGCTAGAGCCCCTGGGCCAGCCCCCCGA DNA Sequence GCCGGCTGGGCGGGCGGGCGGGTGGGAGCAGACGCCGGGCACTGTCACCACGGGTGCG

CCGAGCGCACCGACCCGGGACACGGGCAGCTGGGGACCGCCAGATTCCACCAGCCCCC

CTTGCCCCGCAGGGGTCCTCGGCTCGCGCTCCTGGGTAGCAGCCACCCACCGGGGCGG

AGGGAGATGTCGCCCGGGGCCAGCCGCGGTCCCCGGGGAAGCCAGGCGCCGCTGATCG

CGCCCCTCTGCTGCGCCGCGGCCGCGCTGGGGATGTTGCTGTGGTCCCCCGCCTGTCA GGCGTTCAACCTGGACGTGGAAAAGCTCACAGTGTACAGCGGCCCCAAGGGCAGCTAC TTCGGCTACGCCGTGGACTTCCACATACCCGACGCCCGCACAGCGAGTGTCTTGGTGG GGGCGCCCAAAGCCAACACCAGCCAGCCCGATATCGTGGAAGGGGGAGCCGTCTATTA CTGTCCTTGGCCCGCGGAGGGGTCTGCGCAGTGCAGGCAGATACCGTTTGACACCACC AACAACAGAAAGATCAGAGTTAATGGAACCAAAGAACCTATCGAGTTCAAATCCAATC AGTGGTTTGGAGCAACAGTGAAAGCTCACAAAGGAAAAGTTGTGGCCTGTGCTCCTTT ATATCACTGGAGAACTCTTAAACCGACACCAGAAAAGGACCCAGTTGGCACCTGCTAT GTAGCAATTCAGAACTTCAGCGCCTATGCCGAGTTCTCTCCTTGCCGGAACAGCAATG CTGATCCGGAAGGCCAGGGTTACTGCCAAGCAGGATTTAGTCTGGATTTTTATAAGAA TGGAGACCTTATTGTGGGAGGACCTGGGAGTTTCTACTGGCAAGGACAAGTGATCACT GCCAGTGTTGCAGATATCATTGCAAATTACTCATTCAAGGATATCCTCAGGAAACTGG CAGGAGAAAAGCAGACGGAAGTGGCTCCAGCTTCCTATGATGACAGTTACCTTGGATA CTCAGTTGCTGCTGGGGAGTTTACTGGGGATTCTCAGCAAGAATTGGTTGCTGGAATT CCAAGAGGAGCACAGAATTTTGGATATGTTTCCATCATTAACTCTACGGATATGACGT TTATTCAGAATTTCACGGGAGAACAGATGGCATCTTATTTTGGATATACCGTTGTCGT ATCAGATGTTAACAGTGATGGACTGGATGATGTCCTGGTTGGGGCACCTCTCTTTATG GAACGTGAATTTGAGAGCAACCCCAGAGAAGTAGGGCAAATCTACCTGTATTTGCAAG TGAGCTCTCTCCTCTTCAGAGACCCCCAGATCCTCACTGGCACCGAGACGTTTGGGAG ATTCGGTAGTGCTATGGCACACTTAGGAGACCTGAACCAAGATGGATACAATGACATT GCCATCGGAGTGCCTTTTGCAGGCAAGGATCAAAGAGGCAAAGTGCTCATTTATAATG GGAACAAAGATGGCTTAAACACCAAGCCTTCCCAAGTTCTGCAAGGAGTGTGGGCCTC ACATGCTGTCCCTTCCGGATTTGGCTTTACTTTAAGAGGAGATTCAGACATAGACAAG AATGATTACCCAGATTTGATTGTGGGTGCATTTGGAACAGGAAAAGTCGCTGTTTACA GAGCAAGACCGGTTGTGACTGTAGATGCCCAGCTTCTGCTGCACCCAATGATTATCAA TCTTGAAAATAAAACTTGCCAGGTTCCAGACTCTATGACATCTGCTGCCTGCTTTTCT TTAAGAGTATGTGCATCTGTCACAGGCCAGAGCATTGCAAACACAATAGTCTTGATGG CAGAGGTGCAATTAGATTCCCTGAAACAGAAAGGAGCTATTAAACGGACGCTCTTCCT TGATAACCATCAGGCTCATCGCGTCTTCCCTCTTGTGATAAAAAGGCAGAAATCCCAC CAGTGCCAGGATTTCATCGTTTACCTTCGAGATGAAACTGAATTCCGAGATAAATTAT CTCCAATCAACATTAGTTTGAATTACAGTTTGGACGAATCCACCTTTAAAGAAGGCCT GGAAGTGAAACCAATATTGAACTACTACAGAGAAAACATTGTTAGTGAACAGGCTCAC ATTCTGGTGGACTGTGGAGAAGACAATCTGTGTGTTCCTGACTTGAAGCTGTCGGCTA GACCAGATAAGCATCAGGTAATCATTGGAGATGAAAATCACCTTATGCTCATAATAAA TGCAAGAAATGAAGGGGAAGGAGCATATGAAGCTGAACTCTTTGTAATGATACCAGAA GAGGCAGATTATGTTGGAATCGAACGCAACAACAAGGGATTTCGACCACTGAGCTGTG AGTACAAGATGGAAAATGTAACCAGGATGGTGGTGTGTGACCTTGGGAACCCTATGGT GTCTGGAACAAATTATTCCCTGGGCCTCCGATTTGCAGTTCCACGTCTTGAGAAAACA AACATGAGCATTAACTTCGATCTCCAAATCAGAAGTTCCAACAAGGACAATCCAGACA GCAATTTTGTGAGCCTGCAAATCAACATCACTGCTGTAGCGCAGGTGGAAATAAGAGG AGTGTCACACCCTCCGCAGATTGTTCTGCCCATTCATAACTGGGAACCAGAAGAGGAG CCCCACAAAGAGGAGGAGGTTGGACCATTGGTGGAACATATTTATGAGCTGCACAATA TTGGACCAAGTACCATCAGTGACACCATCCTGGAGGTGGGCTGGCCTTTCTCTGCCCG GGATGAATTTCTTCTCTATATTTTCCATATTCAAACTCTGGGACCTCTGCAGTGCCAA CCAAATCCTAATATCAATCCACAGGATATAAAGCCTGCTGCCTCCCCAGAGGACACCC CTGAGCTCAGCGCCTTTTTGCGAAACTCTACTATTCCTCATCTTGTCAGGAAGAGGGA TGTACATGTGGTCGAATTCCACAGACAGAGCCCTGCAAAAATACTGAATTGTACAAAT ATCGAGTGTTTACAAATCTCCTGTGCAGTGGGACGACTCGAAGGAGGAGAAAGCGCAG TCCTGAAAGTCAGGTCACGATTATGGGCCCACACCTTCCTCCAGAGAAAAAATGATCC CTATGCTCTTGCATCCCTGGTGTCCTTTGAAGTTAAGAAGATGCCTTATACAGATCAG CCAGCAAAACTCCCAGAAGGAAGCATAGTAATTAAGACATCAGTTATTTGGGCAACTC CGAATGTTTCCTTCTCAATCCCATTATGGGTAATAATACTAGCAATACTTCTTGGATT GTTGGTTCTCGCCATTTTAACCTTAGCTTTATGGAAGTGTGGATTCTTTGACAGAGCC AGACCTCCTCAGGAGGACATGACCGACAGGGAACAGCTGACAAATGACAAGACCCCTG AGGCATGACAAGAAAAAAAAAGAAGACCAAAGACCTCAAACACTGGTCCTGTTCAAAG

AAAAAGAAAGAACATGAGGCC

ORF Start: ATG at 355 ORF Stop: TGA at 3544

SEQ ID NO: 64 1063 aa MW at l l7472.3kD

NOV24a, SPGASRGPRGSQAPLIAP CCAAAA GM LWSPACQAFNLDVEKLTVYSGPKGSYFG CGI 05973-01 YAVDFHIPDARTASVLVGAPKANTSQPDIVEGGAVYYCP PAEGSAQCRQIPFDTTlsTN RKIRVNGTKEPIEFKSNQ FGATVKAHKGKVVACAPI.YHWRT KPTPE DPVGTCYVA Protein Sequence QNFSAYAEFSPCRNSNADPEGQGYCQAGFSLDFYK GD IVGGPGSFY QGQVITAS VADIIANYSFKDILRKLAGEKQTEVA ASYDDSYLGYSVAAGEFTGDSQQELVAGIPR GAQNFGYVSIINSTDMTFIQNFTGEQMASYFGYTVWSDVNSDGLDDVLVGAPLFMER EFΞSNPREVGQIY YLQVSS LFRDPQI TGTΞTFGRFGSAMAHLGD NQDGYNDIAI GVPFAGKDQRGKV IYNGNKDGLNTKPSQVLQGV ASHAVPSGFGFTLRGDSDIDKND YPDLIVGAFGTG VAVYRARPWTVDAQ LLHPMIINLENKTCQVPDSMTSAACFSLR VCASVTGQSIA TIV MAEVQ DSLKQKGAIKRTLFLDNHQAHRVFPLVIKRQKSHQC QDFIVYLRDETEFRDKLSPINISLNYSLDΞSTFKEGLEVKPI YYRENIVSEQAHIL VDCGEDNLCVPDLK SARPDKHQVIIGDENHLMLIINARNEGEGAYEAELFVMIPEEA DYVGIERNNKGFRP SCEYKME3 TRI^sA7CDLGNPMVSGTIπr:SLGLRFAVPRLEKTlSlM SINFDLQIRSSNKDNPDSNFVSLQINITAVAQVEIRGVSHPPQI LPIH EPEEEPH KEEEVGPLVEHIYELHNIGPSTISDTI EVGWPFSARDEFLLYIFHIQT GPLQCQPN PNINPQDIKPAASPEDTPELSAFLRNSTIPH VRKRDVHWEFHRQSPAKILNCTNIE CLQISCAVGRLEGGESAVL VRSRLWAHTFLQRKNDPYALAS VSFEVKKMPYTDQPA KLPΞGSIVIKTSVI ATPlWSFSIPL VIII^IL G LV AIIiTI-AL KCGFFDRARP PQEDMTDREQLTNDKTPEA

SEQ ID NO: 65 3617 bp

NOV24b, GAGATGGGACTGCAATAGAAATCCGGGCAGCCCGAAGAGGCACCCAGCGCTCCAGCCA CGI 05973-02 CCAGCTGGGCCGCCCGGGAGTCCCTGGCTCTAGACCAGCCGCGAGGAGGCGCCGCGAG

AGAGCTGGTCCCTGCCCGCGGCCGGAGGAGGGCTAGAGCCCCTGGGCCAGCCCCCCGA DNA Sequence GCCGGCTGGGCGGGCGGGCGGGTGGGAGCAGACGCCGGGCACTGTCACCACGGGTGCG

CCGAGCGCACCGACCCGGGACACGGGCAGCTGGGGACCGCCAGATTCCACCAGCCCCC

CTTGCCCCGCAGGGGTCCTCGGCTCGCGCTCCTGGGTAGCAGCCACCCACCGGGGCGG

AGGGAGATGTCGCCCGGGGCCAGCCGCGGTCCCCGGGGAAGCCAGGCGCCGCTGATCG

CGCCCCTCTGCTGCGCCGCGGCCGCGCTGGGGATGTTGCTGTGGTCCCCCGCCTGTCA GGCGTTCAACCTGGACGTGGAAAAGCTCACAGTGTACAGCGGCCCCAAGGGCAGCTAC TTCGGCTACGCCGTGGACTTCCACATACCCGACGCCCGCACAGCGAGTGTCTTGGTGG GGGCGCCCAAAGCCAACACCAGCCAGCCCGATATCGTGGAAGGGGGAGCCGTCTATTA CTGTCCTTGGCCCGCGGAGGGGTCCGCGCAGTGCAGGCAGATACCGTTTGACACCACC AACAACAGAAAGATCAGAGTTAATGGAACCAAAGAACCTATCGAGTTCAAATCCAATC AGTGGTTTGGAGCAACAGTGAAAGCTCACAAAGGAAAAGTTGTGGCCTGTGCTCCTTT ATATCACTGGAGAACTCTTAAACCGACACCAGAAAAGGACCCAGTTGGCACCTGCTAT GTAGCAATTCAGAACTTCAGCGCCTATGCCGAGTTCTCTCCTTGCCGGAACAGCAATG CTGATCCGGAAGGCCAGGGTTACTGCCAAGCAGGATTTAGTCTGGATTTTTATAAGAA TGGAGACCTTATTGTGGGAGGACCTGGGAGTTTCTACTGGCAAGGACAAGTGATCACT GCCAGTGTTGCAGATATCATTGCAAATTACTCATTCAAGGATATCCTCAGGAAACTGG CAGGAGAAAAGCAGACGGAAGTGGCTCCAGCTTCCTATGATGACAGTTACCTTGGATA CTCAGTTGCTGCTGGGGAGTTTACTGGGGATTCTCAGCAAGAATTGGTTGCTGGAATT CCAAGAGGAGCACAGAATTTTGGATATGTTTCCATCATTAACTCTACGGATATGACGT TTATTCAGAATTTCACGGGAGAACAGATGGCATCTTATTTTGGATATACCGTTGTCGT ATCAGATGTTAACAGTGATGGACTGGATGATGTCCTGGTTGGGGCACCTCTCTTTATG GAACGTGAATTTGAGAGCAACCCCAGAGAAGTAGGGCAAATCTACCTGTATTTGCAAG TGAGCTCTCTCCTCTTCAGAGACCCCCAGATCCTCACTGGCACCGAGACGTTTGGGAG ATTCGGTAGTGCTATGGCACACTTAGGAGACCTGAACCAAGATGGATACAATGACATT GCCATCGGAGTGCCTTTTGCAGGCAAGGATCAAAGAGGCAAAGTGCTCATTTATAATG GGAACAAAGATGGCTTAAACACCAAGCCTTCCCAAGTTCTGCAAGGAGTGTGGGCCTC ACATGCTGTCCCTTCCGGATTTGGCTTTACTTTAAGAGGAGATTCAGACATAGACAAG AATGATTACCCAGATTTGATTGTGGGTGCATTTGGAACAGGAAAAGTCGCTGTTTACA GAGCAAGACCGGTTGTGACTGTAGATGCCCAGCTTCTGCTGCACCCAATGATTATCAA TCTTGAAAATAAAACTTGCCAGGTTCCAGACTCTATGACATCTGCTGCCTGCTTTTCT TTAAGAGTATGTGCATCTGTCACAGGCCAGAGCATTGCAAACACAATAGTCTTGATGG CAGAGGTGCAATTAGATTCCCTGAAACAGAAAGGAGCTATTAAACGGACGCTCTTCCT TGATAACCATCAGGCTCATCGCGTCTTCCCTCTTGTGATAAAAAGGCAGAAATCCCAC CAGTGCCAGGATTTCATCGTTTACCTTCGAGATGAAACTGAATTCCGAGATAAATTAT CTCCAATCAACATTAGTTTGAATTACAGTTTGGACGAATCCACCTTTAAAGAAGGCCT GGAAGTGAAACCAATATTGAACTACTACAGAGAAAACATTGTTAGTGAACAGGCTCAC ATTCTGGTGGACTGTGGAGAAGACAATCTGTGTGTTCCTGACTTGAAGCTGTCGGCTA GACCAGATAAGCATCAGGTAATCATTGGAGATGAAAATCACCTTATGCTCATAATAAA TGCAAGAAATGAAGGGGAGGGAGCATATGAAGCTGAACTCTTTGTAATGATACCAGAA GAGGCAGATTATGTTGGAATCGAACGCAACAACAAGGGATTTCGACCACTGAGCTGTG AGTACAAGATGGAAAATGTAACCAGGATGGTGGTGTGTGACCTTGGGAACCCTATGGT GTCTGGAACAAATTATTCCCTGGGCCTCCGATTTGCAGTTCCACGTCTTGAGAAAACA AACATGAGCATTAACTTCGATCTCCAAATCAGAAGTTCCAACAAGGACAATCCAGACA GCAATTTTGTGAGCCTGCAAATCAACATCACTGCTGTAGCGCAGGTGGAAATAAGAGG AGTGTCACACCCTCCGCAGATTGTTCTGCCCATTCATAACTGGGAACCAGAAGAGGAG CCCCACAAAGAGGAGGAGGTTGGACCATTGGTGGAACATATTTATGAGCTGCACAATA TTGGACCAAGTACCATCAGTGACACCATCCTGGAGGTGGGCTGGCCTTTCTCTGCCCG GGATGAATTTCTTCTCTATATTTTCCATATTCAAACTCTGGGACCTCTGCAGTGCCAA CCAAATCCTAATATCAATCCACAGGATATAAAGCCTGCTGCCTCCCCAGAGGACACCC CTGAGCTCAGCGCCTTTTTGCGAAACTCTACTATTCCTCATCTTGTCAGGAAGAGGGA TGTACATGTGGTCGAATTCCACAGACAGAGCCCTGCAAAAATACTGAATTGTACAAAT ATCGAGTGTTTACAAATCTCCTGTGCAGTGGGACGACTCGAAGGAGGAGAAAGCGCAG TCCTGAAAGTCAGGTCACGATTATGGGCCCACACCTTCCTCCAGAGAAAAAATGATCC CTATGCTCTTGCATCCCTGGTGTCCTTTGAAGTTAAGAAGATGCCTTATACAGATCAG CCAGCAAAACTCCCAGAAGGAAGCATAGCAATTAAGACATCAGTTATTTGGGCAACTC CGAATGTTTCCTTCTCAATCCCATTATGGGTAATAATACTAGCAATACTTCTTGGATT GTTGGTTCTCGCCATTTTAACCTTAGCTTTATGGAAGTGTGGATTCTTTGACAGAGCC AGACCTCCTCAGGAGGACATGACCGACAGGGAACAGCTGACAAATGACAAGACCCCTG AGGCATGACAAGAAAAAAAAAGAAGACCAAAGACCTCAAACACTGGTCCTGTTCAAAG

AAAAAGAAAGAACATGAGGCC

ORF Start: ATG at 355 ORF Stop: TGA at 3544

SEQ ID NO: 66 1063 aa |MW at 117444 r7

NOV24b, MSPGASRGPRGSQAPLIAPLCCAAAALGMLL SPACQAFNLDVEKLTVYSGPKGSYFG CGI 05973-02 YAVDFHIPDARTASVLVGAPKANTSQPDIVEGGAVYYCPWPAEGSAQCRQIPFDTTIMIM RKIRV GTKEPIEFKSNQWFGATVKAHKGKWACAPLYH RTLKPTPEKDPVGTCYVA Protein Sequence IQNFSAYAEFSPCR SNADPEGQGYCQAGFSLDFYKNGD IVGGPGSFYWQGQVITAS VADIIANYSFKDILRKLAGEKQTEVAPASYDDSYLGYSVAAGEFTGDSQQELVAGIPR GAQNFGYVSIIIsTSTDMTFIQNFTGEQMASYFGYTVWSDVNSDG DDVLVGAPLFMER EFESNPREVGQIY Y QVSSL FRDPQI TGTETFGRFGSAMAHLGD NQDGYNDIAI GVPFAGKDQRGKVLIYNGNKDGLNTKPSQVLQGV ASHAVPSGFGFTLRGDSDID ND YPD IVGAFGTGKVAVYRARPWTVDAQ LLHPMIIN ENKTCQVPDSMTSAACFS R VCASVTGQSIANTIV MAEVQLDS KQKGAIKRTLF DNHQAHRVFPLVIKRQ SHQC QDFIVYLRDΞTEFRDKLSPINISLNYSLDESTFKEG EVKPI NYYRENIVSEQAHI VDCGEDNLCVPD KLSARPDKHQVIIGDENHLMLIINARNEGEGAYEAELFVMIPEEA DYVGIERNNKGFRPLSCEYKMENVTRMWCDLGNPMVSGTNYSLGLRFAVPRLEKTN SINFDLQIRSSNKDNPDSNFVSLQINITAVAQVEIRGVSHPPQIVL.PIHN EPEΞEPH EEEVGP VΞHIYELHNIGPSTISDTILEVG PFSARDEF LYIFHIQTLGP QCQPN PNINPQDIKPAASPEDTPE SAFLRNSTIPH VR RDVHWEFHRQSPAKILNCTNIE C QISCAVGRLEGGESAV KVRSRL AHTFLQRKNDPYA ASLVSFEVKKMPYTDQPA KLPEGSIAIKTSVIWATPNVSFSIP VIILAIL G VLAILTLA KCGFFDRARP PQEDMTDREQ TNDKTPEA

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 24B.

Further analysis of the NOV24a protein yielded the following properties shown in Table 24C.

Table 24C. Protein Sequence Properties NOV24a

PSort 0.4600 probability located in plasma membrane; 0.1125 probability located in analysis: microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 39 and 40 analysis:

A search of the NOV24a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 24D.

In a BLAST search of public sequence databases, the NOV24a protein was found to have homology to the proteins shown in the BLASTP data in Table 24E.

PFam analysis predicts that the NOV24a protein contains the domains shown in the Table

24F.

Example 25.

The NOV25 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 25A.

Further analysis of the NOV25a protein yielded the following properties shown in Table 25B.

Table 25B. Protein Sequence Properties NOV25a analysis: probability located in plasma membrane; 0.3000 probability located in microbody (peroxisome); 0.2622 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOV25a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 25C.

In a BLAST search of public sequence databases, the NOV25a protein was found to have homology to the proteins shown in the BLASTP data in Table 25D.

PFam analysis predicts that the NOV25a protein contains the domains shown in the Table

25E.

Example 26.

The NOV26 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 26A.

Table 26A. NOV26 Sequence Analysis

SEQ ID NO: 69 3757 bp

NOV26a, CTCTTTGCCATCATGTTGCGGTTGGTGGCAGCTTGCCCTGAGTCATGTGTGGTGTGCA CG106924-01 CCAAAGATGTAACCCTCTGTCACCAGCTAACCTATATAGTAGCAGCCCCTATGACCAC GAGGGTTTTAATCATCACCGATGGATATCTCTCCTCTATTGAGAGCACAAACCTGTCT DNA Sequence CTCTTGTTTAATCTTGCCCTGCTCTCCCTAAGCAGAAATGGTATCGAGGATGTTCAGG AAGATGCCCTGCATGGGCTTACGATGTTGCGGACCTTGTTGCTGGAGCACAACCAAAT ATCCAGCTCTTCGCTCACTGATCACACCTTCAGCAAGCTTCACAGCCTGCAGGTACTG GTGCTGAGCAATAATGCTCTCCGCACCCTACGAGGGTCTTGGTTCCGAAACACAAGCG GCCTGACCCGGCTCCAGCTGGATGGGAATCAGATTACTAATCTCACAGACAGTTCTTT CGGAGGCACGAATCTCCACAGTCTCAGGTATCTGGATTTATCCAACAATTTTATTTCC TACATTGGGAAAGATGCCTTCCGGCCCCTGCCTCAACTACAGGAAGTGGACCTTTCCC GAAATAGGTTAGCCCACATGCCGGATGTGTTTACTCCACTGAAGCAGTTAATCCTTCT GAGCTTAGATAAGAACCAGTGGAGCTGCACTTGTGATCTCCATCCCCTTGCTCGGTTT TTAAGAAACTACATTAAGTCTTCTGCTCACACGCTCAGGAATGCCAAGGACCTAAATT GCCAGCCATCTACCGCAGCTGTGGCAGCTGCACAGAGTGTGCTGAGGCTGTCTGAGAC CAACTGTGATTCCAAAGCTCCCAACTTCACTCTGGTTCTAAAGGACAGAAGTCCCCTC CTCCCAGGACCAGATGTGGCCCTGCTGACTGTCCTTGGCTTCGCAGGTGCTGTTGGTC TCACTTGCCTAGGTTTAGTTGTATTTAACTGGAAACTCCACCAAGGCAAAGCAAATGA ACACACATCAGAAAACCTTTGTTGCAGAACCTTCGATGAACCCCTGTGTGCTCATGAG GCAAGAAATTACCACACTAAGGGATACTGCAACTGCCACTTAACTCAGGAAAACGAGA TAAAGGTCATGTCCATTGTGGGGTCCAGAAAAGAAATGCCACTTTTACAGGAAAATAG CCATCAAGCAACATCGGCCTCTGAGTCTGCAACCCTTGACAGATCATTTAGAAACCTG AAAAAGAAAGACCGTGGGGTAGGCAGCACTTTATTTTGCCAGGATGGTAGATTGCTGC ATTCGGAATGTTCAGAGCCTCCTGGAAATATGAGAGCTTTTAATGAAGCAGGCTTACT TACAACATATAATCCAAGGAAAGTTCAAAAGCTATGGAATCTTGAGCCTGGAGAAGTC CAGCCTCAAACTCTGCAACACCATATAATAAGAACAGAAGATATCAGCAGTGACATAT TTAGAAGAAGATATGCAACACCCGCTTCAGCCTTGGCAGGAGAAAGTCTTGAGAAGCG TTTAACAAATGAATCATGGCAGCCTCCAΆTAGAAAAAGAΆGACAATGGCTTACACCCT CACAGGCAAAGACATTTTATTACAAGCTCATCATCCAAGCCTTGTGAGCCTGAGGAAC CTATGTACAAAATATCGTACAAAAAAATAGATCAAAATATGATGATCCTTGTGGACT GTTAAAACAGAGCAAACCTAGGTATTTTCAGCCAAACAΆTTCTCTTATCTGTAAATAT GTGCCCTGTGAGCAATTTGAΆGATTACATGAAAGAAAAGAAGCCAAATCGTAGACAAC ACTCAAAGCCTGAGAAAGAGCAAATCCAAATTAACAGTGCAATAGAAAAATTTCTTAT GAGTGAGGACAACATAGATTTATCAGGATTATCAACAAAAACCAAGAAAGCATATTCC CCAAAGAGGGTTATCTTCCATGATCCTGATTTAGTAGAAATAAATAGGTCGATGATGT CACCCAAAATATCAACCCCTTGGAAACGACAGAAAAATCAAAGTAACCAACTGACTAA GTTGGATGTTAAAAAATTTAGCAACACTGGGGAGAGAAACAAAGGAGAAAAATGGTTT ACTAATTCATGGGTTCTGAAAAGGAAGAGAACCCCTCAGTCTGACCTCAAAGGGAAAA TTAAAGGACAAAACTTAAAATTAAATTTACATCCTTTTAGAAAAGTCAGAGTCCATCC AGAAAAATCCTTGTCAAGTCTCCCAAAGCAATGCAAGCAGGTATTGTTGCCTCCTAAG AAATTATCCAAAACTTCTGAGACAGAAGCCAAAATAAATACTGTGTGTTCTGCAGATT TTCTTCAACAGTCAGAGAGTAGCAACTATGTTAGACTCACTTCAAAGAGGCTGCCTCT GAAACATGACTCAAAGCAGACCCCATATTATCAACGAAACACTAAACGTGCCCCCCTG CTCAGTGCTAACAACTTGCGTGTAGTCAACCAGAGCTCTATAGAAAGCAGCTGTTACT CAGCTGGCCACATTCCTGATGGAAACACATCAAAATTGCCCCAACCTACACCCACTGA TGCTGAGCACAGGCACTCACATTCTCAATTCTCAACTGAGCAAATGGAAGATGCAACT CAGCTTGAATCAAAAGTGCTTAGTTATTTAGCAACTACTTGGGAAAATACAGGAAGTG ATGTTTTACCATTCCAACATTCCAGGAGGGCTACTGACCAAGGGACAACGGAGTCCAC TGAGCACATGGGACAGAATGTATCAAAGACCAGTGAGTTAAATCAGTTTTCTTTGTCC CCGAGGAATCAAACACAACTTTTAGATGCTCACAAGACTGACAGCTACAACAAGGAAT

210062144 NNALRTLRGS FRNTSG TR Q DGNQITN TDSSFGGTN HS RYLDLSNNFIS IG Protein Sequence KDAFRP PQLQEVDLSRNRLAHMPDVFTPLKQ I LSLDKNQ SCTCDLHP ARFLRN YIKSSAHTLRNAKDLNCQPSTAAVAAAQSVLRLSETNCDLE

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 26B.

Further analysis of the NOV26a protein yielded the following properties shown in Table 26C.

Table 26C. Protein Sequence Properties NO 26a

PSort 0.8524 probability located in mitochondrial inner membrane; 0.6000 analysis: probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome); 0.2622 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOV26a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 26D.

In a BLAST search of public sequence databases, the NOV26a protein was found to have homology to the proteins shown in the BLASTP data in Table 26E.

PFam analysis predicts that the NOV26a protein contains the domains shown in the Table 26F.

Example 27.

The NOV27 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 27A.

Table 27A. NOV27 Sequence Analysis

SEQ ID NO: 73 2358 bp

NOV27a, GACTTCCTGGCTCGCCAGCCCCTTCCTTCCGGAGCCTGACCCGGGCCCGGGCGACCTC CGI 06942-01 CCCGCGCGCTTCCCGGCCGCTGCCCAGGGGGTAGAGCGGGCGCAGCCGATCACTACCT

GACGGCCTTTTTGGCGGCCTGGCCGGGCTGTGCAGGGTGGTAGGGCAAGACGCGCGGC DNA Sequence TCCCAATTCTCCCCGGCGCCTTCGCCGGCCCCGGGCTTCTCGCGCTCCGCTCCGGGCT

GCACCGAGTTGGGCCGGCGCGCCGCGTTGGTGTTGCCGCGCGGCGGCAGCTCAGAGTC

TCCAGGTTGGGGCGGGCCTGGGCCGCACGGCTCCTCCACCCAGGTGACGCTGAGCAGG

CTCAGGGTGAAGCCCAGGGAGATGCCCACGGCCACGGGCCCTGCGGGCCGCAGCACCG

ACAGCAGCAGCGATGCCCGCATGGCGCCCGGACCGCGGGTCCCCGGCCCCGGCGAACC

CCCAGAGCAGCCAGAGGAGTCTCCGAGGGGGCGGGACCGGGGAGGGGGCGGATCCGGA

GGGCTCGGGCCCCGCGGGCGGGCCCGCTCCCTCCCCGCAGAGCAGAGCCAGCGGCCCG

AGCCGAATCCCCGGAGCCGCGCCTCGATTCCCCTCCAGCAGCTGCTCTGGGCTGCGCA

GGGTTCTTGCGCTCGGCACTGGAGCCTCAGCCGCGGCCGCAGCTGTCCGACGTGTCAC

TGCAAGGGCCCCGCCCCCGGGGTGGGGTCTCGGGCTCTCGCTACCGGAGAGGGAGGAG

AAGGGGGAGGTTAAAGGGGAAGGACCCCCGGAAGTGCCCCCTCCTCAGTGCGGGAGAG

GGAGACGCCGGGGGCGGAGTCCCCTGCCTCCCGCGGCGTGGTTGGTGCGTCCCATGTG

ACGTCAGAAGCAGCCCGCCCCTGCCTGGATGGTGCGCCCTGAGTGACGTCAGGAGCAG

AGGCCGGAGCTGTCCATCAGCACCAAAGGCCGCGGGCGGGCTCAGGGCATGGGGCCGC

GGTTCTGGGGCGGCCCGAGCCCCGGCTCCTGCGCCTTCCCCTTCCTCAGGCCCAGCCC GAGTTCCCGGACGCCGCGGGACTGGAGTGCCAGCCGGTGTTGGACGTGGAGCGGCGCC GCCACCGCGCCGACACCATTCTCTCCGGCCCAGCAGCCCCCTTCCTCGCACGACGGAC TTTCCCTGGACCCCAGCACTATGCCGGGGACTGTGGCAACACTGCGGTTCCAGCTGCT GCCCCCTGAGCCAGATGATGCCTTCTGGGGTGCACCTTGTGAACAGCCCCTGGAGCGC AGGTACCAGGCACTGCCGGCCCTCGTCTGCATCATGTGCTGTTTGTTTGGAGTCGTCT ACTGCTTCTTCGGTTACCGCTGCTTCAAGGCAGTGCTCTTTCTCACTGGGTTGCTGTT TGGCTCGGTGGTCATCTTCCTCCTCTGCTACCGAGAGCGGGTGCTAGAGACACAGCTG AGTGCTGGGGCGAGCGCGGGCATCGCTCTGGGCATCGGGCTGCTCTGCGGGCTGGTGG CCATGCTAGTGCGCAGCGTGGGCCTCTTCCTGGTGGGGCTGCTGCTCGGCCTGCTGCT CGCAGCTGCTGCCCTGCTGGGCTCCGCACCCTACTACCAGCCAGGCTCCGTGTGGGGT CCACTGGGGCTGTTGCTGGGGGGCGGCCTGCTCTGTGCCCTGCTCACTCTGCGCTGGC CCCGCCCACTCACCACCCTGGCCACCGCCGTGACTGGTGCTGCGCTGATCGCCACTGC CGCTGACTACTTCGCCGAGCTGCTACTGCTGGGGCGCTACGTGGTGGAGCGACTCCGG GCTGCTCCTGTGCCCCCACTCTGCTGGCGAAGCTGGGCCCTGCTGGCACTCTGGCCCC TGCTCAGCCTGATGGGCGTTCTGGTGCAGTGGAGGGTGACAGCTGAGGGGGACTCCCA CACGGAAGTGGTCATCAGCCGGCAGCGCCGACGCGTGCAACTGATGCGGATTCGGCAG CAGGAAGATCGCAAGGAGAAAAGGCGGAAAAAGAGACCTCCTCGGGCTCCCCTCAGAG GTCCCCGGGCTCCTCCCAGGCCTGGGCCACCAGATCCTGCTTATCGGCGCAGGCCAGT GCCCATCAAACGCTTCAATGGAGACGTCCTCTCCCCGAGCTATATCCAGAGCTTCCGA GACCGGCAGACCGGGAGCTCCCTGAGCTCCTTCATGGCCTCACCCACAGATGCGGACT ATGAGTATGGGTCCCGGGGACCTCTGACAGCCTGCTCAGGCCCCCCAGTGCGGGTATA GCCATATCTGTCTGTCTAGACTCTGCAGTCACCAGCTCTGACAGCTCGAGGAGGCCGG

TAGGCTGCAATCAGCTTCCGGTTTGGTGGTCCTTCCCA

ORF Start: ATG at 977 ORF Stop: TAG at 2261

SEQ ID NO: 74 428 aa MW at 46672.9kD

NOV27a, MGPRFWGGPSPGSCAFPFLRPSPSSRTPRDWSASRCWTWSGAATAPTPFSPAQQPPSS CG106942-01 HDGLS DPSTMPGTVAT RFQL PPEPDDAFWGAPCEQP ERRYQA PA VCI CC F GVWCFFGYRCFKAV F TGLLFGSWIFLLCYRΞRV ETQLSAGASAGIALGIGL.LC Protein Sequence GLVAMLVRSVGLFLVGLL GL AAAAIiLGSAPYYQPGSV GPLGI.L. GGGL CA LT LR PRPLTTIiATAVTGAA IATAADYFAE LLLGRYWERLRAAPVPPLCWRS AL A L PLLS MGVLVQWRVTAEGDSHTEWISRQRRRVQLMRIRQQEDRKEKRRKKRPPRA PLRGPRAPPRPGPPDPAYRRRPVPIKRFNGDVLSPSYIQSFRDRQTGSSLSSFMASPT DADYEYGSRGPLTACSGPPVRV

Further analysis of the NOV27a protein yielded the following properties shown in Table 27B.

Table 27B. Protein Sequence Properties NOV27a

PSort i 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.2400 probability located in nucleus

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOV27a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 27C.

In a BLAST search of public sequence databases, the NOV27a protein was found to have homology to the proteins shown in the BLASTP data in Table 27D.

Example 28.

The NOV28 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 28A.

Further analysis of the NOV28a protein yielded the following properties shown in Table 28B.

Table 28B. Protein Sequence Properties NO 28a

PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOV28a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 28C.

In a BLAST search of public sequence databases, the NOV28a protein was found to have homology to the proteins shown in the BLASTP data in Table 28D.

Example 29.

The NOV29 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 29 A.

Table 29A. NOV29 Sequence Analysis

SEQ ID NO: 77 664 bp

NOV29a, ATCGCCCCTCCTGCGCTAGCGGAGGTGATCGCCGCGGCGATGCCGGAGGAGGGTTCGG CG107533-02 GCTGCTCGGTGCGGCGCAGGCCCTATGGGTGCGTCCTGCGGGCTGCTTTGGTCCCATT GGTCGCGGGCTTGGTGATCTGCCTCGTGGTGTGCATCCAGCGCTTCGCACAGGCTCAG DNA Sequence CAGCAGCTGCCGCTCGAGTCACTTGGGGACCTCAGCAGGACCCCAGGCTATACTGGCA GGGGGGCCCAGCACTGGGCCGCTCCTTCCTGCATGGACCAGAGCTGGACAAGGGGCAG CTACGTATCCATCGTGATGGCATCTACATGGTACACATCCAGGTGACGCTGGCCATCT

GCTCCTCCACGACGGCCTCCAGGCACCACCCCACCACCCTGGCCGTGGGAATCTGCTC

TCCCGCCTCCCGTAGCATCAGCCTGCTGCGTCTCAGCTTCCACCAAGGTTGTACCATT

GCCTCCCAGCGCCTGACGCCCCTGGCCCGAGGGGACACACTCTGCACCAACCTCACTG

GGACACTTTTGCCTTCCCGAAACACTGATGAGACCTTCTTTGGAGTGCAGTGGGTGCG

CCCCTGACCACTGCTGCTGATTAGGGTTTTTTAAATTTTATTTTATTTTATTTAAGTT

CAAGAGAAAAAGTGTACACACAGGGG

ORF Start: ATG at 40 ORF Stop: TGA at 334

SEQ ID NO: 78 98 aa MW at l0705.2kD

NOV29a, MPEΞGSGCSVRRRPYGCVIiRAA VPLVAGLVIC VVCIQRFAQAQQQ PLESLGDLSR TPGYTGRGAQH AAPSCMDQS TRGSYVSIV AST YTSR

Further analysis of the NOV29a protein yielded the following properties shown in Table 29B.

Table 29B. Protein Sequence Properties NOV29a

PSort 0.7900 probability located in plasma membrane; 0.3000 probability located in analysis: Golgi body; 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

SignalP Cleavage site between residues 45 and 46 analysis:

A search of the NOV29a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 29C.

In a BLAST search of public sequence databases, the NOV29a protein was found to have homology to the proteins shown in the BLASTP data in Table 29D.

Example 30.

The NOV30 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 30 A.

Table 30A. NOV30 Sequence Analysis

SEQ ID NO: 79 2840 bp

NOV30a, CGGCAGTGGCAGGAGCCGCCTTTCCGATTCCCTACGATGCGGGTGCTGAGCTATGGCA CG107562-01 AAGGGCAGCGAAGTGACGAGCGAGACCCGCGTACGACTGTGAAAGCCACCTGGAGCCA

CCTTGCCGGGATTGTACCTGCAGGCAGAAAGTCTTCCTACGACCGTCTTTTCCCTTAG DNA Sequence AGGCACCAGAATCCCTGTAACCATTCATCCAGGTGTTGAGAAGATATGTAGCAGCCGA

GCACCCATCTTTTGACACCGTCCTCTGAAATCAGCTTTGGAGATGCTTTCACTCTGTC

CGTCTTCTGCAGCAGCCAGGCAGAGTGCCGACTCCTTCACAGCCGTGAGGAACTCTTC

AGGCTCCAGAAGCTCTTAAACCTGATCTACAATGGAAAAAATTCTTTTTTATCTGTTT

CTCATTGGCATAGCAGTGAAAGCTCAGATCTGTCCAAAGCGTTGTGTCTGTCAGATTT TGTCTCCTAATCTTGCAACCCTTTGTGCCAAGAAAGGGCTTTTATTTGTTCCACCAAA CATTGACAGAAGAACTGTGGAACTGCGGTTGGCAGACAATTTTGTTACAAATATTAAA AGGAAAGATTTTGCCAATATGACCAGCTTGGTGGACCTGACTCTATCCAGGAATACAA TAAGTTTTATTACACCTCATGCTTTCGCTGACCTACGAAATTTGAGGGCTTTGCATTT GAATAGCAACAGATTGACTAAAATTACAAATGATATGTTCAGTGGTCTTTCCAATCTT CATCATTTGATACTGAACAACAATCAGCTGACTTTAATTTCCTCTACAGCGTTTGATG ATGTCTTCGCCCTTGAGGAGCTGGATCTGTCCTATAATAATCTAGAAACCATTCCTTG GGATGCTGTTGAGAAGATGGTTAGCTTGCATACCCTTAGTTTGGATCACAATATGATT GATAACATTCCTAAGGGGACCTTCTCCCATTTGCACAAGATGACTCGGTTAGATGTGA CATCAAATAAATTGCAGAAGCTACCACCTGACCCTCTCTTTCAGCGAGCTCAGGTACT AGCAACCTCAGGAATCATAAGCCCATCTACTTTTGCATTAAGTTTTGGTGGAAACCCC TTGCATTGCAATTGTGAATTGTTGTGGTTGAGGCGTCTGTCCAGAGAAGATGACTTAG AGACCTGTGCTTCTCCTCCACTTTTAACTGGCCGCTACTTTTGGTCAATTCCTGAAGA AGAGTTTTTGTGTGAGCCTCCTCTCATTACTCGTCATACACATGAGATGAGAGTCCTG GAGGGACAAAGGGCAACACTGAGGTGCAAAGCCAGGGGAGACCCTGAGCCTGCAATTC ACTGGATTTCTCCTGAAGGGAAGCTTATTTCAAATGCAACAAGATCTCTGGTGTATGA TAACGGAACACTTGACATTCTTATCACAACTGTAAAGGATACAGGTGCTTTTACCTGC ATTGCTTCCAATCCTGCTGGGGAAGCAACACAAATAGTGGATCTTCATATAATTAAGC TCCCTCACTTACTAAATAGTACAAACCATATCCATGAGCCTGATCCTGGTTCTTCAGA TATCTCAACTTCTACCAAGTCAGGTTCTAATACAAGCAGTAGTAATGGTGATACTAAA TTGAGTCAAGATAAAATTGTGGTGGCAGAAGCTACATCATCAACGGCACTACTTAAAT TTAATTTTCAAAGAAATATCCCTGGAATACGTATGTTTCAAATCCAGTACAATGGTAC TTATGATGACACCCTTGTTTACAGGATGATACCTCCTACGAGCAAAACTTTTCTGGTC AATAATCTGGCTGCTGGAACTATGTATGACTTGTGTGTCTTGGCCATATATGATGATG GCATCACTTCCCTCACTGCCACAAGAGTCGTGGGTTGCATCCAGTTTACTACGGAACA GGATTATGTGCGTTGCCATTTCATGCAGTCCCAGTTTTTGGGAGGCACCATGATTATT ATTATTGGTGGAATCATTGTAGCATCTGTGCTGGTATTCATCATTATTCTGATGATCC GGTATAAGGTTTGCAACAATAATGGGCAACACAAGGTCACCAAGGTTAGCAATGTTTA TTCCCAAACTAACGGGGCTCAAATACAAGGCTGTAGTGTAACGCTGCCCCAGTCCGTG TCCAAACAAGCTGTGGGACACGAAGAGAATGCCCAGTGTTGTAAAGCTACCAGTGACA ATGTGATTCAATCTTCAGAAACTTGTTCGAGTCAAGACTCCTCTACCACTACCTCTGC TTTGCCTCCTTCCTGGACTTCAAGCACTTCTGTGTCCCAAAAGCAGAAAAGAAAGACT GGCACAAAGCCAAGTACAGAACCACAGAATGAAGCCGTCACAAATGTTGAATCCCAAA ACACTAACAGGAACAACTCAACTGCCTTGCAGTTAGCTAGCCGTCCTCCCGATTCTGT CACAGAGGGGCCCACGTCTAAAAGAGCACATATAAAGCCAAGTAAGTTTATCACTTTG CCTGCTGAGAGATCCGGAGCAAGGCACAAGTACTCCCTCAATGGAGAATTAAAGGAAT ACTATTGTTATATTAACTCGCCGAACACATGTGGACTGTTTCCTAAAAGAAGCATGTC TATGAATGTGATGTTTATTCAGTCTGACTGTTCTGATGGTCATAGTGGAAAGGCAACT CTCAAATTCTGAGGGACTACTGGAAAGCTCTGTGTAATTTATAATTTCTTTTTCATGA

AAAATCATTTTGAGAACTCACATAGAAGATTGGAATTTGCAATTCCAATGCTGTGTAT

AAATCAACCTTCTCAGATGCTTTGCTGACTAATGTTGACCAGATTGTCCAGGAAAC

ORF Start: ATG at 380 ORF Stop: TGA at 2678

SEQ ID NO: 80 766 aa MW at 84690.6kD

NOV30a, MEKILFYLFLIGIAVIs^QICPI jRCVCQI SPNLATLCAKKGLLFVPPNIDRRTVELRL CGI 07562-01 ADNFVTNI R- FANMTS VDLT SR TISFITPHAFAD RWLPJUJHLNSISTRLTKITN

D FSGLSNLHH ILNNNQLTLISSTAFDDVFALEELD SΗSTNLETIP DAVEKMVSLH Protein Sequence TLSLDHNMIDNIPKGTFSHLHKMTRLDVTSNK QKLPPDP FQRAQV ATSGIISPST FALSFGGNPLHCNCE L LRRLSREDDLETCASPPL TGRYFWSIPEEEFLCEPP IT RHTHEMRVLEGQRATLRCKARGDPEPAIH ISPEGK ISNATRSLVYDNGTLDI ITT VKDTGAFTCIASNPAGEATQIVDLHIIKLPHL NSTNHIHEPDPGSSDISTSTKSGSN TSSSNGDT LSQDKIWAEATSSTA LKFNFQRNIPGIRMFQIQY GTYDDT VYRMI PPTSKTFLVMST AAGTI RY L CVLAIYDDGITSLTATRVVGCIQFTTEQDYVRCHFMQS QFLGGTMIIIIGGIIVASVLVFIIIL IRYKVCRØSNGQHKV'TKVSNVYSQTNGAQIQG CSVTLPQSVSKQAVGHEENAQCCKATSDNVIQSSETCSSQDSSTTTSALPPS TSSTS VSQKQKRKTGTKPSTEPQNEAVTNVESQNTNRNNSTA QLASRPPDSVTEGPTSKRAH IKPSKFITLPAERSGARH YS NGELKEYYCYINSPNTCGLFPKRSMSMNV FIQSDC! SDGHSGKAT KF

SEQ ID NO: 81 2388 bp

NOV30b, GCTCTTAAACCTGATCTACAATGGAAAAAATTCTTTTTTATCTGTTTCTCATTGGCAT CGI 07562-02 AGCAGTGAAAGCTCAGATCTGTCCAAAGCGTTGTGTCTGTCAGATTTTGTCTCCTAAT CTTGCAACCCTTTGTGCCAAGAAAGGGCTTTTATTTGTTCCACCAAACATTGACAGAA DNA Sequence GAACTGTGGAACTGCGGTTGGCAGACAATTTTGTTACAAATATTAAAAGGAAAGATTT TGCCAATATGACCAGCTTGGTGGACCTGACTCTATCCAGGAATACAATAAGTTTTATT ACACCTCATGCTTTCGCTGACCTACGAAATTTGAGGGCTTTGCATTTGAATAGCAACA GATTGACTAAAATTACAAATGATATGTTCAGTGGTCTTTCCAATCTTCATCATTTGAT ACTGAACAACAATCAGCTGACTTTAATTTCCTCTACAGCGTTTGATGATGTCTTCGCC CTTGAGGAGCTGGATCTGTCCTATAATAATCTAGAAACCATTCCTTGGGATGCTGTTG AGAAGATGGTTAGCTTGCATACCCTTAGTTTGGATCACAATATGATTGATAACATTCC TAAGGGGACCTTCTCCCATTTGCACAAGATGACTCGGTTAGATGTGACATCAAATAAA TTGCAGAAGCTACCACCTGACCCTCTCTTTCAGCGAGCTCAGGTACTAGCAACCTCAG GAATCATAAGCCCATCTACTTTTGCATTAAGTTTTGGTGGAAACCCCTTGCATTGCAA TTGTGAATTGTTGTGGTTGAGGCGTCTGTCCAGAGAAGATGACTTAGAGACCTGTGCT TCTCCTCCACTTTTAACTGGCCGCTACTTTTGGTCAATTCCTGAAGAAGAGTTTTTGT GTGAGCCTCCTCTCATTACTCGTCATACACATGAGATGAGAGTCCTGGAGGGACAAAG GGCAACACTGAGGTGCAAAGCCAGGGGAGACCCTGAGCCTGCAATTCACTGGATTTCT CCTGAAGGGAAGCTTATTTCAAATGCAACAAGATCTCTGGTGTATGATAACGGAACAC TTGACATTCTTATCACAACTGTAAAGGATACAGGTGCTTTTACCTGCATTGCTTCCAA TCCTGCTGGGGAAGCAACACAAATAGTGGATCTTCATATAATTAAGCTCCCTCACTTA CTAAATAGTACAAACCATATCCATGAGCCTGATCCTGGTTCTTCAGATATCTCAACTT CTACCAAGTCAGGTTCTAATACAAGCAGTAGTAATGGTGATACTAAATTGAGTCAAGA TAAAATTGTGGTGGCAGAAGCTACATCATCAACGGCACTACTTAACTTTACTTTTCAA AGAACTATCCCTGGAATACGTATGTTTCAAATCCAGTACAATGGTACTTATGATGACA CCCTTGTTTACAGGATGATACCTCCTACGAGCAAAACTTTTCTGGTCAATAATCTGGC TGCTGGAACTATGTATGACTTGTGTGTCTTGGCCATATATGATGATGGCATCACTTCC CTCACTGCCACAAGAGTCGTGGGTTGCATCCAGTTTACTACGGAACAGGATTATGTGC GTTGCCATTTCATGCAGTCCCAGTTTTTGGGAGGCACCATGATTATTATTATTGGTGG AATCATTGTAGCATCTGTGCTGGTATTCATCATTATTCTGATGATCCGGTATAAGGTT TGCAACAATAATGGGCAACACAAGGTCACCAAGGTTAGCAATGTTTATTCCCAAACTA ACGGGGCTCAAATACAAGGCTGTAGTGTAACGCTGCCCCAGTCCGTGTCCAAACAAGC TGTGGGACACGAAGAGATTGCCCAGTGTTGTAAAGCTACCAGTGACAATGTGATTCAA TCTTCAGAAACTTGTTCGAGTCAGGACTCCTCTACCACTACCTCTGCTTTGCCTCCTT CCTGGACTTCAAGCACTTCTGTGTCCCAAAAGCAGAAAAGAAAGACTGGCACAAAGCC AAGTACAGAACCACAGAATGAAGCCGTCACAAATGTTGAATCCCAAAACACTAACAGG AACAACTCAACTGCCTTGCAGTTAGCTAGCCGTCCTCCCGATTCTGTCACAGAGGGGC CCACGTCTAAAAGAGCACATATAAAGCCAAATGCTTTGCTGACTAATGTTGACCAGAT TGTCCAGGAAACACAGAGGCTGGAGTTAATCTGAAGAGCACCACTTCTCCTCTCTCTC

CTGAAAAAATTTGCCACTGATATTTTTACTGGATAAAATTCAAAAATGTTTCAATTCA

CAAAGGCTAATTGTTGAACTGGTGTCGTAGAAGAAATTGTCTACAGGAGCCAAGGTGA

AAGTCTCTGATGACGGCGGAACTGGCTCCATTAGACCATGGTTCATCCTCTTTTAAAA

ACAAATTTTT

ORF Start: ATG at 21 ORF Stop: TGA at 2178

SEQ ID NO: 82 719 aa MW at 79402.7kD

NOV30b, ME IIiFY FLIGIAVKAQICPKRCVCQILSPNLAT CAK G FVPPNIDRRTVE RL CGI 07562-02 ADNFVTNI RKDFAlsMTS VDLT SRlsTTISFITPHAFAD Rl^RALHLNSNRLTKITN DMFSGLSNLHHLILNlSπsIQLTLISSTAFDDVFA EELD SYNNLETIP DAVΞKMVSLH Protein Sequence TLSLDHNMIDNIPKGTFSH HKMTRLDVTSNKLQK PPDPLFQRAQVLATSGIISPST FALSFGGNPLHCNCE L LRRLSREDDLETCASPPL TGRYFWSIPΞEEFLCEPPLIT RHTHEMRVLEGQRATLRCKARGDPEPAIH ISPEGK ISNATRSLVYDNGT DI ITT VKDTGAFTCIASNPAGEATQIVDLHIIKLPH LNSTNHIHEPDPGSSDISTSTKSGSN TSSSNGDTKLSQDKIWAEATSSTALLNFTFQRTIPGIRMFQIQYNGTYDDTLVYRMI PPTSKTF VHNLAAGTI^TDLCV AIYDDGITSLTATRVVGCIQFTTEQDYVRCHFMQS QFLGGTMIIIIGGIIVASV VFIIILMIRY VCNNNGQHKVTKVSNVYSQTNGAQIQG CSVTLPQSVSKQAVGHEEIAQCCKATSDNVIQSSETCSSQDSSTTTSALPPS TSSTS VSQKQKRKTGTKPSTEPQNEAVTNVESQNTNRNNSTALQASRPPDSVTEGPTSKRAH IKPNAL T VDQIVQETQRLΞLI

SEQ ID NO: 83 1545 bp

NOV30c, GGATCCCAGATCTGTCCAAAGCGTTGTGTCTGTCAGATTTTGTCTCCTAATCTTGCAA 210086373 DNA CCCTTTGTGCCAAGAAAGGGCTTTTATTTGTTCCACCAAACATTGACAGAAGAACTGT GGAACTGCGGTTGGCAGACAATTTTGTTACAAATATTAAAAGGAAAGATTTTGCCAAT Sequence ATGACCAGCTTGGTGGACCTGACTCTATCCAGGAATACAATAAGTTTTATTACACCTC ATGCTTTCGCTGACCTACGAAATTTGAGGGCTTTGCATTTGAATAGCAACAGATTGAC TAAAATTACAAATGATATGTTCAGTGGTCTTTCCAATCTTCATCATTTGATACTGAAC AACAATCAGCTGACTTTAATTTCCTCTACAGCGTTTGATGATGTCTTCGCCCTTGAGG AGCTGGATCTGTCCTATAATAATCTAGAAACCATTCCTTGGGATGCTGTTGAGAAGAT GGTTAGCTTGCATACCCTTAGTTTGGATCACAATATGATTGATAACATTCCTAAGGGG ACCTTCTCCCATTTGCACAAGATGACTCGGTTAGATGTGACATCAAATAAATTGCAGA

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 30B.

Further analysis of the NOV30a protein yielded the following properties shown in Table 30C.

Table 30C. Protein Sequence Properties NOV30a

PSort 0.6850 probability located in endoplasmic reticulum (membrane); 0.6400 analysis: probability located in plasma membrane; 0.4600 probability located in Golgi body; 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 18 and 19 analysis:

A search of the NOV30a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 30D.

Table 30D. Geneseq Results for NOV30a

NOV30a Identities/

Geneseq Protein/Organism/Length [Patent Residues/ Similarities for Expect Identifier #, Date] Match the Matched Value Residues Region

AAG67505 j Amino acid sequence of a human 1..766 765/766 (99%) 0.0 secreted polypeptide - Homo 1..766 1661166 (99%) sapiens, 766 aa. [WO200166690- A2, 13-SEP-2001]

AAB09968 I Human brain-specific 1..756 374/780 (47%) 0.0 j transmembrane glycoprotein - 1..770 505/780 (63%) Homo sapiens, 789 aa. [WO200031256-A1, 02-JUN-2000]

AAM39059 J Human polypeptide SEQ ID NO 1..756 373/780 (47%) 0.0 2204 - Homo sapiens, 789 aa. 1..770 504/780 (63%) [WO200153312-A1, 26-JUL-2001]

AAU28092 1 Novel human secretory protein, Seq 1..756 373/780 (47%) 0.0 ID No 261 - Homo sapiens, 789 aa. 1..770 504/780 (63%) [WO200166689-A2, 13-SEP-2001]

AAB 12448 Human hh00149 protein SEQ ID 20..756 368/760 (48%) 0.0 NO:4 - Homo sapiens, 785 aa. 17..766 497/760 (64%) [WO200031255-A1, 02-JUN-2000]

In a BLAST search of public sequence databases, the NOV30a protein was found to have homology to the proteins shown in the BLASTP data in Table 30E.

PFam analysis predicts that the NOV30a protein contains the domains shown in the Table 30F.

Example 31.

The NOV31 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 31 A.

Table 31A. NOV31 Sequence Analysis

SEQ ID NO: 89 1220 bp

NOV31a, TCATGGCGCTGGCGGGCTTGGCCATGGGCTGCATCGACACCGTGGCCAACATGCAGC CGI 08184-01 GGTAAGGATGTACCAGAAGGACTCGGCCGTCTTCCTCCAGGTGCTCCATTTCTTCGTG GGCTTTGGTGCTCTGCTGAGCCCCCTTATTGCTGACCCTTTCCTGTCTGAGGCCAACT DNA Sequence GCTTGCCTGCCAATAGCACGGCCAACACCACCTCCCGAGGCCACCTGTTCCATGTCTC CAGGGTGCTGGGCCAGCACCACGTAGATGCCAAGCCTTGGTCCAACCAGACGTTCCCA GGGCTGACTCCAAAGGACGGGGCAGGGACCCGAGTGTCCTATGCCTTCTGGATCATGG CCCTCATCAATCTTCCAGTGCCCATGGCTGTGCTGATGCTGCTGTCCAAGGAGCGGCT GCTGACCTGCTGTCCCCAGAGGAGGCCCCTGCTTCTGTCTGCTGATGAGCTTGCCTTG GAGACACAGCCTCCTGAGAAGGAAGATGCCTCCTCACTGCCCCCAAAGTTTCAGTCAC ACCTAGGTCATGAGGACCTGTTCAGCTGCTGCCAAAGGAAGAACCTCAGAGGAGCCCC TTATTCCTTCTTTGCCATCCACATCACGGGCGCCCTGGTACTGTTCATGACGGATGGG TTGACGGGTGCCTATTCCGCCTTCGTGTACAGCTATGCTGTGGAGAAGCCCCTGTCTG TGGGACACAAGGTGGCTGGCTACCTCCCCAGCCTCTTCTGGGGCTTCATCACACTGGG CCGGCTCCTCTCCATTCCCATATCCTCAAGAATGAAGCCGGCCACCATGGTTTTCATC AACGTGGTAGGCGTGGTGGTGACGTTCCTGGTGCTGCTTATTTTCTCCTACAACGTCG TGTTCCTGTTCGTGGGGACGGCAAGCCTGGGCCTGTTTCTCAGCAGCACCTTCCCCAG CATGCTGGCCTACACGGAGGACTCGCTGCAGTACAAAGGCTGTGCAACCACAGTGCTG GTGACAGGGGCAGGAGTTGGCGAGATGGTGCTGCAGATGCTGGTTGGTTCGATATTCC

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 3 IB.

Further analysis of the NO V3 la protein yielded the following properties shown in Table 31C.

Table 31C. Protein Sequence Properties NOV31a

PSort J 0.6000 probability located in plasma membrane; 0.4445 probability located in analysis: mitochondrial inner membrane; 0.4000 probability located in Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane)

SignalP j Cleavage site between residues 50 and 51 analysis:

A search of the NO V3 la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3 ID.

In a BLAST search of public sequence databases, the NOV31 a protein was found to have homology to the proteins shown in the BLASTP data in Table 3 IE.

Example 32.

The NOV32 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 32A.

GCGAGGGATGAAGGGGAATTCACCTGCCGAGCTCAGAACCCTCGGGGCTCCCAGCACA TTTCCCTGAGCCTCTCCCTGCAGAATGAGGGCACAGGTACCACATGGCCTGTATCAGG AGTGATGCTGGGGGTGGTCGGGGGAGCTGGAGCCACAGCCCTGGTCTTCCTGTCCTTC TGCGTCATCTTCATCGTGGTGAGGTCCTGCAGGAAGAAATCAGCAAGGCCAGCAGCGG GCATCAGGGATATGGGCATGGAGGATGCAAACGCTGTCAGGGGCTCAGCCTATCAGCA GGGACCCCTGACTGAATCCTGGACAGACGGCAGCCCCCCGAAGCATCCTCCCATGGCT GCCTCCTCCTTAGGAGAAGGAGAGCTCCAGCATGCAACCCTCAGCTTCCATAAGGTCA GGCCTCAGAACGCGCAGGGACAGGAGGCCATGGACAGTGAATACTTGGAGATCAAGAT CCACAAGCGAGAAACTGCAGAGACTCGGGCCTGATTGGGGGATCACGGTCCCTCCAGG

CAAAGGAGAAGTCAGAAGCTGATTCTTCTAAAATTAACAGCCCTCTAGA

ORF Start: ATG at 51 ORF Stop: TGA at 1482

SEQ ID NO: 96 477 aa MW at 51555.7kD

NOV32a, MLLLLPLL GREGVEGQGQQENGYTLQVQREVRVQEGLCVHVPSSFSHPQVALTNSPQ CG108238-01 VHGY FQEGADTAQDAPMATNNP RKVKKETQGRFRLSGNLQMNDCSLSIGDARRKDQ GSFSFFRMERGSMRWNYASNQLHVLVTALTHRPNISSLGTMESGRPGNLTCSVS ACE Protein Sequence QGIPLPSIS MGTSVSFPGRTTARSSVLTLIPKPQDHGTNLTCQVTLPEAGVTLTRTV QFNASDPPQNLTVAIFQADGTASTALGNSSSLSVLEGQSLRLVCAVDSNPPARLSWTQ GSLTLSPSQSSNHGLL LPRVHARDEGEFTCRAQNPRGSQHISLSLSLQNEGTGTT P VSGVMLGWGGAGATALVFLSFCVIFIWRSCRK SARPAAGIRDMGMEDANAVRGSA YQQGPLTESWTDGSPPKHPPMAASSLGEGELQHATLSFHKVRPQNAQGQEAMDSEYLE IKIHKRETAETRA

Further analysis of the NOV32a protein yielded the following properties shown in Table 32B.

Table 32B. Protein Sequence Properties NOV32a

PSort 0.7000 probability located in plasma membrane; 0.3000 probability located in analysis: microbody (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

SignalP Cleavage site between residues 17 and 18 analysis:

A search of the NOV32a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 32C.

In a BLAST search of public sequence databases, the NOV32a protein was found to have homology to the proteins shown in the BLASTP data in Table 32D.

PFam analysis predicts that the NOV32a protein contains the domains shown in the Table 32E.

Example 33.

The NOV33 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 33A. Table 33A. NOV33 Sequence Analysis

SEQ ID NO: 97 1494 bp

NOV33a, TTTAATGCACAGATATAATACAGGAGTATGCTAGGTGGGTCTGTTTTTCAACTTGGAT CG108695-01 CTCTCCTTACAGGGCTACTTTCTCATGTTTTGATGGAAGTCAAGAAGATACCAGTGGA AGAGGGGCTGTGCACTACAATCCCTTGTGCATTTGAATTTCCCAGAGAACCCCCAAGC DNA Sequence AATTCCATGATCATGCACTACTGGCTCAACAAAAACATCAGCTCCCTGGTAGCTACAA ATAAACCCAATGCTACCATTGGTGATAACACCAAGGACAAATTTTACATGACTGGGAA TCTTGATGAAGAAGACTGTACCCTACTCATCCACGATATACTCAAAGGGAACAGCATA ACATATTTATTCTACGCAGATCTAGGAGAACAAAAAAGTGCTTTCCTGGGGGAGAATA TCAAACTTACCCAAAAGCCAGAGCTCCACATGCCAGAGATTCTTTTGGCTGAGAAGAC TGTGACCTTGAACTGTACCCTCAAAGGCACCTGCAAAGAAACCAAAGCCCTCTTCCAC TCCCGGAAGAACCCAGCCATCTCCAGCAGCTCCTCCTCGGTGCTGCACTTCACCCTGA GGCCTGAGGACCATGGCAACACCCTTGGATGTCACTTGAACTTATCCCTAGCCAACGT GACCAGAAGTAGCTTGGTCAAGCTCCAAGTGGTCTGTGAGTGCTGGGCACCTGCCAGG TTGTTCAATTCCTCTTGTTCCTTGGAGAAGACAGTTCTGTGCAGCTGTTCCTTCCACG GGATCCCCACGCCCTCCGTGCAGTGGTGGATGGGAGGTGTCCCTGTGGCTGTGAACAG CATGGATAACATCCTCCGGGTGACTTCTTCCACATGTGCCCCCTGGGCCAACAGCACC ATCAGCCTCATTGGGGAGCCAGAAAGAGTCATGAGACTTCACTGTGAGGGGAAGAACC AATATGGAATTCACACTTCCAGCATCTTCCTGCTTAGAATGAAGATGCTTACCTGGTG GGAGGAGCATCAGAGTCCCAAGGCCAAAGAAGGCTTGCCCCTTAAGAAACCAGAGCTG CTGGAGGAAACAGAAGTACCCAAAATGCCTGAAGCTGACACCCCACCAGACCGGGCTG GAGGTAAGTCCCTGGGACAGTCACAGGCAGACTGTCAAGCAACAGGGCCGCAGGCCAG GGCTCCCACCCCATCACCTGGCAGAACCCCGGGGAGGCACTTGTTCAGGACGGAGAGA CCCAGGCCCCCTCGCCCCACACAGCAGATGCTACATTTGCCAAAACAAAGCCCCACAG ACTGGGCGGCTTGAACGGCAGATACTGATTTTCTCCCCCTCTGGAGGCTGGAAATCCC

AGGTCAAGGTGCCAGCAGCAGAGCTTCCTTCTGAGGCCTCTCACCTTGGCCGGTAGAT

GCTGTCTTCTCCCTGTGTCCTCACAGGGTCATCCCTCTGCGTGTGCCTGGGTCCTAAT

TTCCTTCCCTTGTAAGGACACCAGTCATTGAATTCAGGCCCATC

ORF Start: ATG at 28 ORF Stop: TGA at 1288

SEQ ID NO: 98 420 aa MW at 46435.0kD

NOV33a, MLGGSVFQLGSLLTGLLSHVLMEVKKIPVEEGLCTTIPCAFEFPREPPSNSMIMHYWL CG108695-01 NKNISSLVATNKPNATIGDNTKDKFYMTGNLDEEDCTLLIHDILKGNSITYLFYADLG EQKSAFLGENIKLTQKPELHMPEILLAEKTVTLNCTLKGTCKETKALFHSRKNPAISS Protein Sequence SSSSVLHFTLRPEDHGNTLGCHLNLSLANVTRSSLVKLQVVCΞCWAPARLFNSSCSLE KTVLCSCSFHGIPTPSVQWWMGGVPVAVNSMDNILRVTSSTCAPWANSTISLIGEPER VMRLHCEGKNQYGIHTSSIFLLRMKMLTW EEHQSPKAKEGLPLKKPELLEETEVPKM PEADTPPDRAGG SLGQSQADCQATGPQARAPTPSPGRTPGRHLFRTERPRPPRPTQQ MLHLPKQSPTD AA

Further analysis of the NOV33a protein yielded the following properties shown in Table 33B.

Table 33B. Protein Sequence Properties NO 33a

PSort 30.4500 probability located in cytoplasm; 0.3000 probability located in analysis: I microbody (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP I Cleavage site between residues 23 and 24 analysis:

A search of the NOV33a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 33C.

In a BLAST search of public sequence databases, the NOV33a protein was found to have homology to the proteins shown in the BLASTP data in Table 33D.

Example 34.

The NOV34 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 34A.

Table 34A. NOV34 Sequence Analysis

SEQ ID NO: 99 1152 bp

NOV34a, TGGGACCACGTGGGGATGCTGCCGTGGCTTCTTGTCTTCTCTGCTCTGGGTCTCCAGG CG109505-01 CCTGGGGTTCTTTCTCCTGGAGTGAGACCCAAGCCAGAGGCTTGTCCCAGAGGCTTAT GGACCTGTTTGTCAGCATCTCACAGTTCATTCACAAGGATACTCCCACCATCGTCTCC DNA Sequence CGCAAGGAGTGGGGGGCAAGACCGCTCGCCTGCAGGGCCCTGCTGACCCTGCCTGTGG CCTACATCATCACAGACCAGCTCCCAGGGATGCAGTGCCAGCAGCAGAGCGTTTGCAG CCAGATGCTGCGGGGGTTGCAGTCCCATTCCGTCTACACCATAGGCTGGTGCGACGTG GCGTACAGCTTCCTGGTTGGGGATGATGGCAGGGTGTATGAAGGTGTTGGCTGGAACA TCCAAGGCTTGCACACCCAGGGCTACAACAACATTTCCCTGGGCATCGCCTTCTTTGG CAATAAGAAGGGTCACTCCCCCAGCCCTGCTGCCTTATCAGCTGCAGAGGGTCTGATC TCCTATGCCATCCAGAAGGGTCACCTGTCGCCCAGGTATATTCAGCCACTTCTTCTGA AAGAAGAGACCTGCCTGGACCCTCAACATCCAGTGATGCCCAGGAAGCAGCTTGCCCC GGCGTTGTCCCACGGTCTGTGTGGGGAGCCAGGGAGACCCTTATCAAAAATGAACCTC CCAGCCAAATATGTCATCATCATCCACACCGCTGGCACAAGCTGCACTGTATCCACAG ACTGCCAGACTGTCGTCCGAAACATACAGTCCTTTCACATGGACACACGGAACTTTTG TGACATTGGATATAGCTTCCTGGTGGGCCAGGATGGTGGCGTGTATGAAGGGGTTGGA TGGCACATCCAAGGCTCTCACACTTATGGATTCAACGATATTGCCCTAGGAATTGCCT TCATCGGCATCCCCTACTTTGTAGGTCCAAATGCTGCAGCGCTGGAGGCGGCCCAGGA CCTGATCCAGTGTGCCGTGGTTGAGGGGTACCTGACTCCAAACTACCTGCTGATGGGC

Further analysis of the NOV34a protein yielded the following properties shown in Table 34B.

Table 34B. Protein Sequence Properties NOV34a

PSort 1 0.3894 probability located in outside; 0.1213 probability located in microbody analysis : j (peroxisome); 0.1000 probability located in endoplasmic reticulum

(membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 18 and 19 analysis:

A search of the NOV34a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 34C.

In a BLAST search of public sequence databases, the NOV34a protein was found to have homology to the proteins shown in the BLASTP data in Table 34D.

Example 35.

The NOV35 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 35 A.

GGTAGCATCGGCACTGCCTGGGGCCAGAGCAAGTGCCACAAGTGTCCCCAGCTGCAGT ACACAGGAGTGCAGAAGCCAGGGCCTGTACGTGGGGAAGTGGGCGCTGACTGTCCCCA GGGCTACAAGAGGCTTAACAGCACCCACTGCCAGGACATCAACGAGTGCGCAATGCCG GGCGTGTGTCGCCATGGTGACTGCCTCAACAACCCTGGCTCCTATCGCTGTGTCTGCC CACCTGGCCATAGTTTAGGCCCCTCCCGTACACAGTGCATTGCAGACAAACCGGAGGA GAAGAGCCTGTGTTTCCGCCTGGTGAGCCCTGAGCACCAGTGCCAGCACCCACTGACC ACCCGCCTGACCCGCCAGCTCTGCTGCTGCAGTGTCGGCAAGGCCTGGGGCGCGCGGT GTCAGCGCTGCCCAACAGATGGCACCGCTGCGTTCAAGGAGATCTGCCCAGCTGGGAA GGGATACCACATTCTCACCTCCCACCAGACGCTCACCATTCAGGGCGAGAGTGACTTT TCCCTTTTCCTGCACCCTGACGGGCCACCCAAGCCCCAGCAGCTTCCGGAGAGCCCTA GCCAGGCTCCACCACCTGAGGACACAGAGGAAGAGAGAGGGGTGACCACGGACTCACC GGTGAGTGAGGAGAGGTCAGTGCAGCAGAGCCACCCAACTGCCACCACGACTCCTGCC CGGCCCTACCCCGAGCTGATCTCCCGTCCCTCGCCCCCGACCATGCGCTGGTTCCTGC CGGACTTGCCTCCTTCCCGCAGCGCCGTAGAGATCGCTCCCACTCAGGTCACAGAGAC TGATGAGTGCCGACTGAACCAGAACATCTGTGGCCACGGAGAGTGCGTGCCGGGCCCC CCTGACTACTCCTGCCACTGCAACCCCGGCTACCGGTCACATCCCCAGCACCGCTACT GCGTGGATGTGAACGAGTGCGAGGCAGAGCCCTGTGGCCCGGGGAGGGGCATCTGCAT GAACACCGGCGGCTCCTACAATTGCCACTGCAACCGCGGCTACCGCCTGCACGTGGGC GCCGGGGGGCGCTCGTGCGTGGACCTGAACGAATGCGCCAAGCCCCACCTGTGCGGCG ACGGCGGCTTCTGCATCAACTTTCCCGGTCACTACAAGTGCAACTGCTACCCCGGCTA CCGGCTCAAAGCCTCCCGGCCTCCTGTGTGCGAAGACATCGACGAGTGCCGGGACCCA AGCTCTTGCCCGGATGGCAAATGCGAGAACAAGCCCGGGAGCTTCAAGTGCATCGCCT GTCAGCCTGGCTGGTGCGAGAACCTCCCGGGCTCCTTCCGCTGCACCTGTGCCCAGGG CTACGCGCCCGCGCCCGACGGCCGCAGTTGCTTGGATGTGGACGAGTGTGAGGCTGGG GACGTGTGTGACAATGGCATCTGCAGCAACACGCCAGGATCTTTCCAGTGTCAGTGCC TCTCTGGCTACCATCTGTCCAGGGACCGGAGCCACTGCGAGGACATTGATGAGTGTGA CTTCCCTGCAGCCTGCATTGGGGGTGACTGCATCAATACCAATGGCTCCTACAGATGT CTTTGCCCCCAGGGGCATCGGCTGGTGGGTGGCAGGAAATGCCAAGACATAGATGAGT GCAGCCAGGACCCGAGCCTGTGCCTTCCCCATGGGGCCTGCAAGAACCTTCAGGGCTC CTATGTGTGTGTCTGCGATGAGGGCTTCACTCCCACCCAGGACCAGCACGGTTGTGAG GAGGTGGAGCAGCCCCACCACAAGAAGGAGTGCTACCTGAACTTCGATGACACAGTGT TCTGCGACAGCGTATTGGCCACCAACGTGACCCAGCAGGAGTGCTGCTGCTCTCTGGG GGCCGGCTGGGGCGACCACTGCGAAATCTACCCCTGCCCAGTCTACAGCTCAGCCGAG TTCCACAGCCTCTGCCCAGACGGAAAGGGCTACACCCAGGACAACAACATCGTCAACT ACGGCATCCCAGCCCACCGTGACATCGACGAGTGCATGTTGTTCGGGTCGGAGATTTG CAAGGAGGGCAAGTGCGTGAACACGCAGCCTGGCTACGAGTGCTACTGCAAGCAGGGC TTCTACTACGACGGGAACCTGCTGGAATGCGTGGACGTGGACGAGTGCCTGGACGAGT CCAACTGCCGGAACGGAGTGTGTGAGAACACGCGCGGCGGCTACCGCTGTGCCTGCAC GCCCCCTGCCGAGTACAGTCCCGCGCAGCGCCAGTGCCTGAGCCCGGAAGAGATGGAG CGTGCCCCGGAGCGGCGCGACGTGTGCTGGAGCCAGCGCGGAGAGGACGGCATGTGCG CTGGCCCCCTGGCCGGGCCTGCCCTCACCTTCGACGACTGCTGCTGCCGCCAGGGCCG CGGCTGGGGCGCCCAATGCCGACCGTGCCCGCCGCGCGGCGCGGGGTCCCATTGCCCG ACATCGCAGAGCGAGAGCAATTCCTTCTGGGACACAAGCCCCCTGCTGTTGGGGAAGC CCCCAAGAGATGAGGACAGTTCAGAGGAGGATTCAGACGAGTGTCGCTGCGTGAGTGG CCGCTGCGTGCCGCGGCCGGGCGGCGCCGTGTGCGAGTGTCCCGGCGGCTTCCAGCTC GACGCCTCCCGCGCCCGCTGCGTGGATATCGACGAGTGCCGAGAGCTGAACCAGCGCG GGCTGCTGTGCAAGAGCGAGCGCTGCGTGAACACCAGCGGCTCCTTCCGCTGCGTCTG CAAAGCCGGCTTCGCGCGCAGCCGCCCGCACGGGGCCTGCGTTCCCCAGCGCCGCCGC TGACGCCGCCGACGCCGCCCTCGGCCCAGACCTCGGTGATCACTGAGGGATTTCCGCG

AGCTCGGCCTCACTTCTGCCCCGACTTGTGGCTCGGACCCAGGGACCTTCAGGGCCCG

CAGACCCTCCCGGCGCCTTGAGACCCGAGGCGCCCCTACCGGCCCCCCTCCCCGGTTA

GCGGGCGGTTGTAAGGTCTCCGGCGGGCGCTGCCTGCCTTCCTCCCAGAGGGTGTTTC

CTAGAAACTGATAAATCAGATCGTGCCTCTTTACCCTTGGCTTTCGAAAAAAAAAAAA

AAAAAA

ORF Start: ATG at 1 JORF Stop. TGA at 3655

SEQ ID NO: 102 1218 aa MW at 130645.3kD

NOV35a, MRGAGAAGLLALLLLLLLLLLGLGGRVEGGPAGERGAGGGGALARERF WFAPVICK CG109742-01 RTCLKGQCRDSCQQGSNMTLIGΞNGHSTDTLTGSGFRWVCPLPCMNGGQCSSRNQCL CPPDFTGRFCQVPAGGAGGGTGGSGPGLSRTGALSTGALPPLAPΞGDSVASKHAIYAV

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 35B.

Further analysis of the NOV35a protein yielded the following properties shown in Table

35C.

Table 35C. Protein Sequence Properties NOV35a

PSort 0.8200 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1000 probability located in endoplasmic reticulum (membrane); ! 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 30 and 31 analysis:

A search of the NOV35a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 35D.

In a BLAST search of public sequence databases, the NOV35a protein was found to have homology to the proteins shown in the BLASTP data in Table 35E.

PFam analysis predicts that the NOV35a protein contains the domains shown in the Table 35F.

Example 36.

The NOV36 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 36 A.

Table 36A. NOV36 Sequence Analysis

SEQ ID NO: 111 1846 bp

NOV36a, ATCATGCACTCCCAGAGACCTCCACTTGCACTCCTTGAGGGCTCCACCCTCGATAGAA CGI 09844-01 AAGGAGAAATCGCAGCTTCACTCGTCTCTAGGCTGTGGAAAGTCTCCAATTCAACTCT GTTCCAAATGATGCTGGTCACTGTTTTGTTGGCTACCATTCTTGGTGACTGTGGTCCT DNA Sequence CCACCTGAGTTACCATTTGCTTTTCCAATAAATCCGTTGTATGATACTGAATTCAAAA CTGGAACTACTCTGAAGTACACCTGCCACCCTGGGCATGGTAAAATCAATTCAAGTCG ACTGATTTGTGATGCCAAAGACTCGTGGAACTATAGTATCTTTTGTGCAAGTAAGCGA TGCAGAAATCCAGAATTAATCAATGGGATAGTGGAAGTTAAAAAAGATCTTCTCCTTG GTTCAACCATAAAATTCAGCTGCTCAGAGGGGTTTTTCTTAATTGGCTCAACCACCAG TCATTGTCAGATCCAAGGTAAAGGAGTTGATTGGAGTGATCCTCTCCCAGAAACCTCA GTTGCCAAGTGCGAGCCCCCTCCAGACATCAGGAATGGGAAGCACAGCGGTGGAGATC AAGAATTCTACACATATGCCTCCTCTGTCACCTACAGCTGCAACCCCTACTTCTCACT CATAGGCAACGTCTCCATCTCCTGCACCGTGGAGAATGAAACAATAGGTGTCTGGAGC CCAAACCCTCCTATCTGTGAAGAAATTGTCTGTCGTCGACCACAGATTCCAAAGGCAA TCTTTGTTTCTGGATTTGGACCCCTCTATACTTACAAAGACTCTATTATGGTTAACTG TGAGGAAGGTTATATCCTCAGAGGCAGCAGTTTAATCTATTGTGAAACGAATAATGAG TGGTATCCTTCTGTTCCCTCTTGCAGAGTGAATGGTTGCACTGTCCTACCGGACATTT CCTATGCTTCCTGGGAGAGAAATGACTACAACCTAAGTGATCACGAAATATTTGAAAT TGGAACTGAGTTGAAATATCTATGCAAACCTGGCTATAGACCTGTTTTAGATGAGCCT CTGACTGTGACTTGTCAGGAAAATTTGACATGGACATCTTCCAATGAGTGTGAGAGTG TATGTTGCCCAACACCAGATCTGGAGAATATCAGAATCATAAATGAAAGGAGGTATTT CACTGGTAGATGTGTCTATGCCTATGGAGACTATATTTCATATATGTGTGATGAAGGC TATTACCCTATTTCTGTTGACGGGGAGAGTTCCTGCCACACAGATGGCACATGGAAGC CTAAAATGCCAGCATGTGAGCCAGGTTGCAGTTTTGCCCCTAGTTTTGCCCATGGGCA TCCTAAACAAGTTAATTTATGCAACTGTTTCAAAAATGAGGCTGTATATAAATGTGAT GAAGGCTACACTGTGATCGGACAGGTGAAACTCACCTGCATTTCTTCCTGCTGGTCAT CTCCAGCCCCTCAATGTAAAAGTCTGTGTCTGAAACCAGAAATAGTGAATGGAAGGCT GTCTGTGGATAAGGATCAGTATGTTGAGTCTGAAAATGTTACCATTGAATGTGATTCT GGCTATGGTGTGGTTGGTCTCAAAAGTATCACTTGCTCAGAGAAGAGAACCTGGTACC CAGAAGTGCCCAGGTGTGAGTGGGAGGCACCTGAAGGTTGTGAGCAAGTGCTCACAGG CAGAAAACTCATGCAGTGTCTCCCAAGCCCAGAGGATGTGAAAGTGGCCCTGGAGGTG TATAAGCTGTCTCTGGAGATAAAACAACTTGAAAAAGAGAGAGACAAATTGATGAACA CCCATCAGAAATTTTCTGAAAAAGAGGAATGAAGGACTTATTTTTCCC

ORF Start: ATG at 4 ORF Stop: TGA at 1828

SEQ ID NO: 112 608 aa MW at 68085.6kD

NOV36a, MHSQRPPLALLEGSTLDRKGEIAASLVSRL VSNSTLFQMMLVTVLLATILGDCGPP CGI09844-01 PELPFAFPINPLYDTEFKTGTTLKYTCHPGHGKINSSRLICDAKDS NYSIFCAS RC RNPELINGIVEVKKDLLLGSTIKFSCSEGFFLIGSTTSHCQIQGKGVDWSDPLPETSV Protein Sequence AKCEPPPDIRNGKHSGGDQEFYTYASSVTYSCNPYFSLIGNVSISCTVENETIGVWSP NPPICEEIVCRRPQIPKAIFVSGFGPLYTYKDSIMVNCEEGYILRGSSLIYCETNNE YPSVPSCRVNGCTVLPDISYAS ERNDYNLSDHEIFEIGTELKYLCKPGYRPVLDEPL TVTCQENLTWTSSNECESVCCPTPDLENIRIINERRYFTGRCVYAYGDYISYMCDEGY YPISVDGESSCHTDGT KPKMPACEPGCSFAPSFAHGHPKQVNLCNCFKNEAVY CDE GYTVIGQVKLTCISSC SSPAPQCKSLCLKPEIVNGRLSVDKDQYVESENVTIECDSG YGWGLKSI CSEKRT YPEVPR_CE EAPEGCEQVLTGRKLMQCLPSPEDVKVALEVY

KLSLEIKQLEKΞRDKLMNTHQ FSEKEE Further analysis of the NOV36a protein yielded the following properties shown in Table 36B.

Table 36B. Protein Sequence Properties NOV36a

PSort 0.7900 probability located in plasma membrane; 0.3000 probability located in analysis: microbody (peroxisome); 0.3000 probability located in Golgi body; 0.2000 probability located in endoplasmic reticulum (membrane)

SignalP Cleavage site between residues 54 and 55 analysis:

A search of the NOV36a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 36C.

In a BLAST search of public sequence databases, the NOV36a protein was found to have homology to the proteins shown in the BLASTP data in Table 36D.

PFam analysis predicts that the NOV36a protein contains the domains shown in the Table 36E.

Example 37.

The NO V37 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 37 A.

Table 37A. NOV37 Sequence Analysis

SEQ ID NO: 113 2974 bp

NOV37a, CGGGGACTCGGAGGTACTGGGCGCGCGCGGCTCCGGCTCGGGACGCCTCGGGACGCCT CGI 10014-02 CGGGGTCGGGTTCCGGTTGCGGCTGCTGCTGCGGCGCCCGCGCTTCCGTAGCGTTCCG

CCTCCTGTGCCCGCCGCGGAGCAAGTCTGCGCGCCCGCCGTGCGCCCCTAAGCTCCTT DNA Sequence TTACCTGAGCCCGCCGCGATGGGAGCTGCGCGGGGATCCCCGGCCAGACCCCGCCGGT

TGCCTCTGCTCAGCGTCCTGCTGCTGCCGCTGCTGGGCGGTACCCAGACAGCCATTGT CTTCATCAAGCAGCCGTCCTCCCAGGATGCACTGCAGGGGCGCCGGGCGCTGCTTCGC TGTGAGGTTGAGGCTCCGGGCCCGGTACATGTGTACTGGCTGCTCGATGGGGCCCCTG TCCAGGACACGGAGCGGCGTTTCGCCCAGGGCAGCAGCCTGAGCTTTGCAGCTGTGGA CCCGCTGCAGGACTCTGGCACCTTCCAGTGTGTGGCTCGGGATGATGTCACTGGAGAA GAAGCCCGCAGTGCCAACGCCTCCTTCAACATCAAATGGATTGAGGCAGGTCCTGTGG TCCTGAAGCATCCAGCCTCGGAAGCTGAGATCCAGCCACAGACCCAGGTCAAACTTCG TTGCCACATTGATGGGCACCCTCGGCCCACCTACCAATGGTTCCGAGATGGGACCCCC CTTTCTGATGGTCAGAGCAACCACACAGTCAGCAGCAAGGAGCGGAACCTGACGCTCC GGCCAGCTGGTCCTGAGCATAGTGGGCTGTATTCCTGCTGCGCCCACAGTGCTTTTGG CCAGGCTTGCAGCAGCCAGAACTTCACCTTGAGCATTGCTGATGAAAGCTTTGCCAGG GTGGTGCTGGCACCCCAGGACGTGGTAGTAGCGAGGTATGAGGAGGCCATGTTCCATT GCCAGTTCTCAGCCCAGCCACCCCCGAGCCTGCAGTGGCTCTTTGAGGATGAGACTCC CATCACTAACCGCAGTCGCCCCCCACACCTCCGCAGAGCCACAGTGTTTGCCAACGGG TCTCTGCTGCTGACCCAGGTCCGGCCACGCAATGCAGGGATCTACCGCTGCATTGGCC AGGGGCAGAGGGGCCCACCCATCATCCTGGAAGCCACACTTCACCTAGCAGAGATTGA AGACATGCCGCTATTTGAGCCACGGGTGTTTACAGCTGGCAGCGAGGAGCGTGTGACC TGCCTTCCCCCCAAGGGTCTGCCAGAGCCCAGCGTGTGGTGGGAGCACGCGGGAGTCC GGCTGCCCACCCATGGCAGGGTCTACCAGAAGGGCCACGAGCTGGTGTTGGCCAATAT TGCTGAAAGTGATGCTGGTGTCTACACCTGCCACGCGGCCAACCTGGCTGGTCAGCGG AGACAGGATGCCAACATCACTGTGGCCACTGTGCCCTCCTGGCTGAAGAAGCCCCAAG ACAGCCAGCTGGAGGAGGGCAAACCCGGCTACTTGGATTGCCTGACCCAGGCCACACC AAAACCTACAGTTGTCTGGTACAGAAACCAGATGCTCATCTCAGAGGACTCACGGTTC GAGGTCTTCAAGAATGGGACCTTGCGCATCAACAGCGTGGAGGTGTATGATGGGACAT GGTACCGTTGTATGAGCAGCACCCCAGCCGGCAGCATCGAGGCGCAAGCCCGTGTCCA AGTGCTGGAAAAGCTCAAGTTCACACCACCACCCCAGCCACAGCAGTGCATGGAGTTT GACAAGGAGGCCACGGTGCCCTGTTCAGCCACAGGCCGAGAGAAGCCCACTATTAAGT GGGAACGGGCAGATGGGAGCAGCCTCCCAGAGTGGGTGACAGACAACGCTGGGACCCT GCATTTTGCCCGGGTGACTCGAGATGACGCTGGCAACTACACTTGCATTGCCTCCAAC GGGCCGCAGGGCCAGATTCGTGCCCATGTCCAGCTCACTGTGGCAGTTTTTATCACCT TCAAAGTGGAACCAGAGCGTACGACTGTGTACCCTTCCAAACTCTATCGGCTGATGCA GCGCTGCTGGGCCCTCAGCCCCAAGGACCGGCCCTCCTTCAGTGAGATTGCCAGCGCC CTGGGAGACAGCACCGTGGACAGCAAGCCGTGAGGAGGGAGCCCGCTCAGGATGGCCT

GGGCAGGGGAGGACATCTCTAGAGGGAAGCTCACAGCATGATGGGCAAGATCCCTGTC

CTCCTGGGCCCTGAGGCCCCTGCCCTAGTGCAACAGGCATTGCTGAGGTCTGAGCAGG

GCCTGGCCTTTCCTCCTCTTCCTCACCCTCATCCTTTGGGAGGCTGACTTGGACCCAA

ACTGGGCGACTAGGGCTTTGAGCTGGGCAGTTTTCCCTGCCACCTCTTCCTCTATCAG

GGACAGTGTGGGTGCCACAGGTAACCCCAATTTCTGGCCTTCAACTTCTCCCCTTGAC

CGGGTCCAACTCTGCCACTCATCTGCCAACTTTGCCTGGGGAGGGCTAGGCTTGGGAT

GAGCTGGGTTTGTGGGGAGTTCCTTAATATTCTCAAGTTCTGGGCACACAGGGTTAAT

GAGTCTCTTGGCCCACTGGTCCCACTTGGGGGTCTAGACCAGGATTATAGAGGACACA

GCAAGTGAGTCCTCCCCACTCTGGGCTTGTGCACACTGACCCAGACCCACGGTCTTCC

CCACCCTTCTCTCCTTTCCTCATCCTAAGTGCCTGGCAGATGAAGGAGTTTTCAGGAG

CTTTTGACACTATATAAACCGCCCTTTTTGTATGCACCACGGGCGGCTTTTATATGTA

ATTGCAGCGTGGGGTGGGTGGGCATGGGAGGTAGGGGTGGGCCCTGGAGATGAGGAGG

GTGGGCCATCCTTACCCCACACTTTTATTGTTGTCGTTTTTTGTGTGTTTGTGTTTTT

TTGTTTTTGTTTTTGTTTTTACACTCGCTGCTCTCAATAAATAAGCCTTTTTAAAAAA

AAAAAAAAAAAAAAAA

ORF Start: ATG at 193 ORF Stop: TGA at 2119

SEQ ID NO: 114 642 aa MW at 70935.5kD

NOV37a, MGAARGSPARPRRLPLLSVLLLPLLGGTQTAIVFIKQPSSQDALQGRRALLRCEVEAP CGI 10014-02 GPVHVY LLDGAPVQDTERRFAQGSSLSFAAVDPLQDSGTFQCVARDDVTGEEARSAN ASFNIKWIEAGPWLKHPASEAEIQPQTQVKLRCHIDGHPRPTYQWFRDGTPLSDGQS Protein Sequence NHTVSSKERNLTLRPAGPEHSGLYSCCAHSAFGQACSSQNFTLSIADESFARWLAPQ DVWARYEEAMFHCQFSAQPPPSLQWLFEDETPITNRSRPPHLRRATVFANGSLLLTQ VRPRNAGIYRCIGQGQRGPPIILEATLHLAEIEDMPLFEPRVFTAGSEERVTCLPPKG LPΞPSV EHAGVRLPTHGRVYQKGHELVLANIAESDAGVYTCHAANLAGQRRQDANI TVATVPSWLKKPQDSQLEEGKPGYLDCLTQATPKPTV YRNQMLISEDSRFEVFKNG TLRINSVΞVYDGT YRCMSSTPAGSIEAQARVQVLEKLKFTPPPQPQQCMEFDKEATV PCSATGRΞKPTIKWERADGSSLPE VTDNAGTLHFARVTRDDAGNYTCIASNGPQGQI RAHVQLTVAVFITFKVEPERTTVYPSKLYRLMQRC ALSPKDRPSFSEIASALGDSTV DSKP

SEQ ID NO: 115 3693 bp

NOV37b, CTTTTCCTGAGCCCGCCGCGATGGGAGCTGCGCGGGGATCCCCGGCCAGACCCCGCCG CGI 10014-03 GTTGCCTCTGCTCAGCGTCCTGCTGCTGCCGCTGCTGGGCGGTACCCAGACAGCCATT GTCTTCATCAAGCAGCCGTCCTCCCAGGATGCACTGCAGGGGCGCCGGGCGCTGCTTC DNA Sequence GCTGTGAGGTTGAGGCTCCGGGCCCGGTACATGTGTACTGGCTGCTCGATGGGGCCCC TGTCCAGGACACGGAGCGGCGTTTCGCCCAGGGCAGCAGCCTGAGCTTTGCAGCTGTG GACCGGCTGCAGGACTCTGGCACCTTCCAGTGTGTGGCTCGGGATGATGTCACTGGAG AAGAAGCCCGCAGTGCCAACGCCTCCTTCAACATCAAATGGATTGAGGCAGGTCCTGT

GGTCCTGAAGCATCCAGCCTCGGAAGCTGAGATCCAGCCACAGACCCAGGTCACACTT

CGTTGCCACATTGATGGGCACCCTCGATGAAAGCTTTGCCAGGGTGGTGCTGGCACCC

CAGGACGTGGTAGTAGCGAGGTATGAGGAGGCCATGTTCCATTGCCAGTTCTCAGCCC AGCCACCCCCGAGCCTGCAGTGGCTCTTTGAGGATGAGACTCCCATCACTAACCGCAG TCGCCCCCCACACCTCCGCAGAGCCACAGTGTTTGCCAACGGGTCTCTGCTGCTGACC CAGGTCCGGCCACGCAATGCAGGGATCTACCGCTGCATTGGCCAGGGGCAGAGGGGCC CACCCATCATCCTGGAAGCCACACTTCACCTAGCAGAGATTGAAGACATGCCGCTATT TGAGCCACGGGTGTTTACAGCTGGCAGCGAGGAGCGTGTGACCTGCCTTCCCCCCAAG GGTCTGCCAGAGCCCAGCGTGTGGTGGGAGCACGCGGGAGTCCGGCTGCCCACCCATG GCAGGGTCTACCAGAAGGGCCACGAGCTGGTGTTGGCCAATATTGCTGAAAGTGATGC TGGTGTCTACACCTGCCACGCGGCCAACCTGGCTGGTCAGCGGAGACAGGATGTCAAC ATCACTGTGGCCACTGTGCCCTCCTGGCTGAAGAAGCCCCAAGACAGCCAGCTGGAGG AGGGCAAACCCGGCTACTTGGATTGCCTGACCCAGGCCACACCAAAACCTACAGTTGT CTGGTACAGAAACCAGATGCTCATCTCAGAGGACTCACGGTTCGAGGTCTTCAAGAAT GGGACCTTGCGCATCAACAGCGTGGAGGTGTATGATGGGACATGGTACCGTTGTATGA GCAGCACCCCAGCCGGCAGCATCGAGGCGCAAGCCCGTGTCCAAGTGCTGGAAAAGCT CAAGTTCACACCACCACCCCAGCCACAGCAGTGCATGGAGTTTGACAAGGAGGCCACG GTGCCCTGTTCAGCCACAGGCCGAGAGAAGCCCACTATTAAGTGGGAACGGGCAGATG GGAGCAGCCTCCCAGAGTGGGTGACAGACAACGCTGGGACCCTGCATTTTGCCCGGGT GACTCGAGATGACGCTGGCAACTACACTTGCATTGCCTCCAACGGGCCGCAGGGCCAG ATTCGTGCCCATGTCCAGCTCACTGTGGCAGTTTTTATCACCTTCAAAGTGGAACCAG AGCGTACGACTGTGTACCAGGGCCACACAGCCCTACTGCAGTGCGAGGCCCAGGGAGA CCCCAAGCCGCTGATTCAGTGGAAAGGCAAGGACCGCATCCTGGACCCCACCAAGCTG GGACCCAGGATGCACATCTTCCAGAATGGCTCCCTGGTGATCCATGACGTGGCCCCTG AGGACTCAGGCCGCTACACCTGCATTGCAGGCAACAGCTGCAACATCAAGCACACGGA GGCCCCCCTCTATGTCGTGGACAAGCCTGTGCCGGAGGAGTCGGAGGGCCCTGGCAGC CCTCCCCCCTACAAGATGATCCAGACCATTGGGTTGTCGGTGGGTGCCGCTGTGGCCT ACATCATTGCCGTGCTGGGCCTCATGTTCTACTGCAAGAAGCGCTGCAAAGCCAAGCG GCTGCAGAAGCAGCCCGAGGGCGAGGAGCCAGAGATGGAATGCCTCAACGGTGGGCCT TTGCAGAACGGGCAGCCCTCAGCAGAGATCCAAGAAGAAGTGGCCTTGACCAGCTTGG GCTCCGGCCCCGCGGCCCCCAACAAACGCCACAGCACAAGTGATAAGATGCACTTCCC ACGGTCTAGCCTGCAGCCCATCACCACGCTGGGGAAGAGTGAGTTTGGGGAGGTGTTC CTGGCAAAGGCTCAGGGCTTGGAGGAGGGAGTGGCAGAGACCCTGGTACTTGTGAAGA GCCTGCAGAGCAAGGATGAGCAGCAGCAGCTGGACTTCCGGAGGGAGTTGGAGATGTT TGGGAAGCTGAACCACGCCAACGTGGTGCGGCTCCTGGGGCTGTGCCGGGAGGCTGAG CCCCACTACATGGTGCTGGAATATGTGGATCTGGGAGACCTCAAGCAGTTCCTGAGGA TTTCCAAGAGCAAGGATGAAAAATTGAAGTCACGGCCCCTCAGCACCAAGCAGAAGGT GGCCCTATGCACCCAGGTAGCCCTGGGCATGGAGCACCTGTCCAACAACCGCTTTGTG CATAAGGACTTGGCTGCGCGTAACTGCCTGGTCAGTGCCCAGAGACAAGTGAAGGTGT CTGCCCTGGGCCTCAGCAAGGATGTGTACAACAGTGAGTACTACCACTTCCGCCAGGC CTGGGTGCCGCTGCGCTGGATGTCCCCCGAGGCCATCCTGGAGGGTGACTTCTCTACC AAGTCTGATGTCTGGGCCTTCGGTGTGCTGATGTGGGAAGTGTTTACACATGGAGAGA TGCCCCATGGTGGGCAGGCAGATGATGAAGTACTGGCAGATTTGCAGGCTGGGAAGGC TAGACTTCCTCAGCCCGAGGGCTGCCCTTCCAAACTCTATCGGCTGATGCAGCGCTGC TGGGCCCTCAGCCCCAAGGACCGGCCCTCCTTCAGTGAGATTGCCAGCGCCCTGGGAG ACAGCACCGTGGACAGCAAGCCGTGAGGAGGGAGCCCGCTCAGGATGGCCTGGGCAGG

GGAGGACATCTCTAGAGGGAAGCTCACAGCATGATGGGCAAGATCCCTGTCCTCCTGG

GCCCTGAGGCCCCTGCCCTAGTGCAACAGGCATTGCTGAGGTCTGAGCAGGGCCTGGC

CTTTCCTCCTCTTCCTCACCCTCATCCTTTGGGAGGCTGACTTGGACCCAAACTGGGC

GACTAGGGCTTTGAGCTGGGCAGTTTTCCCTGCCACCTCTTCCTCTATCAGGGACAGT

GTGGGTGCCACAGGTAACCCCAATTTCTGGCCTTCAACTTCTCCCCTTGACCGGGTCC

AACTCTGCCACTCATCTGCCAACTTTGCCTGGGGAGGGCTAGGCTTGGGATGAGCTGG

GTTTGTGGGGAGTTCCTTAATATTCTCAAGTTCTGGGCACACAGGGTTAATGAGTCTC

TTGGCCCACTGGTCCCACTTGGGGGTCTAGACCAGGATTATAGAGGACACAGCAAGTG

AGTCCTCCCCACTCTGGGCTTGTGCACACTGACCCAGACCCACGTCTTCCCCACCCTT

CTCTCCTTTCCTCATCCTAAGTGCCTGGCAGATGAAGGAGTTTTCAGGAGCTTTTGAC

ACTATATAAACCGCCCTTTTCGTATGCACCACGGGCGGC

ORF Start: ATG at 478 ORF Stop: TGA at 3040 I SEQ ID NO: 116 854 aa MW at 95008.5kD

NOV37b, MGTLDESFARWLAPQDVWARYΞEAMFHCQFSAQPPPSLQ LFEDETPITNRSRPPH CGI 10014-03 LRRATVFANGSLLLTQVRPRNAGIYRCIGQGQRGPPIILEATLHLAEIΞDMPLFEPRV FTAGSEERVTCLPPKGLPEPSVW EHAGVRLPTHGRVYQKGHELVLANIAESDAGVYT Protein Sequence CHAANLAGQRRQDVNITVATVPSWLKKPQDSQLEEGKPGYLDCLTQATPKPTVV YRN QMLISEDSRFEVFKNGTLRINSVEVYDGT YRCMSSTPAGSIEAQARVQVLEKLKFTP PPQPQQCMEFDKEATVPCSATGRΞKPTIK ERADGSSLPE VTDNAGTLHFARVTRDD AGNYTCIASNGPQGQIRAHVQLTVAVFITFKVEPERTTVYQGHTALLQCEAQGDPKPL IQWKGKDRILDPTKLGPRMHIFQNGSLVIHDVAPΞDSGRYTCIAGNSCNIKHTEAPLY WDKPVPEESEGPGSPPPYKMIQTIGLSVGAAVAYIIAVLGLMFYCKKRCKAKRLQKQ PEGEEPEMECLNGGPLQNGQPSAΞIQEEVALTSLGSGPAAPNKRHSTSDKMHFPRSSL QPITTLG SEFGEVFLAKAQGLEEGVAETLVLVKSLQSKDEQQQLDFRRELEMFGKLN HANWRLLGLCREAEPHYMVLEYVDLGDL QFLRISKSKDEKLKSRPLSTKQKVALCT QVALGMEHLSNNRFVHKDLAARNCLVSAQRQVKVSALGLSKDVYNSEYYHFRQAWVPL R MSPEAILEGDFSTKSDV AFGVLM EVFTHGEMPHGGQADDEVLADLQAGKARLPQ PEGCPSKLYRLMQRCWALSPKDRPSFSEIASALGDSTVDSKP

SEQ ID NO: 117 2866 bp

NOV37c, CTCAGCTCCTTTTCCTGAGCCCGCCGCGATGGGAGCTGCGCGGGGATCCCCGGCCAGA CGI 10014-04 CCCCGCCGGTTGCCTCTGCTCAGCGTCCTGCTGCTGCCGCTGCTGGGCGGTACCCAGA CAGCCATTGTCTTCATCAAGCAGCCGTCCTCCCAGGATGCACTGCAGGGGCGCCGGGC DNA Sequence GCTGCTTCGCTGTGAGGTTGAGGCTCCGGGCCCGGTACATGTGTACTGGCTGCTCGAT GGGGCCCCTGTCCAGGACACGGAGCGGCGTTTCGCCCAGGGCAGCAGCCTGAGCTTTG CAGCTGTGGACCGGCTGCAGGACTCTGGCACCTTCCAGTGTGTGGCTCGGGATGATGT CACTGGAGAAGAAGCCCGCAGTGCCAACGCCTCCTTCAACATCAAATGGATTGAGGCA GGTCCTGTGGTCCTGAAGCATCCAGCCTCGGAAGCTGAGATCCAGCCACAGACCCAGG TCACACTTCGTTGCCACATTGATGGGCACCCTCGGCCCACCTACCAATGGTTCCGAGA TGGGACCCCCCTTTCTGATGGTCAGAGCAACCACACAGTCAGCAGCAAGGAGCGGAAC CTGACGCTCCGGCCAGCTGGTCCTGAGCATAGTGGGCTGTATTCCTGCTGCGCCCACA GTGCTTTTGGCCAGGCTTGCAGCAGCCAGAACTTCACCTTGAGCATTGCTGATGAAAG CTTTGCCAGGGTGGTGCTGGCACCCCAGGACGTGGTAGTAGCGAGGTATGAGGAGGCC ATGTTCCATTGCCAGTTCTCAGCCCAGCCACCCCCGAGCCTGCAGTGGCTCTTTGAGG ATGAGACTCCCATCACTAACCGCAGTCGCCCCCCACACCTCCGCAGAGCCACAGTGTT TGCCAACGGGTCTCTGCTGCTGACCCAGGTCCGGCCACGCAATGCAGGGATCTACCGC TGCATTGGCCAGGGGCAGAGGGGCCCACCCATCATCCTGGAAGCCACACTTCACCTAG CAGAGATTGAAGACATGCCGCTATTTGAGCCACGGGTGTTTACAGCTGGCAGCGAGGA GCGTGTGACCTGCCTTCCCCCCAAGGGTCTGCCAGAGCCCAGCGTGTGGTGGGAGCAC GCGGGAGTCCGGCTGCCCACCCATGGCAGGGTCTACCAGAAGGGCCACGAGCTGGTGT TGGCCAATATTGCTGAAAGTGATGCTGGTGTCTACACCTGCCACGCGGCCAACCTGGC TGGTCAGCGGAGACAGGATGTCAACATCACTGTGGCCACTGTGCCCTCCTGGCTGAAG AAGCCCCAAGACAGCCAGCTGGAGGAGGGCAAACCCGGCTACTTGGATTGCCTGACCC AGGCCACACCAAAACCTACAGTTGTCTGGTACAGAAACCAGATGCTCATCTCAGAGGA CTCACGGTTCGAGGTGTTCCTGGCAAAGGCTCAGGGCTTGGAGGAGGGAGTGGCAGAG ACCCTGGTACTTGTGAAGAGCCTGCAGAGCAAGGATGAGCAGCAGCAGCTGGACTTCC GGAGGGAGTTGGAGATGTTTGGGAAGCTGAACCACGCCAACGTGGTGCGGCTCCTGGG GCTGTGCCGGGAGGCTGAGCCCCACTACATGGTGCTGGAATATGTGGATCTGGGAGAC CTCAAGCAGTTCCTGAGGATTTCCAAGAGCAAGGATGAAAAATTGAAGTCACAGCCCC TCAGCACCAAGCAGAAGGTGGCCCTATGCACCCAGGTAGCCCTGGGCATGGAGCACCT GTCCAACAACCGCTTTGTGCATAAGGACTTGGCTGCGCGTAACTGCCTGGTCAGTGCC CAGAGACAAGTGAAGGTGTCTGCCCTGGGCCTCAGCAAGGATGTGTACAACAGTGAGT ACTACCACTTCCGCCAGGCCTGGGTGCCGCTGCGCTGGATGTCCCCCGAGGCCATCCT GGAGGGTGACTTCTCTACCAAGTCTGATGTCTGGGCCTTCGGTGTGCTGATGTGGGAA GTGTTTACACATGGAGAGATGCCCCATGGTGGGCAGGCAGATGATGAAGTACTGGCAG ATTTGCAGGCTGGGAAGGCTAGACTTCCTCAGCCCGAGGGCTGCCCTTCCAAACTCTA TCGGCTGATGCAGCGCTGCTGGGCCCTCAGCCCCAAGGACCGGCCCTCCTTCAGTGAG ATTGCCAGCGCCCTGGGAGACAGCACCGTGGACAGCAAGCCGTGAGGAGGGAGCCCGC TCAGGATGGCCTGGGCAGGGGAGGACATCTCTAGAGGGAAGCTCACAGCATGATGGGC AAGATCCCTGTCCTCCTGGGCCCTGAGGCCCCTGCCCTAGTGCAACAGGCATTGCTGA GGTCTGAGCAGGGCCTGGCCTTTCCTCCTCTTCCTCACCCTCATCCTTTGGGAGGCTG ACTTGGACCCAAACTGGGCGACTAGGGCTTTGAGCTGGGCAGTTTTCCCTGCCACCTC TTCCTCTATCAGGGACAGTGTGGGTGCCACAGGTAACCCCAATTTCTGGCCTTCAACT

TCTCCCCTTGACCGGGTCCAACTCTGCCACTCATCTGCCAACTTTGCCTGGGGAGGGC

TAGGCTTGGGATGAGCTGGGTTTGTGGGGAGTTCCTTAATATTCTCAAGTTCTGGGCA

CACAGGGTTAATGAGTCTCTTGGCCCACTGGTCCCACTTGGGGGTCTAGACCAGGATT

ATAGAGGACACAGCAAGTGAGTCCTCCCCACTCTGGGCTTGTGCACACTGACCCAGAC

CCACGTCTTCCCCACCCTTCTCTCCTTTCCTCATCCTAAGTGCCTGGCAGATGAAGGA

GTTTTCAGGAGCTTTTGACACTATATAAACCGCCCTTTTTGTATGCACCACGGGCGGC

TTTTATATGTAATTGCAGCGTGGG

ORF Start: ATG at 29 ORF Stop: TGA at 2189

SEQ ID NO: 118 720 aa MW at 80086.2kD

NOV37c, MGAARGS PARPRRLPLLS VLLLPLLGGTQTAI VFIKQPS SQDALQGRRALLRCEVEAP CGI 10014-04 GP^"VHVY LLDGAPVQDTERRFAQGSSLSFAAVDRLQDSGTFQCVARDDVTGEEARSAN ASFNI WIEAGPWLKHPASEAEIQPQTQVTLRCHIDGHPRPTYQ FRDGTPLSDGQS Protein Sequence NHTVS S KERNLTLRPAGPEHSGLYS CCAHS AFGQACS SQNFTLS IADES FARWLAPQ DWVARYEEAMFHCQFSAQPPPSLQWLFEDETPITNRSRPPHLRRATVFANGSLLLTQ VRPRNAGIYRCIGQGQRGPPIILEATLHLAEIEDMPLFEPRVFTAGSEERVTCLPPKG LPEPSV WEHAGVRLPTHGRVYQKGHELVLANIAESDAGVYTCHAANLAGQRRQDVNI TVATVPSWLKKPQDSQLEEGKPGYLDCLTQATPKPTVV YRNQMLISEDSRFEVFLAK AQGLEEGVAETLVLVKSLQSi EQQQLDFRRELEMFGiαLjNHANVVRLLGLCREAEPHY MVLEYVDLGDLKQFLRISKSKDΞKLKSQPLSTKQKVALCTQVALGMEHLSNNRFVHKD LAARNCLVSAQRQVKVSALGLSKDλrYNSEYYHFRQA VPLRWISPEAILEGDFSTKSD V AFGVLM EVFTHGEMPHGGQADDEVLADLQAGKARLPQPEGCPSKLYRLMQRC ALi SPKDRPSFSEIASALGDSTVDSKP

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 37B.

Further analysis of the NOV37a protein yielded the following properties shown in Table 37C.

Table 37C. Protein Sequence Properties NO 37a

PSort 0.6950 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1900 probability located in plasma membrane; 0.1363 probability located in microbody (peroxisome)

SignalP Cleavage site between residues 31 and 32 analysis:

A search of the NOV37a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 37D.

In a BLAST search of public sequence databases, the NOV37a protein was found to have homology to the proteins shown in the BLASTP data in Table 37E.

PFam analysis predicts that the NOV37a protein contains the domains shown in the Table 37F.

Example 38.

The NOV38 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 38 A.

Table 38A. NOV38 Sequence Analysis

SEQ ID NO: 119 2894 bp

NOV38a, GATGGTGGGCTGTGGGGTGGCAGTTTTATGTTTGTGGGTTTCCTGCGGCGCTGCAGCG CGI 10187-01 GGACAGCTCGAGTACTCAGTGCCGGAGGAGACGGAGCGGGGCGTAGCCGTAGGCAATC TCTCCGCGGACTTGAGGCTGCCAGCGGCCGCTATGTCCTCGCGGAACTTTCGCTTCCT DNA Sequence TTCCAGCCACCGCGAGCTCTACTTCGGGGTGGATCTACCCAGCGGCAATTTGGTGGTC AGAGAGCCGGCGGACCGCGAACAGCTGTGCAGGGCCAAAGCTGCCTGCGTCTTGACCT ACGACCTGGTGCTCGAGGACCCGCTGGAGCTGCACAAGATTCGGATTCACGTCCTGGA CACCAATGACAACTCACCTCTCTTTCCTGCCGGCGACGTGCAGCTGCACATCCCCGAG TTCCTGACGCCCGGAGCCCGCTTTACTCTCCCGAATGCCCAAGATGACGACGAGGGAA GCAATGGGATACTAAGCTACAGCCTAAGCCCCAGTCAGCACTTTCGCCTGGACATGGG ATCGCGGGTTGACGGCAGCGAATACCCGGAGTTGGTGTTGGAGAAAGCACTGGATCGC GAACAGCGCGCCACCCACCTGCTGGTGCTTACAGCTCGGGACGGCGGGCTACCTGCCC GCTCAGGAGACGCACAAGTCACCATCATTGTGGTGGACACAAATGACAACGCGCCTGT ATTTGAGCGCTCCGTATACCGCACCAAGGTTCCAGAGACTGCACCCAATGGGACTGTG TTATTCCGAGTTCAAGCCTTGGATCCAGATGAAGGGTCCAATGGGGAAGTCCAATACT CCCTAAGCAACAGCACGCAAGCAGAGCTGCGACACCGCTTTCACGTTCACCCTAAAAG TGGGGAGGTGCAAGTAGCTGCTTCACTAGGTCCGCCTGAAACGCTCTTGGAGGCATAC ATTGAGGCGAGGGACGAAGGTGTCTTTGGTTTAGCTAGCACCGCTAAACTGCTGGTGG AGGTGACTGACGTGAACGATCATGCCCCCGAACTGGACTTCCTGACTCTTTCGAACCC AGTACCTGAGGACGCTGCCCCTGGCACAGTGATTGCTCTCTTTAGTGTAAAGGATGAA GACCTCGATTCTAATGGTAGGGTCATTTGTGGCATGTCTAGTGCAGGCCCTTTTCAGC TGACGGCTTCCTTTGACAACTACTACAGCCTGCTGATTGATGGGCCCCTGGACCGGGA GCAGATCAGTGAATACCAAGTCCTGATCACGGCCTCAGATAGTGGCTCACCCCCACTT AGCACCCGAAGGACAATCACTGTGTCAGTTGCTGATGTGAATGACAATACACCAAACT TTCCTCAACCCCAGCAGGAACTTTTCGTTGCTGAAAACAATGGCCCTGGGGCCTCTCT AGGCCGAGTGTTTGCCCAGGACCCCGACCTGGGGAAGAATGGCCTTGTCTCTTATGAG CTGTTGGATGTTATCTCTGAACGGCCATCAGCCTCTAGCTTGGTGGCAGTGGAATCAG CCAGTGGGGCCATCACTGCCAAAACTTCCTTTGACTTTGAGCAGCTCAGGGGGTTTCA TTTCCAAGTAGAGGGCCGGGATGGTGGCATTCCTCCCAGAAGTGCAACAGTGACTATA AACTTGTTTGTGGTAGATAGGAATGACAATTATCCGGTTATCTTGGTTCCCTTGCCCA GAAATGGTTCTGTCCCAGTGGAAATTGTGCCCCGCTCTGCCAGGACTGGACACTTGGT CACAAAAGTGGTAGCAGAGGATGCTGACAGTGGTTCTAATGCCTGGCTTTCCTACCAC ATCTCCCGGGCGTCTGACTCTAGTCTCTTTAGAATTTCAGCCAATATAGGTGAGCTCC GTACTGCTCGCTTAGTTCTTCCCACTGATGCAGTTAAGCAGAGGGTGGTGGTAGTGGT TCGGGACCATGGAGACCCACCACTTTCCTCCTCTGTCACTCTGGGTGTGCTGTTGAGC AACTCTGTCCCTCAGTTACTTCCAGACTTTGAAGATGTCTGGGAACCAGGAGGGCAGC TTTCTGCCCAGAACTTGTATTTAGTAATTGCCTTGGCTTGTATTTCCTTTTTATTTCT GGGGTGCTTACTTTTCTTCGTGTGTACCAAGTTGCACCAGAGCCCAGGCTGTTGCGCT CAGAGCTGCTGTCGCTCTACAGAGGATCTGAGGTATGGAAGTAAGATGGTTTCAAATC CTTGCATGACATCAGCCACCATAGATGTCACTACAGTTGAGAGACTTTCTCAGACTTA TCTCTATCGGGCCTCTCTGGGACTTGGTTCTGATAATAACAGTTTGCTGTTGCGTGGG GAGTACAATGCTGCCGACCTGCGAAATCTTGCCACTGGGGTAGGACTGAATTTGCCAA TATCCTGTATTCAGATTCGGAATAGGAAAGGGGATCACGCTAATGTCAATGCCATGCC ACGACAGCCCAACCCTGACTGGCGTTACTCTGCCTCCCTGAGAGCAGGCATGCACAGC TCTGTGCACCTAGAGGAGGCTGGCATTCTACGGGCTGGTCCAGGAGGGCCTGATCAGC AGTGGCCAACAGTATCCAGTGCAACACCAGAACCAGAGGCAGGAGAAGTGTCCCCTCC AGTCGGTGCGGGTGTCAACAGCAACAGCTGGACCTTTAAATACGGACCAGGCAACCCC AAACAATCCGGTCCCGGTGAGTTGCCCGACAAATTCATTATCCCAGGATCTCCTGCAA TCATCTCCATCCGGCAGGAGCCTACTAACAGCCAAATTGACAAAAGTGACTTCATAAC CTTCGGCAAAAAGGAGGAGACCAAGAAAAAGAAGAAAAAGAAGAAGGGTAACAAGACC CAGGAGAAAAAAGAGAAAGGGAACAGCACGACTGACAACAGTGACCAGTGAG

ORF Start: ATG at 2 ORF Stop: TGA at 2891

SEQ ID NO: 120 963 aa MW at l03961.5kD

NOV38a, MVGCGVAVLCLWVSCGAAAGQLEYSVPEΞTERGVAVGNLSADLRLPAAAMSSRNFRFL CGI 10187-01 SSHRELYFGVDLPSGNLWREPADREQLCRA AACVLTYDLVLEDPLELHKIRIHVLD TNDNSPLFPAGDVQLHIPEFLTPGARFTLPNAQDDDEGSNGILSYSLSPSQHFRLDMG Protein Sequence SRVDGSEYPELVLEKALDREQRATHLLVLTARDGGLPARSGDAQVTIIWDTNDNAPV FERSVYRT VPETAPNGTVLFRVQALDPDEGSNGEVQYSLSNSTQAELRHRFHVHPKS GΞVQVAASLGPPETLLEAYIEARDEGVFGLASTA LLVEVTDVNDHAPELDFLTLSNP VPEDAAPGTVIALFSVKDEDLDSNGRVICGMSSAGPFQLTASFDNYYSLLIDGPLDRE QISEYQVLITASDSGSPPLSTRRTITVSVADVNDNTPNFPQPQQELFVAENNGPGASL GRVFAQDPDLGKNGLVSYELLDV SERPSASSLVAVESASGAITAKTSFDFEQLRGFH FQVEGRDGGIPPRSATVTINLFWDRNDNYPVILVPLPRNGSVPVΞIVPRSARTGHLV TKVVAEDADSGSNA LSYHISRASDSSLFRISANIGELRTARLVLPTDAVKQR WW RDHGDPPLSSSVTLGVLLSNSVPQLLPDFEDV EPGGQLSAQNLYLVIALACISFLFL GCLLFFVCTKLHQSPGCCAQSCCRSTEDLRYGS MVSNPCMTSATIDVTTVERLSQTY LYRASLGLGSDNNSLLLRGEYNAADLRNLATGVGLNLPISCIQIRNRKGDHANVNAMP RQPNPD RYSASLRAGMHSSVHLEEAGILRAGPGGPDQQ PTVSSATPEPEAGEVSPP VGAGVNSNSWTFKYGPGNPKQSGPGELPDKFIIPGSPAIISIRQEPTNSQIDKSDFIT FGK EETKKKKKKKKGNKTQΞKKEKGNSTTDNSDQ

SEQ ID NO: 121 2010 bp

NOV38b, AGATCTGCGGGACAGCTCGAGTACTCAGTGCGGGAGGAGACGGAGCGGGGCGTAGCCG CGI 10187-03 TAGGCAATCTCTCCGCGGACTTGAGGCTGCCAGCGGCCGCTATGTCCTCGCGGAACTT TCGCTTCCTTTCCAGCCACCGCGAGCTCTACTTCGGGGTGGATCTACCCAGCGGCAAT DNA Sequence TTGGTGGTCAGAGAGCCGGCGGACCGCGAACAGCTGTGCAGGGCCAAAGCTGCCTGCG TCTTGACCTACGACCTGGTGCTCGAGGACCCGCTGGAGCTGCACAAGATTCGGATTCA CGTCCTGGACACCAATGACAACTCACCTCTCTTTCCTGCCGGCGACGTGCAGCTGCAC

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 38B.

Further analysis of the NOV38a protein yielded the following properties shown in Table 38C.

Table 38C. Protein Sequence Properties NOV38a

PSort 0.4600 probability located in plasma membrane; 0.2400 probability located in analysis: j nucleus; 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 19 and 20 analysis:

A search of the NOV38a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 38D.

In a BLAST search of public sequence databases, the NOV38a protein was found to have homology to the proteins shown in the BLASTP data in Table 38E.

PFam analysis predicts that the NOV38a protein contains the domains shown in the Table 38F.

Example 39.

The NOV39 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 39A.

Table 39A. NOV39 Sequence Analysis

SEQ ID NO: 123 3630 bp

NOV39a, TGCGGCCGCGGAAAGAATGCGCGCCGCCCGTGCGCTCCGCCTGCCGCGTCTGGCCACC CGI 10205-01 CGCAGCCGCCGCGTCCGCACCTGACCATGGAGTGCGCCCTCCTGCTCGCGTGTGCCTT

CCCGGCTGCGGGTTCGGGCCCGCCGAGGGGCCTGGCGGGACTGGGGCGCGTGGCCAAG DNA Sequence GCGCTCCAGCTGTGCTGCCTCTGCTGTGCGTCGGTCGCCGCGGCCTTAGCCAGTGACA GCAGCAGCGGCGCCAGCGGATTAAATGATGATTACGTCTTTGTCACGCCAGTAGAAGT AGACTCAGCCGGGTCATATATTTCACACGACATTTTGCACAACGGCAGGAAAAAGCGA TCGGCGCAGAATGCCAGAAGCTCCCTGCACTACCGATTTTCAGCATTTGGACAGGAAC TGCACTTAGAACTTAAGCCCTCGGCGATTTTGAGCAGTCACTTTATTGTCCAGGTACT TGGAAAAGATGGTGCTTCAGAGACTCAGAAACCCGAGGTGCAGCAATGCTTCTATCAG GGATTTATCAGAAATGACAGCTCCTCCTCTGTCGCTGTGTCTACGTGTGCTGGCTTGT CAGGTTTAATAAGGACACGAAAAAATGAATTCCTCATCTCGCCATTACCTCAGCTTC GGCCCAGGAACACAACTACAGCTCCCCTGCGGGTCACCATCCTCACGTACTGTACAAA AGGACAGCAGAGGAGAAGATCCAGCGGTACCGTGGCTACCCCGGCTCTGGCCGGAATT ATCCTGGTTACTCCCCAAGTCACATTCCCCATGCATCTCAGAGTCGAGAGACAGAGTA TCACCATCGAAGGTTGCAAAAGCAGCATTTTTGTGGACGACGCAAGAAATATGCTCCC AAGCCTCCCACAGAGGACACCTATCTAAGGTTTGATGAATATGGGAGCTCTGGGCGAC CCAGAAGATCAGCTGGAAAATCACAAAAGGGCCTCAATGTGGAAACCCTCGTGGTGGC AGACAAGAAAATGGTGGAAAAGCATGGCAAGGGAAATGTCACCACATACATTCTCACA^: GTAATGAACATGGTTTCTGGCCTATTTAAAGATGGGACTATTGGAAGTGACATAAACG TGGTTGTGGTGAGCCTAATTCTTCTGGAACAAGAACCTGGAGGATTATTGATCAACCA TCATGCAGACCAGTCTCTGAATAGTTTTTGTCAATGGCAGTCTGCCCTCATTGGAAAG AATGGCAAGAGACATGATCATGCCATCTTACTAACAGGATTTGATATTTGTTCTTGGA; AGAATGAACCATGTGACACTCTAGGGTTTGCCCCCATCAGTGGAATGTGCTCTAAGTA CCGAAGTTGTACCATCAATGAGGACACAGGACTTGGCCTTGCCTTCACCATCGCTCAT GAGTCAGGGCACAACTTTGGTATGATTCACGATGGAGAAGGGAATCCCTGCAGAAAGG CTGAAGGCAATATCATGTCTCCCACACTGACCGGAAACAATGGAGTGTTTTCATGGTC TTCCTGCAGCCGCCAGTATCTCAAGAAATTCCTCAGCACACCTCAGGCGGGGTGTCTA GTGGATGAGCCCAAGCAAGCAGGACAGTATAAATATCCGGACAAACTACCAGGACAGA TTTATGATGCTGACACACAGTGTAAATGGCAATTTGGAGCAAAAGCCAAGTTATGCAG CCTTGGTTTTGTGAAGGATATTTGCAAATCACTTTGGTGCCACCGAGTAGGCCACAGG TGTGAGACCAAGTTTATGCCCGCAGCAGAAGGGACCGTTTGTGGCTTGAGTATGTGGT GTCGGCAAGGCCAGTGCGTAAAGTTTGGGGAGCTCGGGCCCCGGCCCATCCACGGCCA GTGGTCCGCCTGGTCGAAGTGGTCAGAATGTTCCCGGACATGTGGTGGAGGAGTCAAG TTCCAGGAGAGACACTGCAATAACCCCAAGCCTCAGTATGGTGGCTTATTCTGTCCAG GTTCTAGCCGTATTTATCAGCTGTGCAATATTAACCCTTGCAATGAAAATAGCTTGGA TTTTCGGGCTCAACAGTGTGCAGAATATAACAGCAAACCTTTCCGTGGATGGTTCTAC CAGTGGAAACCCTATACAAAAGTGGAAGAGGAAGATCGATGCAAACTGTACTGCAAGG CTGAGAACTTTGAATTTTTTTTTGCAATGTCCGGCAAAGTGAAAGATGGAACTCCCTG CTCCCCAAACAAAAATGATGTTTGTATTGACGGGGTTTGTGAACTAGTGGGATGTGAT CATGAACTAGGCTCTAAAGCAGTTTCAGATGCTTGTGGCGTTTGCAAAGGTGATAATT CAACTTGCAAGTTTTATAAAGGCCTGTACCTCAACCAGCATAAAGCAAATGAATATTA TCCGGTGGTCCTCATTCCAGCTGGCGCCCGAAGCATCGAAATCCAGGAGCTGCAGGTT TCCTCCAGTTACCTCGCAGTTCGAAGCCTCAGTCAAAAGTATTACCTCACCGGGGGCT GGAGCATCGACTGGCCTGGGGAGTTCCCCTTCGCTGGGACCACGTTTGAATACCAGCG CTCTTTCAACCGCCCGGAACGTCTGTACGCGCCAGGGCCCACAAATGAGACGCTGATT CTGATGCAAGGCAAAAATCCAGGGATAGCTTGGAAGTATGCACTTCCCAAGGTCATGA ATGGAACTCCACCAGCCACAAAAAGACCTGCCTATACCTGCTGGATGCCAGGTGAATG GAGTACATGCAGCAAGGCCTGTGCTGGAGGCCAGCAGAGCCGAAAGATCCAGTGTGTG CAAAAGAAGCCCTTCCAAAAGGAGGAAGCAGTGTTGCATTCTCTCTGTCCAGTGAGCA CACCCACTCAGGTCCAAGCCTGCAACAGCCATGCCTGCCCTCCACAATGGAGCCTTGG ACCCTGGTCTCAGTGTTCCAAGACCTGTGGACGAGGGGTGAGGAAGCGTGAACTCCTC TGCAAGGGCTCTGCCGCAGAAACCCTCCCCGAGAGCCAGTGTACCAGTCTCCCCAGAC CTGAGCTGCAGGAGGGCTGTGTGCTTGGACGATGCCCCAAGAACAGCCGGCTACAGTG GGTCGCTTCTTCGTGGAGCGAGTGTTCTGCAACCTGTGGTTTGGGTGTGAGGAAGAGG GAGATGAAGTGCAGCGAGAAGGGCTTCCAGGGAAAGCTGATAACTTTCCCAGAGCGAA GATGCCGTAATATTAAGAAACCAAATCTGGACTTGGAAGAGACCTGCAACCGACGGGC TTGCCCAGCCCATCCAGTGTACAACATGGTAGCTGGATGGTATTCATTGCCGTGGCAG CAGTGCACAGTCACCTGTGGGGGAGGGGTCCAGACCCGGTCAGTCCACTGTGTTCAGC AAGGCCGGCCTTCCTCAAGTTGTCTGCTCCATCAGAAACCTCCGGTGCTACGAGCCTG TAATACAAACTTCTGTCCAGCTCCTGAAAAGAGAGAGGATCCATCCTGCGTAGATTTC TTCAACTGGTGTCACCTAGTTCCTCAGCATGGTGTCTGCAACCACAAGTTTTACGGAA AACAATGCTGCAAGTCATGCACAAGGAAGATCTGATCTTGGTGTCCTCCCCAGCACCT TATGGCCAGGGGCTTACCTTTCAACCTCTAGAGA

ORF Start: ATG at 85 ORF Stop: TGA at 3571

SEQ ID NO: 124 1162 aa MW at 128776.6kD

NOV39a, MECALLLACAFPAAGSGPPRGLAGLGRVAKALQLCCLCCASVAAALASDSSSGASGLN CGI 10205-01 DDYVFVTPVEVDSAGSYISHDILHNGRKKRSAQNARSSLHYRFSAFGQELHLELKPSA ILSSHFIVQVLGKDGASETQKPEVQQCFYQGFIRNDSSSSVAVSTCAGLSGLIRTRKN Protein Sequence EFLISPLPQLLAQEHNYSSPAGHHPHVLYKRTAEEKIQRYRGYPGSGRNYPGYSPSHI PHASQSRETEYHHRRLQKQHFCGRRKKYAPKPPTEDTYLRFDEYGSSGRPRRSAGKSQ KGLNVETLWADKKMVEKHGKGNVTTYILTVMNMVSGLFKDGTIGSDINWWSLILL EQEPGGLLINHHADQSLNSFCQ QSALIGKNGKRHDHAILLTGFDICS KNEPCDTLG FAPISGMCSKYRSCTINEDTGLGLAFTIAHΞSGHNFGMIHDGEGNPCRKAEGNIMSPT LTGNNGVFSWSSCSRQYLKKFLSTPQAGCLVDEPKQAGQYKYPDKLPGQIYDADTQCK WQFGAKAKLCSLGFVKDICKSLWCHRVGHRCETKF PAAEGTVCGLSMWCRQGQCVKF GELGPRPIHGQWSAWSK SECSRTCGGGVKFQERHCNNPKPQYGGLFCPGSSRIYQLC NINPCNENSLDFRAQQCAEYNSKPFRG FYQWKPYTKVEEEDRCKLYCKAENFΞFFFA MSGKVKDGTPCSPNKNDVCIDGVCELVGCDHELGSKAVSDACGVCKGDNSTCKFYKGL YLNQHKANΞYYPWLIPAGARSIΞIQELQVSSSYLAVRSLSQKYYLTGGWSID PGEF PFAGTTFEYQRSFNRPERLYAPGPTNETLILMQGKNPGIAWKYALPKVMNGTPPATKR PAYTC MPGΞWSTCSKACAGGQQSRKIQCVQKKPFQKEEAVLHSLCPVSTPTQVQACN SHACPPQWSLGP SQCSKTCGRGVRKRELLCKGSAAETLPESQCTSLPRPELQEGCVL GRCP NSRLQ VASSWSECSATCGLGVRKREMKCSEKGFQGKLITFPERRCRNIKKPN

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 39B.

Further analysis of the NOV39a protein yielded the following properties shown in Table 39C.

Table 39C. Protein Sequence Properties NOV39a

PSort 0.6400 probability located in plasma membrane; 0.4600 probability located in analysis: Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane); 0.1000 probability Ideated in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 48 and 49 analysis:

A search of the NOV39a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 39D.

In a BLAST search of public sequence databases, the NOV39a protein was found to have homology to the proteins shown in the BLASTP data in Table 39E.

PFam analysis predicts that the NOV39a protein contains the domains shown in the Table 39F.

Example 40.

The NOV40 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 40A.

GTGTGGGAAATCAAGGCAAATGCATCTGATCATATACTGCTGGCATTTCCACATCTTC TTGACTGCACCAATGAATATTTTGAAATCCTGGACGGTCCACCATCCTCAGTAAAGTC ATTGGGGAGGACCTGCTCTGGCTTCCAACACACCTACATCTCCTCCTCCAGCTCAATG ACCCTCGTGTATTTCCGAAGCTTCAACAACCTAGGAAAATGGCTATTGACGATGTATT TCCTTGTACTTGCAGAGGCAGTGTTGCAGACCCCACATCTAATCAGTCAGTGCCCCCA GAGGACAACAGTCACCAGATCTCTCTCTGCAGGGGACTGGCCGGAGCTGCAGCTGGTG GGTGGCTCTGGCCGGTGCTCAGGACGCGTGGAGATTCTCCACCAGGGCGCCTGGGGCA CCGTGTGTGATGACCTGTGGGACCTGAACGAAGCTGAGGTTGTGTGCCGGCAGCTTGG GTGTGGTCGAGCCATGTCTGCCCTTGGAAAGGCCCACTTTGGCCCCGGCTCAGGAGAC ATCTTCCTGGACAACCTCCAGTGCGCTGGTGTGGAGCGCTACCTGGGCCAGTGCACCC ACTCGGGCTGGTCAGAGCACAACCATGTTTCATATTCAGGCATAATTTCCACTTCAGA AGAAGTAACTCCTTCACCTGGTTGTGGCGGTTACCTGGATACCTTGGAAGGATCCTTC ACCAGCCCCAATTACCCAAAGCCGCATCCTGAGCTGGCTTATTGTGTGTGGCACATAC AAGTGGAGAAAGATTACAAGATAAAACTAAACTTCAAAGAGATTGAAATAGACAAACA GTGCAAATTTGATTTTCTTGCCATCTATGATGGCCCCTCCACCAACTCTGGCCTGATT GGACAAGTCTGTGGCCGTGTGACTCCCACCTTCGAATCGTCATCAAACTCTCTGACTG TCGTGTTGTCTACAGATTATGCCAATTCTTACCGGGGATTTTCTGCTTCCTACACCTC AATTTATGCAGAAAACATCACAGCATCTTTAACTTGCTCTTCTGACAGGATGAGAGTT ATTATAAGCAAATCCTACCTAGAGGCTTTTAACTCTAATGGGAATAACTTGCAACTAA AAGACCCAACTTGCAGACCAAAATTATCAAATGTTGTGGAATTTTCTGTCCCTCTTAA TGGATGTGGTACAATCAGACAGGTAGAAGATCAGTCAATTACTTACACCAATATAATC ACCTTTTCTGCATCCTCAACTTCTGAAGTGATCACCCGTCAGAAACAACTCCAGATTA TTGTGAAGTGTGAAATGGGACATAATTCTACAGTGGAGATAATATACATAACAGAAGA TGATGTAATACAAAGTCAAAATGCACTGGGCAAATATAACACCAGCATGGCTCTTTTT GAATCCAATTCATTTGAAAAGACTATACTTGAATCACCATATTATGTGGATTTGAACC AAACTCTTTTTGTTCAAGTTAGTCTGCACACCTCAGATCCAAATTTGGTGGTGTTTCT TGATACCTGTAGAGCCTCTCCCACCTCTGACTTTGCATCTCCAACCTACGACCTAATC AAGAGTGGGTGTAGTCGAGATGAAACTTGTAAGGTGTATCCCTTATTTGGACACTATG GGAGATTCCAGTTTAATGCCTTTAAATTCTTGAGAAGTATGAGCTCTGTGTATCTGCA GTGTAAAGTTTTGATATGTGATAGCAGTGACCACCAGTCTCGCTGCAATCAAGGTTGT GTCTCCAGAAGCAAACGAGACATTTCTTCATATAAATGGAAAACAGATTCCATCATAG GACCCATTCGTCTGAAAAGGGATCGAΆGTGCAΆGTGGCAATTCAGGATCTCAGCATGA AACACATGCGGAAGAAACTCCAAACCAGCCTTTCAACAGTGTGCATCTGTTTTCCTTC ATGGTTCTAGCTCTGAATGTGGTGACTGTAGCGACAATCACAGTGAGGCATTTTGTAA ATCAACGGGCAGACTACAAATACCAGAAGCTGCAGAACTATTAACTAACAGGTCCAAC CCTAAGTGAGACATGTTTCTCCAGGATGCCAAA

ORF Start: ATG at 25 ORF Stop: TAA at 3058

SEQ ID NO: 136 1011 aa MWatll0883.1kD

NOV40a, MEDRVLRDDL NLAKATWCRQLQCGRAVAAPTGAHFGAGSGKILLDDVQCVGSESHL CGI10242-01 GQCVHGGRARHNCGHLEDASVICSRPLPSVPTSCASPGAWMEVRLLNGTGRCSGRVEV LVQGT GTVCDDL DLAEATWCRQLQCGQAVAAPTGAHFRAGSGKILLDDMQCVGSE Protein Sequence SHLGQCMRGDQARHNCGHLEDASVICTHHQLPAAGACMEVRLLNGTGRCLGRVEVLIQ GT GTVCDHFWNLAEAAWCRQLQCGQAMAAHFGASSGKVLLDDMQCVGSKSHLGRCV HRGWARHNCGHLEDASVICAEKSRCGG11TNSSGAIRNPPQNEMHDNITCV EIKANA SDHILLAFPHLLDCTNEYFEILDGPPSSVKSLGRTCSGFQHTYISSSSSMTLVYFRSF NNLGK LLTMYFLVLAEAVLQTPHLISQCPQRTTVTRSLSAGDWPELQLVGGSGRCSG RVEILHQGA GTVCDDL DLNEAEWCRQLGCGRAMSALGKAHFGPGSGDIFLDNLQC AGVERYLGQCTHSGWSEHNHVSYSGIISTSEEVTPSPGCGGYLDTLEGSFTSPNYPKP HPELAYCV HIQVEKDYKIKLNFKEIEIDKQCKFDFLAIYDGPSTNSGLIGQVCGRVT PTFESSSNSLTWLSTDYANSYRGFSASYTSIYAENITASLTCSSDRMRVIISKSYLE AFNSNGNNLQLKDPTCRPKLSNWEFSVPLNGCGTIRQVEDQSITYTNIITFSASSTS EVITRQKQLQIIVKCEMGHNSTVEIIYITEDDVIQSQNALGKYNTSMALFESNSFEKT ILESPYYVDLNQTLFVQVSLHTSDPNLWFLDTCRASPTSDFASPTYDLIKSGCSRDE TCKVYPLFGHYGRFQFNAFKFLRSMSS"VYLQCKVLICDSSDHQSRCNQGCVSRSKRDI SSYKWKTDSIIGPIRLKRDRSASGNSGSQHETHAEETPNQPFNSVHLFSFMVLALNW TVATITVRHFVNQRADYKYQKLQNY

SEQ ID NO: 137 744 bp

NOV40b, GGTACCACTTGCTCTTCTGACAGGATGAGAGTTATTATAAGCAAATCCTACCTAGAGG

Sequence comparison of the above protein sequences yields the following sequence relationships shown in Table 40B.

Further analysis of the NOV40a protein yielded the following properties shown in Table 40C. Table 40C. Protein Sequence Properties NOVlOa

PSort 0.7000 probability located in plasma membrane; 0.5843 probability located in analysis: mitochondrial inner membrane; 0.3000 probability located in microbody (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Predicted analysis:

A search of the NOVlOa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 40D.

In a BLAST search of public sequence databases, the NOV40a protein was found to have homology to the proteins shown in the BLASTP data in Table 40E.

PFam analysis predicts that the NOV40a protein contains the domains shown in the Table 40F.

Example 41.

The NOV41 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 41 A.

TGCTCGGCCCCCAGCCAGCTCTTGGTTCCACAGCTGGTCTTCTATCAGTACCTGAGTG GGTCTGAGGCTGGCTGCCTCCAGCTGTTCCTGCAGACTCTGGGGCCCGGCGCCCCCCG GGCCCCCGTCCTGCTGCGGAGGCGCCGAGGGGAGCTGGGGACCGCCTGGGTCCGAGAC CGTGTTGACATCCAGAGCGCCTACCCCTTCCAGATCCTCCTGGCCGGGCAGACAGGCC CGGGGGGCGTCGTGGGTCTGGACGACCTCATCCTGTCTGACCACTGCAGACCAGTCTC GGAGGTGTCCACCCTGCAGCCGCTGCCTCCTGGGCCCCGGGCCCCAGCCCCCCAGCCC CTGCCGCCCAGCTCGCGGCTCCAGGATTCCTGCAAGCAGGGGCATCTTGCCTGCGGGG ACCTGTGTGTGCCCCCGGAACAACTGTGTGACTTCGAGGAGCAGTGCGCAGGGGGCGA GGACGAGCAGGCCTGTGGTAAAGGGGCTCAACCTCCTGCAGACCTCCTGCTGCGGAGC CAAGGGGGCACCACAGACTTTGAGTCCCCCGAGGCTGGGGGCTGGGAGGACGCCAGCG TGGGGCGGCTGCAGTGGCGGCGTGTCTCAGCCCAGGAGAGCCAGGGGTCCAGTGCAGC TGCTGCTGGCTTCCTGGCACTAGTTGTGGTGGACAACGGCTCCCGGGAGCTGGCATGG CAGGCCCTGAGCAGCAGTGCAGGCATCTGGAAGGTGGACAAGGTCCTTCTAGGGGCCC GCCGCCGGCCCTTCCGGCTGGAGTTTGTCGGTTTGGTGGACTTGGATGGCCCTGACCA GCAGGGAGCTGGGGTGGACAACGTGACCCTGAGGGACTGTAGCCCCACAGTGACCACC GAGAGAGACAGAGAGGTCTCCTGTAACTTTGAGCGGGACACATGCAGCTGGTACCCAG GCCACCTCTCAGACACACACTGGCGCTGGGTGGAGAGCCGCGGCCCTGACCACGACCA CACCACAGGCCAAGGCCACTTTGTGCTCCTGGACCCCACAGACCCCCTGGCCTGGGGC CACAGTGCCCACCTGCTCTCCAGGCCCCAGGTGCCAGCAGCACCCACGGAGTGTCTCA GCTTCTGGTACCACCTCCATGGGCCCCAGATTGGGACTCTGCGCCTAGCCATGAGACG GGAAGGGGAGGAGACACACCTGTGGTCGCGGTCAGGCACCCAGGGCAACCGCTGGCAC GAGGCCTGGGCCACCCTTTCCCACCAGCCTGGCTCCCATGCCCAGTACCAGCTGCTGT TCGAGGGCCTCCGGGACGGATACCACGGCACCATGGCGCTGGACGATGTGGCCGTGCG GCCGGGCCCCTGCTGGGCCCCTAATTACTGCTCCTTTGAGGACTCAGACTGCGGCTTC TCCCCTGGAGGCCAAGGTCTCTGGAGGCGGCAGGCCAATGCCTCGGGCCATGCTGCCT GGGGCCCCCCAACAGACCATACCACTGAGACAGCCCAAGGGCACTACATGGTGGTGGA CACAAGCCCAGACGCACTACCCCGGGGCCAGACGGCCTCCCTGACCTCCAAGGAGCAC AGGCCCCTGGCCCAGCCTGCTTGTCTGACCTTCTGGTACCACGGGAGCCTCCGCAGCC CAGGCACCCTGCGGGTCTACCTGGAGGAGCGCGGGAGGCACCAGGTGCTCAGCCTCAG TGCCCACGGCGGGCTTGCCTGGCGCCTGGGCAGCATGGACGTGCAGGCCGAGCGAGCC TGGAGGGTGGTGTTTGAGGCAGTGGCCGCAGGCGTGGCACACTCCTACGTGGCTCTGG ATGATCTGCTCCTCCAGGACGGGCCCTGCCCTCAGCCAGGTTCCTGTGATTTTGAGTC TGGCCTGTGTGGCTGGAGCCACCTGGCCTGGCCCGGCCTGGGCGGATACAGCTGGGAC TGGGGCGGGGGAGCCACCCCCTCTCGTTACCCCCAGCCCCCTGTGGACCACACCCTGG GCACAGAGGCAGGCCACTTTGCCTTCTTTGAAACTGGCGTGCTGGGCCCCGGGGGCCG GGCCGCCTGGCTGCGCAGCGAGCCTCTGCCGGCCACCCCAGCCTCCTGCCTCCGCTTC TGGTACCACATGGGTTTTCCTGAGCACTTCTACAAGGGGGAGCTGAAGGTACTGCTGC ACAGTGCTCAGGGCCAGCTGGCTGTGTGGGGCGCAGGCGGGCATCGGCGGCACCAGTG GCTGGAGGCCCAGGTGGAGGTAGCCAGTGCCAAGGAGTTCCAGATCGTGTTTGAAGCC ACTCTGGGCGGCCAGCCAGCCCTGGGGCCCATTGCCCTGGATGACGTGGAGTATCTGG CTGGGCAGCATTGCCAGCAGCCTGCCCCCAGCCCGGGGAACACAGCCGCACCCGGGTC TGTGCCAGCTGTGGTTGGCAGTGCCCTCCTATTGCTCATGCTCCTGGTGCTGCTGGGA CTTGGGGGACGGCGCTGGCTGCAGAAGAAGGGGAGCTGCCCCTTCCAGAGCAACACAG AGGCCACAGCCCCTGGCTTTGACAACATCCTTTTCAATGCGGAGCCATGCGGTGTTGG AGGGCACAGCACAGCACCCTTGCCAGCCGCTAGGCTCCCATCCGCCCTGGGGACTAAG TCCCAGCGGAGGGCGGCAGTTGGGCACGGCTACCGCCGTCCCTCGTCTTCAGGTGCCG TGGGGCTGACCAGTGCCCACCAACTGTCCACGCAGATGGGCGAAGAGGAAATGGCCCT GCAGAGACCTTCAGAGCTCCCCCCGGCAGCCCACTCCCGGGCATCAGTCATGAAAATT CACCAGCTTTCCCCACAACTAGGGGCCTGGGAGCTGAGAGCAGGACCGGACAATCTGG CCCCAGCGCCAAGGGCAGGAACTTTTCCCAGCTTCTCTTCAGAGCTGCATCAAAGAAA GCAGCGCCCAGTGACACCGCTCCTCTTCCTTCCACGCCTCAGGCCTCCACCCCTCACC CTTGTATAA

ORF Start: ATG at 1 ORF Stop: TAA at 4009

SEQ ID NO: 146 1336 aa MW at 144032.7kD

NOV41a, MPLSSHLLPALVLFLGHLAVNLPAAGSSG AVPNHCRSPGQAVCNFVCDCRDCSDEA CG99598-01 QCGYHGASPTLGAPFACDFEQDPCGWRDISTSGYSWLRDRAGAALEGPGPHSDHTLGT DLG YMAVGTHRGKEASTAALRSPTLRΞAASSCKLRL YHAASGDVAELRVELTHGAE Protein Sequence TLTLWQSTGP GPG QΞLAVTTGRIRGDFRVTFSATRNATHRGAVALDDLEFWDCGLP TPQANCPPGHHHCQNKVCVEPQQLCDGEDNCGDLSDENPLTCGRHIATDFETGLGPWN RSEG SRNHRAGGPERPS PRRDHSRNSAQGSFLVSVAEPGTPAILSSPEFQASGTSN CSAPSQLLVPQLVFYQYLSGSEAGCLQLFLQTLGPGAPRAPVLLRRRRGELGTAWVRD RVDIQSAYPFQILLAGQTGPGGWGLDDLILSDHCRPVSEVSTLQPLPPGPRAPAPQP LPPSSRLQDSCKQGHLACGDLCVPPEQLCDFEEQCAGGEDEQACGKGAQPPADLLLRS QGGTTDFESPEAGG EDASVGRLQ RRVSAQESQGSSAAAAGFLAL WDNGSRΞLAW QALSSSAGI KVDKVLLGARRRPFRLEFVGLVDLDGPDQQGAGVDNVTLRDCSPTVTT ERDREVSCNFERDTCS YPGHLSDTH R VΞSRGPDHDHTTGQGHFVLLDPTDPLA G HSAHLLSRPQVPAAPTECLSF YHLHGPQIGTLRLAMRREGEETHL SRSGTQGNR H EA ATLSHQPGSHAQYQLLFEGLRDGYHGTMALDDVAVRPGPC APNYCSFEDSDCGF SPGGQGL RRQANASGHAAWGPPTDHTTETAQGHYMWDTSPDALPRGQTASLTSKEH RPLAQPACLTFWYHGSLRSPGTLRVYLEERGRHQVLSLSAHGGLA RLGSMDVQAERA RWFEAVAAGVAHSYVALDDLLLQDGPCPQPGSCDFESGLCGWSHLA PGLGGYS D WGGGATPSRYPQPPVDHTLGTEAGHFAFFETGVLGPGGRAA LRSEPLPATPASCLRF YHMGFPEHFYKGΞLKVLLHSAQGQLAV GAGGHRRHQWLEAQVEVASAKEFQIVFEA TLGGQPALGPIALDDVEYLAGQHCQQPAPSPGNTAAPGSVPAWGSALLLLMLLVLLG LGGRRWLQKKGSCPFQSNTEATAPGFDNILFNAEPCGVGGHSTAPLPAARLPSALGTK SQRRAAVGHGYRRPSSSGAVGLTSAHQLSTQMGEEEMALQRPSELPPAAHSRASVMKI HQLSPQLGA ELRAGPDNLAPAPRAGTFPSFSSELHQRKQRPVTPLLFLPRLRPPPLT LV

Further analysis of the NOV41a protein yielded the following properties shown in Table 41B.

Table 41B. Protein Sequence Properties NOVlla

PSort 0.4600 probability located in plasma membrane; 0.2464 probability located in analysis: microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 20 and 21 analysis:

A search of the NOV41a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 41 C.

In a BLAST search of public sequence databases, the NOV4 la protein was found to have homology to the proteins shown in the BLASTP data in Table 4 ID.

PFam analysis predicts that the NOV41 a protein contains the domains shown in the Table 41E.

Example B: Sequencing Methodology and Identification of NOVX Clones

1. GeneCalling™ Technology: This is a proprietary method of performing differential gene expression profiling between two or more samples developed at CuraGen and described by Shimkets, et al., "Gene expression analysis by transcript profiling coupled to a gene database query" Nature Biotechnology 17:198-803 (1999). cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then digested with up to as many as 120 pairs of restriction enzymes and pairs of linker-adaptors specific for each pair of restriction enzymes were ligated to the appropriate end. The restriction digestion generates a mixture of unique cDNA gene fragments. Limited PCR amplification is performed with primers homologous to the linker adapter sequence where one primer is biotinylated and the other is fluorescently labeled. The doubly labeled material is isolated and the fluorescently labeled single strand is resolved by capillary gel electrophoresis. A computer algorithm compares the electropherograms from an experimental and control group for each of the restriction digestions. This and additional sequence-derived information is used to predict the identity of each differentially expressed gene fragment using a variety of genetic databases. The identity of the gene fragment is confirmed by additional, gene-specific competitive PCR or by isolation and sequencing of the gene fragment.

2. SeqCalling™ Technology: cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then sequenced using CuraGen's proprietary SeqCalling technology. Sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations.

3. PathCalling™ Technology:

The NOVX nucleic acid sequences are derived by laboratory screening of cDNA library by the two-hybrid approach. cDNA fragments covering either the full length of the DNA sequence, or part of the sequence, or both, are sequenced. In silico prediction was based on sequences available in CuraGen Corporation's proprietary sequence databases or in the public human sequence databases, and provided either the full length DNA sequence, or some portion thereof. The laboratory screening was performed using the methods summarized below:

cDNA libraries were derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then directionally cloned into the appropriate two-hybrid vector (Gal4-activation domain (Gal4-AD) fusion). Such cDNA libraries as well as commercially available cDNA libraries from Clontech (Palo Alto, CA) were then transferred from E.coli into a CuraGen Corporation proprietary yeast strain (disclosed in U. S. Patents 6,057,101 and 6,083,693, incorporated herein by reference in their entireties).

Gal4-binding domain (Gal4-BD) fusions of a CuraGen Corportion proprietary library of human sequences was used to screen multiple Gal4-AD fusion cDNA libraries resulting in the selection of yeast hybrid diploids in each of which the Gal4-AD fusion contains an individual cDNA. Each sample was amplified using the polymerase chain reaction (PCR) using non-specific primers at the cDNA insert boundaries. Such PCR product was sequenced; sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations.

Physical clone: the cDNA fragment derived by the screening procedure, covering the entire open reading frame is, as a recombinant DNA, cloned into pACT2 plasmid (Clontech) used to make the cDNA library. The recombinant plasmid is inserted into the host and selected by the yeast hybrid diploid generated during the screening procedure by the mating of both CuraGen Corporation proprietary yeast strains N106' and YULH (U. S. Patents 6,057,101 and 6,083,693). 4. RACE: Techniques based on the polymerase chain reaction such as rapid amplification of cDNA ends (RACE), were used to isolate or complete the predicted sequence of the cDNA of the invention. Usually multiple clones were sequenced from one or more human samples to derive the sequences for fragments. Various human tissue samples from different donors were used for the RACE reaction. The sequences derived from these procedures were included in the SeqCalling Assembly process described in preceding paragraphs.

5. Exon Linking: The NOVX target sequences identified in the present invention were subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or protein sequence of the target sequence, or by translated homology of the predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component of the assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein. 6. Physical Clone: Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein.

The PCR product derived by exon linking, covering the entire open reading frame, was cloned into the pCR2.1 vector from Invitrogen to provide clones used for expression and screening purposes.

Example C: Quantitative expression analysis of clones in various cells and tissues

The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel 5D/5I (containing human tissues and cell lines with an emphasis on metabolic diseases), AI_comprehensive_panel (containing normal tissue and samples from autoimmune diseases), Panel CNSD.01 (containing central nervous system samples from normal and diseased brains) and CNS neurodegenerationjpanel (containing samples from normal and Alzheimer's diseased brains).

RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s:18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon. First, the RNA samples were normalized to reference nucleic acids sucή as constitutively expressed genes (for example, β-actin and GAPDH). Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions.

In other cases, non-normalized RNA samples were converted to single strand cDNA (sscDNA) using Superscript II (Invitrogen Corporation; Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 μg of total RNA were performed in a volume of 20 μl and incubated for 60 minutes at 42 °C. This reaction can be scaled up to 50 μg of total RNA in a final volume of 100 μl. sscDNA samples are then normalized to reference nucleic acids as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions.

Probes and primers were designed for each assay according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for reaction conditions and the following parameters were set before selecting primers: primer concentration = 250 nM, primer melting temperature (Tm) range = 58 °-60 °C, primer optimal Tm = 59 °C, maximum primer difference = 2 °C, probe does not have 5'G, probe Tm must be 10 °C greater than primer Tm, amplicon size 75bp to lOObp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, TX, USA). Probes were double purified by HPLC to remove uncoupled dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5' and 3' ends of the probe, respectively. Their final concentrations were: forward and reverse primers, 900nM each, and probe, 200nM.

PCR conditions: When working with RNA samples, normalized RNA from each tissue and each cell line was spotted in each well of either a 96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 48 °C for 30 minutes followed by amplification/PCR cycles as follows^': 95°C 10 min, then 40 cycles of 95 °C for 15 seconds, 60 °C for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100.

When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95 °C 10 min, then 40 cycles of 95 °C for 15 seconds, 60 °C for 1 minute. Results were analyzed and processed as described previously.

Panels 1, 1.1, 1.2, and 1.3D The plates for Panels 1 , 1.1, 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose.

In the results for Panels 1, 1.1, 1.2 and 1.3D, the following abbreviations are used: ca. = carcinoma, * = established from metastasis, met = metastasis, s cell var = small cell variant, non-s = non-sm = non-small, squam = squamous, pi. eff = pi effusion = pleural effusion, glio = glioma, astro = astrocytoma, and neuro = neuroblastoma.

General_screening_panel_vl.4

The plates for Panel 1.4 include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in Panel 1.4 are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panel 1.4 are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panel 1.4 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D.

Panels 2D and 2.2 The plates for Panels 2D and 2.2 generally include 2 control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI). The tissues are derived from human malignancies and in cases where indicated many malignant tissues have "matched margins" obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted "NAT" in the results below The tumor tissue and the "matched margins" are evaluated by two independent pathologists (the surgical^' pathologists and again by a pathologist at NDRI or CHTN). This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated "NAT", for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, CA), Research Genetics, and Invitrogen. General oncology screening panel_v_2.4 is an updated version of Panel 2D.

Panel 3D

The plates of Panel 3D are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D and 1.3D are of the most common cell lines used in the scientific literature. Oncology_cell_line_screening_panel_v3.2 is an updated version of Panel 3. The cell lines in panel 3D, 1.3D and oncology_celI_line_screening_panel_v3.2 are of the most common cell lines used in the scientific literature.

Panels 4D, 4R, and 4.1D

Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D/4. ID) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, CA) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, CA). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, PA).

Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, MD) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12- 14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately 1- 5ng/ml, TNF alpha at approximately 5-lOng/ml, IFN gamma at approximately 20-50ng/ml, IL-4 at approximately 5-10ng/ml, IL-9 at approximately 5-10ng/ml, IL-13 at approximately 5-1 Ong/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1 % serum.

Mononuclear cells were prepared from blood of employees at CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco/Life Technologies, Rockville, MD), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and lOmM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20ng/ml PMA and l-2μg/ml ionomycin, IL-12 at 5-10ng/ml, IFN gamma at 20-50ng/ml and IL-18 at 5-10ng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and lOmM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5μg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1:1 at a final concentration of approximately 2x10⁶cells/ml in DMEM 5% FCS (Hyclone), 1 OOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol (5.5x10^"5M) (Gibco), and lOmM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1- 7 days for RNA preparation.

Monocytes were isolated from mononuclear cells using CD 14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, UT), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), and lOmM Hepes (Gibco), 50ng/ml GMCSF and 5ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^'5M (Gibco), lOmM Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50ng/ml. Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at lOOng/ml. Dendritic cells were also stimulated with anti-CD40 monoclonal antibody (Pharmingen) at lOμg/ml for 6 and 12-14 hours.

CD4 lymphoc tes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), and 10mM Hepes (Gibco) and plated at 10 cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5μg/ml anti-CD28 (Pharmingen) and 3ug/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), and lOmM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culxure. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and 1 OmM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared.

To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spxin down and resupended at 10⁶ cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), and lOmM Hepes (Gibco). To activate the cells, we used PWM at 5 μg/ml or anti-CD40 (Pharmingen) at approximately lOμg/ml and IL-4 at 5-10ng/ml. Cells were harvested for RNA preparation at 24, 48 and 72 hours.

To prepare the primary and secondary Thl/Th2 and Tri cells, six- well Falcon plates were coated overnight with lOμg/ml anti-CD28 (Pharmingen) and 2μg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, MD) were cultured at 10⁵- 10⁶cells/ml in DMEM 5% FCS

(Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), lOmM Hepes (Gibco) and IL-2 (4ng/ml). IL-12 (5ng/ml) and anti-IL4 (1 μg/ml) were used to direct to Thl, while IL-4 (5ng/ml) and anti- IFN gamma (1 μg/ml) were used to direct to Th2 and IL-10 at 5ng/ml was used to direct to Tri . After 4-5 days, the activated Thl , Th2 and Tri lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), lOmM Hepes (Gibco) and IL-2 (lng/ml). Following this, the activated Thl, Th2 and Tri lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (1 μg/ml) to prevent apoptosis. After 4-5 days, the Thl, Th2 and Tri lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Thl and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Thl, Th2 and Tri after 6 and 24 hours following the second and third activations with plate bound anti- CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2. The following leukocyte cells lines were obtained from the ^'ATCC :^"Tamos, EϋL-1, KU-812. EOL cells were further differentiated by culture in O.lmM dbcAMP at 5xl0⁵cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to 5x10⁵ cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), 1 OOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), lOmM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at lOng/ml and ionomycin at 1 μg/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), 1 OOμM non essential amino acids (Gibco), ImM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), and lOmM Hepes (Gibco). CCD1106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and 1 ng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5ng/ml IL-4, 5ng/ml IL-9, 5ng/ml IL- 13 and 25ng/ml IFN gamma.

For these cell lines and blood cells, RNA was prepared by lysing approximately 10⁷cells/ml using Trizol (Gibco BRL). Briefly, 1/10 volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was removed and placed in a 15ml Falcon Tube. An equal volume of isopropanol was added and left at -20 °C overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70% ethanol. The pellet was redissolved in 300μl of RNAse-free water and 35μl buffer (Promega) 5μl DTT, 7μl RNAsin and 8μl DNAse were added. The tube was incubated at 37 °C for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re- precipitated with 1/10 volume of 3M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in RNAse free water. RNA was stored at -80 °C.

Al comprehensive panel vl.O

The plates for AI_comprehensive panel_vl .0 include two control wells and 89 test samples comprised of cDNA isolated from surgical and postmortem human tissues obtained from the Backus Hospital and Clinomics (Frederick, MD). Total RNA was extracted from tissue samples from the Backus Hospital in the Facility at CuraGen. Total RNA from other tissues was obtained from Clinomics.

Joint tissues including synovial fluid, synovium, bone and cartilage were obtained from patients undergoing total knee or hip replacement surgery at the Backus Hospital. Tissue samples were immediately snap frozen in liquid nitrogen to ensure that isolated RNA was of optimal quality and not degraded. Additional samples of osteoarthritis and rheumatoid arthritis joint tissues were obtained from Clinomics. Normal control tissues were supplied by Clinomics and were obtained during autopsy of trauma victims.

Surgical specimens of psoriatic tissues and adjacent matched tissues were provided as total RNA by Clinomics. Two male and two female patients were selected between the ages of 25 and 47. None of the patients were taking prescription drugs at the time samples were isolated.

Surgical specimens of diseased colon from patients with ulcerative colitis and Crohns disease and adjacent matched tissues were obtained from Clinomics. Bowel tissue from three female and three male Crohn's patients between the ages of 41 -69 were used. Two patients were not on prescription medication while the others were taking dexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue was from three male and four female patients. Four of the patients were taking lebvid and two were on phenobarbital.

Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha- lanti- trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35- 80 and included both smokers and non-smokers. Most patients were taking corticosteroids, and bronchodilators.

In the labels employed to identify tissues in the AI_comprehensive panel_vl .0 panel, the following abbreviations are used: Al = Autoimmunity Syn = Synovial

Normal = No apparent disease Rep22 /Rep20 = individual patients RA = Rheumatoid arthritis

Backus = From Backus Hospital OA = Osteoarthritis (SS) (BA) (MF) = Individual patients Adj = Adjacent tissue Match control = adjacent tissues

-M = Male -F = Female COPD = Chronic obstructive pulmonary disease

Panels 5D and 51 The plates for Panel 5D and 51 include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained.

In the Gestational Diabetes study subjects are young (18 - 40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (<1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile saline, blotted and fast frozen within 5 minutes from the time of removal. The tissue was then flash frozen in liquid nitrogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus) and subcutaneous adipose. Patient descriptions are as follows:

Patient 2 Diabetic Hispanic, overweight, not on insulin

Patient 7-9 Nondiabetic Caucasian and obese (BMI>30)

Patient 10 Diabetic Hispanic, overweight, on insulin

Patient 11 Nondiabetic African American and overweight Patient 12 Diabetic Hispanic on insulin

Adipocyte differentiation was induced in donor progenitor cells obtained from

Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stem cells (HuMSCs) for CuraGen based on the published protocol found m Mark F. Pittenger, et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells Science Apr 2 1999: 143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDNA production. A general description of each donor is as follows:

Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated Donor 2 and 3 AD: Adipose, Adipose Differentiated

Human cell lines were generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA.

Panel 51 contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 51.

In the labels employed to identify tissues in the 5D and 51 panels, the following abbreviations are used:

GO Adipose = Greater Omentum Adipose SK = Skeletal Muscle UT = Uterus PL = Placenta

AD = Adipose Differentiated

AM = Adipose Midway Differentiated

U = Undifferentiated Stem Cells

Panel CNSD.01 The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists ^"to confirm diagnoses with clear associated neuropathology.

Disease diagnoses are taken from patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease, Hxmtington's disease, Progressive Supernuclear Palsy, Depression, and "Normal controls". Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.

In the labels employed to identify tissues in the CNS panel, the following abbreviations are used:

PSP = Progressive supranuclear palsy Sub Nigra = Substantia nigra Glob Palladus= Globus palladus Temp Pole = Temporal pole

Cing Gyr = Cingulate gyrus BA 4 = Brodman Area 4

Panel CNS Neurodegeneration Vl.O

The plates for Panel CNS_Neurodegeneration_Vl .0 include two control wells and 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

Disease diagnoses are taken from patient records. The panel contains six brains from Alzheimer's disease (AD) patients, and eight brains from "Normal controls" who showed no evidence of dementia prior to death. The eight normal control brains are divided into two categories: Controls with no dementia and no Alzheimer's like pathology (Controls) and controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0 = no evidence of plaques, 3 = severe AD senile plaque load). Within each of these brains, the following regions are represented: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), and occipital cortex (Brodman area 17). These regions were chosen to encompass all levels of neurodegeneration in AD. The hippocampus is a region of early and severe neuronal loss in AD; the temporal cortex is known to show neurodegeneration in AD after the hippocampus; the parietal cortex shows moderate neuronal death in the late stages of the disease; the occipital cortex is spared in AD and therefore acts as a "control" region within AD patients. Not all brain regions are represented in all cases.

In the labels employed to identify tissues in the CNS_Neurodegeneration_Vl .0 panel, the following abbreviations are used:

AD = Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy

Control = Control brains; patient not demented, showing no neuropathology

Control (Path) = Control brains; pateint not demented but showing sever AD-like pathology

SupTemporal Ctx = Superior Temporal Cortex

Inf Temporal Ctx = Inferior Temporal Cortex

A. CGI 00689-01: LRR Protein Expression of gene CG100689-01 was assessed using the primer-probe set Ag4186, described in Table AA. Results of the RTQ-PCR runs are shown in Tables AB and AC.

Table AA. Probe Name Ag4186

Table AB. General_screening_panel_vl .4

Table AC. Panel 4. ID

General_screening_panel_vl.4 Summary: Ag4186 Expression of this gene is restricted to the testis (CT=33.7). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker of testicular tissue. Therapeutic modulation of the expression or function of this gene may be useful in the treatment of male infertility and hypogonadism.

Panel 4.1D Summary: Ag4186 Expression of this gene is restricted to the kidney, thymus, and activated B lymphocytes (CTs=30-33). Thus, expression of this gene could be used to differentiate between the kidney derived sample and other samples on this panel and as a marker of kidney tissue. Therapeutic modulation of the expression or function of this gene could modulate kidney function and be important in the treatment of inflammatory or autoimmune diseases that affect the kidney, including lupus and glomerulonephritis . B. CG100760-01: LRR Protein

Expression of gene CG100760-01 was assessed using the primer-probe set Ag4192, described in Table BA. Results of the RTQ-PCR runs are shown in Tables BB, BC and BD.

Table BA. Probe Name Ag4192

Table BB. General_screening_panel_vl .4

Table BC. Panel 4.1D

Table BD. general oncology screening panel_v_2.4

General_screening_panel_vl.4 Summary: Ag4192 Highest expression of the CGI 00760-01 is seen in a lung cancer cell line (CT=29.6). Moderate levels of expression are also seen in a cluster of cell lines derived from lung, colon, and brain cancers. Thus, expression of this gene could be used to differentiate the lung cancer cell line sample from other samples on this panel and as a marker of lung, colon and brain cancer. Furthermore, this restricted pattern of expression suggests that therapeutic modulation of the expression or function of this gene may be useful in the treatment of these cancers. Panel 4.1D Summary: Ag4192 Expression of this gene is^" limited to a few samples on this panel, with highest expression of the CG100760-01 gene in Ramos B cells stimulated with ionomycin (CT=30.4). Lower but still significant levels of expression are seen in untreated Ramos B cells, activated B lymphocytes, kidney and thymus. B cells represent a principle component of immunity and contribute to the immune response in a number of important functional roles, including antibody production. Production of antibodies against self- antigens is a major component in autoimmune disorders. Since B cells play an important role in autoimmunity, inflammatory processes and inflammatory cascades, therapeutic modulation of this gene product may reduce or eliminate the symptoms of patients suffering from asthma, allergies, chronic obstructive pulmonary disease, emphysema, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, osteoarthritis, systemic lupus erythematosus and other autoimmune disorders.

general oncology screening panel_v_2.4 Summary: Ag4192 Expression of the CGI 00760-01 gene is limited in kidney cancer (CT=32) and melanoma on this panel. This expression in cancer derived samples is consistent with expression seen in Panel 1.4. Thus, expression of this gene could be used to differentiate the kidney cancer sample from other samples on this panel and as a marker of kidney cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of kidney cancer.

C. CG101068-01: Claudin-9

Expression of gene CGI 01068-01 was assessed using the primer-probe set Ag4202, described in Table CA. Results of the RTQ-PCR runs are shown in Table CB.

Table CA. Probe Name Ag4202

Primers Start SEQ ID

Sequences jLengthl Position No

Forward! 5' -tataactccttgccatgcaaac-3 ' | 22 1 1296 j 153

TET-5 ' -tcaagaggccaatatattcctggcca-3 ' -

Probe 154 TAMRA 26 1320

!Reverse]5 ' -gcatttgcatggctctaagtt-3 ' I 21 j 1370 155

Table CB. General_screeningjpanel_vl.4

ns_ss_uu_ee _Namm_ee | Rel _R E_ux_np 2.(2%11)7 A87g544202, j r^" TIⁱ~ssue _N N_aa_ιm_nee f j ^" R- Euxnp 2.2(%11)7 A87g542ttT

Liver ca. HepG2 0.0 jSpinal Cord Pool 0.0

Kidney Pool 0.0 JAdrenal Gland j 0.0

Fetal Kidney 0.0 jPituitary gland Pool 0.0

Renal ca. 786-0 0.0 jjSalivary Gland 0.1

Renal ca. A498 6.8 JThyroid (female) 3.5

Renal ca. ACHN 3.9 jPancreatic ca. CAPAN2 6.7

Renal ca. UO-31 0.0 jPancreas Pool 0.1

General_screening_panel_vl.4 Summary: Ag4202 Highest expression of the CGI 01068-01 gene is seen in a gastric cancer cell line (CT=26.5). Moderate levels of expression are seen in cell lines derived from pancreatic, brain, renal, lung, colon, breast and ovarian cancers. Thus, expression of this gene may be used to differentiate the gastric cancer cell line from other samples on this panel and as a marker of these cancers. This gene encodes a protein with homology to claudin, a family of proteins that are integral components of the tight junction. Members of this family have been shown to be upregulated in pancreatic cancer and colon cancer and in the former case proposed as novel targets for the treatment of this disease (Michl P. Gastroenterology 2001 Sep;121(3):678- 84; Miwa, N. Oncol Res 2001;12(11-12):469-76) Therefore, therapeutic modulation of the expression or function of this protein may be of use in the treatment of these cancers.

Claudin 11 has been shown to be a component of the CNS myelin and has been implicated in the regulation of growth and differentiation via signal transduction pathways.

Furthermore, evidence has been presented that shows that claudin 11 may be involved in the autoantigen that is responsible for the development of autoimmune demyelinating disease.(Bronstein JM. J Nexrrosci Res 2000 Mar 15;59(6):706-11). Therefore, therapeutic modulation of the expression or function of this putative claudin may be of use in the treatment of demyelinating diseases such as multiple sclerosis and in restoring normal function to the CNS.

D. CG101231-01 and CG101231-02: Integral membrane protein

Expression of gene CGI 01231-01 and CGI 01231-02 was assessed using the primer-probe sets Ag4208 and Ag4997, described in Tables DA and DB. Results of the RTQ-PCR runs are shown in Tables DC and DD.

Table DA. Probe Name Ag4208

Table DB. Probe Name Ag4997

Table DC. General_screening_panel_vl.4

Table DP. Panel 4. ID

General_screening_panel_vl.4 Summary: Ag4997 Highest expression of the CGI 01231-01 gene is detected in an ovarian cancer SK-OV-3 cell line (CT=27). In addition, expression of this gene is also seen in cluster of cancer cell lines including pancreatic, CNS, colon, gastric, renal, lung, breast, ovarian, prostate, squamous cell carcinoma, and melanoma cancer cell lines. Overall, expression of this gene appears to be higher in samples derived from cancer cell lines than in normal tissues. Thus, expression of this gene could be used as a marker to detect the presence of cancer. Furthermore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CTs=29) when compared to adult lung and liver(CTs=33-38). This observation suggests that expression of this gene can be used to distinguish fetal from adult lung and liver. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance growth or development of liver and lung in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver and lung related diseases.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play an important role in central nervous system and therapeutic modulation of this gene product may be useful in the treatment of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4997 Highest expression of the CGI 01231-01 gene is detected in PMA/ionomycin treated basophils (CT=29.4). This gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, lymphocytes, endothelial cell, as well as epithelial and fibroblast cell types from lung and skin, arid normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in

General_screemng_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

E. CG101362-01: Prion Protein

Expression of gene CG101362-01 was assessed using the primer-probe set Ag6902, described in Table EA. Results of the RTQ-PCR runs are shown in Table EB.

Table EA. Probe Name Ag6902

Table EB. General_screening_panel_vl .6

General_screeningjpanel_vl.6 Summary: Ag6902 Highest expression of the CG101362-01 gene is detected in prostate cancer cell line (CT=29.5). Moderate to low levels of expression of this gene is also seen in cluster of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, fetal skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=33.7) when compared to adult liver (CT=37). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as

Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

F. CG101458-01: von Willebrand domain protein

Expression of gene CG101458-01 was assessed using the primer-probe set Ag4220, described in Table FA. Results of the RTQ-PCR runs are shown in Tables FB, FC, FD and FE.

Table FA. Probe Name Ag4220

Start J SEQ ID

Primersj Sequences fLengthj Position j No jForward 5 ' -ccaacaagcacacctttgac-3 ' j^""*20 ^" | ^" 777 j 165

L , ITET- 5 ' -ctgtggagatcctcatccaccccag-3 ' Probe ,._m, 25 801 166 ( JTAMRA jReverse|5 ' -ctatcaggacatggggcata-3 ' I ²⁰ 1 835 1 ¹⁶⁷

Table FB. CNS_neurodegeneration_vl.0

Table FC. General_screening_panel_vl .4

Rel. Exp.(%) Ag4220, Rel. Exp.(%) Ag4220,

Tissue Name Tissue Name Run 221153243 Run 221153243

287 Liver ca. HepG2 0.0 jSpinal Cord Pool 8.9

Kidney Pool 0.0 f Adrenal Gland 7.7

Fetal Kidney 21.9 (Pituitary gland Pool ! 100.0

Renal ca. 786-0 0.0 jSalivary Gland ^{ 17.6

Renal ca. A498 0.0 JThyroid (female) 8.6

Renal ca. ACHN 0.0 fPancreatic ca. CAPAN2 0.0

Renal ca. UO-31 2.4 gPancreas Pool 5.1

Table FD. Panel 4.1D

Table FE. general oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4220 This panel confirms the expression of the CG101458-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4220 Highest expression of the CGI 01458-01 gene is detected in pituitary gland (CT=27.9). Furthermore, moderate to low levels of expression of this gene is also seen in other tissues with metabolic or endocrine functions including pancrease, adrenal gland, thyroid, skeletal muscle, and small intestine. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at moderate to low levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Moderate expression of this gene is also seen in testis. Therefore, Therapeutic modulation of this gene product may be useful in the treatment of testis related diseases such as fertility and hypogonadism.

Significant expression of this gene is seen in fetal kidney and lung. Interestingly, this gene is expressed at much higher levels in fetal (CTs=30-32) when compared to adult kidney and lung(CTs^:=40). This observation suggests that expression of this gene can be used to distinguish fetal from adult kidney and lung. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance growth or development of kidney and lung in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of kidney and lung related diseases.

Panel 4.1D Summary: Ag4220 Significant expression of the CGI 01458-01 gene is detected exclusively in kidney (CT=32.3). Therefore, expression of this gene may be used to distinguish kidney sample from other samples in this panel. In addition, therapeutic modulation of this gene product may be beneficial in the treatment of autoimmune and inflammatory diseases that affect kidney, including lupus and golomerulonephritis.

general oncology screening panel_v_2.4 Summary: Ag4220 Highest expression of the CG101458-01 gene is detected in control kidney samples (CTs=31). Interestingly, expression of this gene is higher in control samples as compared to kidney cancer samples. Therefore, expression of this gene may be used to distinguish between cancer and normal kidney samples. In addition, therapeutic modulation of this gene product that stimulates the function or expression of the this gene product may be beneficial in the treatment of kidney cancer.

In addition, significant expression of this gene is also seen in a bladder cancer, a lung cancer and a metastatic melanoma samples. Expression of this gene is higher in these cancer samples as compared to the adjacent control samples. Therefore, expression of this gene may be used as diagnostic marker for detection of these cancers and therapeutic modulation of this gene product may be beneficial in the treatment of these cancers.

G. CG101475-01: Novel plasma membrane protein containing lectin C- type domain Expression of gene CG101475-01 was assessed using the primer-probe set Ag4214, described in Table GA. Results of the RTQ-PCR runs are shown in Tables GB, GC and GD.

Table GA. Probe Name Ag4214

Table GB. Al comprehensive panel vl.O

Table GC. General_screening_panel_vl.4

Tissue Name Rel. Exp.(%) Ag4214, Rel. Exp.(%) Ag4214,

Tissue Name Run 221254821 Run 221254821

Adipose 0.0 Renal ca. TK-10 0.0

Table GD. Panel 4. ID

AI_comprehensive panel_vl.O Summary: Ag4214 Highest expression of the CG101475- 01 gene is detected in Crohn's disease sample (CT=29). In addition, significant expression of this gene is also seen in samples derived from normal lung samples, COPD lung, emphysema, atopic asthma, asthma, allergy, Crohn's disease (normal matched control and diseased), ulcerative colitis(normal matched control and diseased), psoriasis (normal matched control and diseased), bone (Orthoarthritis and matched control), OA synovium and rheumatoid arthritis cartilage Rep2. Therefore, therapeutic modulation of this gene product may ameliorate symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis

General_screening_panel_yl.4 Summary: Ag4214 Moderate level of expression of the CG101475-01 gene is detected only in testis (CT=31). Therefore, expression of this gene may be used to distinguish testis from other samples used in this panel. In addition, therapeutic modulation of this gene may be useful in the treatment of testis related diseases, including fertility and hypogonadism.

Low levels of expression of this gene is also detected in one of the CNS cancer cell line. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of CNS cancer.

Panel 4.1D Summary: Ag4214 Highest expression of the CG101475-01 gene is detected in LPS treated monocytes (CT=33). Low levels of expression of this gene is also detected in resting monocytes and LAK cells. Therefore, expression of this gene may be used to distinguish monocytes and LAK cells from other samples used in this panel. The expression of this gene in resting cells suggests that the protein encoded by this gene may be involved in normal immunological processes associated with immune homeostasis. In addition, expression of this gene in activated monocytes suggests that this gene may be involved in their function as antigen-presenting cells and antibodies or small molecule therapeutics that block the function of this membrane protein may be useful as anti- inflammatory therapeutics for the treatment of autoimmune and inflammatory diseases.

H. CG101475-02: Novel plasma membrane protein containing lectin C- type domain

Expression of gene CG101475-02 was assessed using the primer-probe set Ag6376, described in Table HA. Please note that CGI 01475-02 represents a full-length physical clone

Table HA. Probe Name Ag6376

I. CG102575-01 and CG102575-02: Novel ATPase associated with various cellular activities Expression of gene CG102575-01 and CG102575-02 was assessed using the primer-probe set Ag4238, described in Table IA. Results of the RTQ-PCR rxms are shown in Tables IB, IC, ID and IE. Please note that CGI 02575-02 represents a full-length physical clone of the CGI 02575-01 gene, validating the prediction of the gene sequence.

Table IA. Probe Name Ag4238

Table IB. CNS_neurodegeneration_vl .0

Table IC. General_screening_panel_vl.4

Table ID. Panel 4. ID

Table IE. general oncology screening panel_v_2.4

CNS_neurodegeneration_vl.0 Summary: Ag4238 This panel does not show differential expression of this gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag4238 Highest expression of this gene is seen in a breast cancer cell line (CT=30.2). This gene is widely expressed in this panel, with moderate expression seen in brain, colon, gastric, lung, breast, ovarian, and melanoma cancers. This expression profile suggests a role for this gene product in cell survival and proliferation. Modulation of this gene product may be useful in the treatment of cancer.

Among tissues with metabolic function, this gene is expressed at low but significant levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=32) when compared to adult liver (CT=37). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.

This gene is also expressed at low but significant levels in the CNS, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. Therefore, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

Panel 4.1D Summary: Ag4238 Highest expression of this gene is seen in acutely activated Thl cells (CT=33.2). In addition, this gene is expressed in a wide range of cell types including activated T cells, LAK cells, dermal fibroblasts, and basophils. This pattern of expression is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

general oncology screening panel_v_2.4 Summary: Ag4238 This gene is widely expressed in this panel, with highest expression in lung cancer (CT=32.6). In addition, this gene is more highly expressed in lung and kidney cancer than in the corresponding normal adjacent tissue. In addition, significant expression of this gene is also associated with colon, and prostate cancer and also with melanoma. Thus, expression of this gene could be used as a marker of these cancers. Furthemore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of lung and kidney cancer.

J. CG102615-01: mat8

Expression of gene CGI 02615 -01 was assessed using the primer-probe set Ag2173, described in Table JA. Results of the RTQ-PCR runs are shown in Tables JB, JC, JD and JE.

Table JA. Probe Name Ag2173

Table JB. Panel 1.3D

Table JC. Panel 2D

Table JD. Panel 4D

Table JE. Panel 5 Islet

Panel 1.3D Summary: Ag2173 Highest expression of the CG102615-01 gene is detected in colorectal sample (CT=24). Therefore, expression of this gene may be used to distinguish this sample from other samples used in this panel. In addition, significant expression of this gene is seen in number of cancer cell lines including melanoma, ovarian, breast, lung, colon, pancreatic and liver cancer cell lines. The CG102615-01 gene codes for chloride conductane inducer protein MAT-8 precursor. MAT-8 is known to mediate chloride flow, affecting the membrane potential of the cell (Morrison et al., 1995, J. Biol. Chem. 270:2176-2182, PMID=7836447). Changes in membrane potential can affect tumor cell and associated smooth muscle cells (therefore tumor-induced vasculature) growth and motility. In this respect the expression of this gene in fetal muscle is an indication of a role in muscle growth/development. Therapeutic targeting of the CGI 02615-01 gene product with a monoclonal antibody is anticipated to limit or block the extent of tumor cell growth and motility and tumor associated angiogenesis, preferably in breast, ovarian bladder, lung tumors.

Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, thyroid, pituitary gland, skeletal muscle, heart, and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at low levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 2D Summary: Ag2173 Highest expression of the CG102615-01 gene is detected in normal prostate (CT=22.8). High expression of this gene is seen in normal and cancer samples derived from colon, prostate, lung, melanoma, uterus, thyroid, breast, liver, bladder, ovary, and stomach. Interestingly, expression of this gene is higher in ovarian, bladder, breast, uterine, and lung cancer samples as compared to their corresponding adjacent control samples. Therefore, therapeutic targeting of the CG102615-01 gene product with antibodies or small molecule inhibitors is anticipated to limit or block the extent of tumor cell growth and motility as well as tumor associated angiogenesis, preferably in ovarian, bladder, breast, uterine, and lung cancer.

Also the expression of this gene is decreased in kidney cancers compared to the normal adjacent tissues. Hence the protein product or fragments of this protein may be useful in the treatment of kidney cancer.

Panel 4D Summary: Ag2173 Highest expression of the CG102615-01 gene is detected in NCI-H292 cells (CT=23.8). High to moderate level of this gene is also found in lung derived cell types: small airway and bronchial epithelium treated with TNF-a and II- 1, lung fibroblast treated with IFN. This pattern of expression suggests a role for this gene in pathology of lung inflammatory dideases. Therefore therapeutic modulation of this gene product may be beneficial in the treatment of asthma, emphysema or lung infection. Interestingly, high to low levels of expression of this gene is also seen in keratinocytes, basophils, IFN gamma treated dermal fibroblasts, liver cirrhosis, IBD colitis and Crohn's disease samples and normal tissues represented by colon, lung, thymus and kidney. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment ^• of autoimmune and inflammatory disease associated with these cell types and tissues including asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Panel 5 Islet Summary: Ag2173 Highest expression of the CG102615-01 gene is detected in untreated liver HepG2 samples (CT=28.6). In addition, high to low levels of expression of this gene is also seen in islet cells, placenta, uterus, small intestine, kidney and adipose tissues. The CGI 02615-01 gene codes for chloride conductane inducer protein MAT-8 precursor. MAT-8 is known to mediate chloride flow, affecting the membrane potential of the cell (Morrison et al., 1995, J. Biol. Chem. 270:2176-2182, PMID=^::7836447). Since membrane potential is critical in the secretory process in the beta cell, therapeutic modulation of the activity of this gene may prove useful in enhancing insulin secretion in Type II diabetes.

K. CG102646-01: High Affinity Proline Permease Like

Expression of gene CGI 02646-01 was assessed using the primer-probe set Ag4241, described in Table KA.

Table KA. Probe Name Ag4241

L. CG102878-01 and CG102878-02: Hypothetical Transmembrane

Expression of gene CG102878-01 and CG102878-02 was assessed using the primer-probe set Ag4246, described in Table LA. Results of the RTQ-PCR runs are shown in Tables LB, LC, LD and LE. Please note that CGI 02878-02 represents a full-length physical clone of the CGI 02878-01 gene, validating the prediction of the gene sequence.

Table LA. Probe Name Ag4246

Table LB. CNS_neurodegeneration_vl.0

Control (Path) 1 Control (Path) 3

55.5 32.5 Temporal Ctx Parietal Ctx

Control (Path) 2 Control (Path) 4

67.8 76.8 Temporal Ctx Parietal Ctx

Table LC. General_screening_panel_vl.4

Table LD. Panel 4. ID

Table LE. general oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4246 This panel confirms the expression of the CG102878-01 gene at low levels in the brain in an independent group of individuals. This gene is found to be down-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this receptor may be of use in reversing the dementia/memory loss associated with this disease and neuronal death.

General_screening_panel_vl.4 Summary: Ag4246 Highest expression of the CGI 02878-01 gene is detected in breast cancer T47D cell line (CT=26.2). Significant expression of this gene is also seen in clusters of cancer cell lines derived from melanoma, pancreatic, renal, gastric, colon, lung, breast, ovarian and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, breast, ovarian and brain cancer. Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4246 Highest expression of the CG102878-01 gene is detected in kidney (CT=31.9). This gene is expressed at moderate to low levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

general oncology screening panel_v_2.4 Summary: Ag4246 Highest expression of the CG102878-01 gene is detected in kidney cancer sample (CT=31). Moderate to low levels of expression of this gene is seen in normal and cancer samples derived from kidney, colon, lung, and prostate. Significant expression of this gene is also seen in metastatic melanoma. Interestingly, expression of this gene is higher in lung cancer samples as compared to adjacent control samples. Therefore, expression of this gene may be used as diagnostic marker for Ixmg cancer and metastic melanoma. Furtherermore, therapeutic modulation of this gene product may be beneficial in the treatment of melanoma, colon, lung, prostate and some cases of kidney cancer.

M. CG103459-01: Novel Peptide/Histidine Transporter

Expression of gene CGI 03459-01 was assessed using the primer-probe set Ag4262, described in Table MA. Results of the RTQ-PCR runs are shown in Tables MB, MC and MD.

Table MA. Probe Name Ag4262

Start J SEQ ID

Primers Sequences 1 Length! Position No

Forward; 5 ' -cagagtaatggtgaaggcattg-3 ' T__rι 845 J 186

TET-5 ' -tcagcaatcttctaaacaaagtctgtttga-

Probe 3 ' -TAMRA J 30 j 874 187

Reverse 5 ' -cccaccatgagacatcttacat-3 ' 1 ²² I 907 } 188

Table MB. CNS_neurodegeneration_vl.O

Table MC. General_screening__panel_vl.4

Table MD. Panel 4.1D

CNSjneurodegeneration vl.O Summary: Ag4262 This panel confirms the expression of the CG103459-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag4262 Highest expression of the

CG103459-01 gene is detected in CNS cancer (astro) SNB-75 cell line (28.7). High to moderate levels of expression of this gene is seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, renal, lung, breast, ovarian, prostate, squamous cell carcinoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4262 Highest expression of the CG103459-01 gene is detected in resting neutrophils (CT=29.3). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

N. CG104210-01: type III membrane protein

Expression of gene CG104210-01 was assessed using the primer-probe set Ag4270, described in Table NA. Results of the RTQ-PCR runs are shown in Tables NB, NC, ND and NE.

Table NA. Probe Name Ag4270

Table NB. CNS_neurodegeneration_v 1.0

Table NC. HASS Panel vl.O

Table ND. Panel 4.1D

Table NE. general oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4270 This panel confirms the expression of the CGI 04210-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Low expression of this gene in brain suggests that this gene may play role in neurological disorders such as Parkinson's disease, epilepsy, multiple sclerosis,^""schi^"zophrenia and depression. Therefore, therapeutic modulation of this gene may be useful in the treatment of these neurological disorders.

HASS Panel vl.O Summary: Ag4270 Highest expression of the CG104210-01 gene is detected in LnCAP (Al 1) cell line sample (CT=31.6) that are exposed to an acidic environment. CaPAN cells also show a modest increase in gene expression when exposed to an acidic environment (A10, Al 1 compared to A4, A5 resp.)

This suggests a possible induction of this gene in acidotic regions of prostate and pancreatic cancer.

Panel 4.1D Summary: Ag4270 Highest expression of the CG104210-01 gene is detected in activated CD45RA CD4 lymphocyte (CT=29), which represent activated naive T cells. In activated memory T cells (CD45RO CD4 lymphocyte) or CD4 Thl or Th2 cells, resting CD4 cells (CTs=40), the expression of CGI 04210-01 is strongly down regulated suggesting a role for this putative protein in differentiation or activation of naive T cells. Therefore, expression of this gene may be used to distinguish this sample from other samples used in this panel. In addition, Therefore modulation of the expression and/or activity of this putative protein encoded by this gene might be beneficial for the control of autoimmune diseases and T cell mediated diseases such as arthritis, psoriasis, IBD and asthma.

Furthermore, low expression of this gene is also seen in small airway epithelium, and PMA/ionomycin treated LAK cells. In addition, moderate expression of this gene is also seen in kidney and thymus. Therefore, therapeutic modulation of this gene product may be useful in the treatment of autoimmune and inflammatory diseases involving these cell and tissue types such as asthma, COPD, arthritis, psoriasis, IBD, lupus, viral and bacterial infection.

general oncology screening panel_v_2.4 Summary: Ag4270 Highest expression of the CG104210-01 gene is detected in metastatic melanoma (CT=33). Significant expression of this gene is also seen in melanoma and a lung cancer (OD06850-03C) samples. Interestingly, expression of this gene in lung cancer is higher as compared to the adjacent control sample. Therefore, expression of this gene may be used as diagnostic marker for detection of melanoma and lung cancer. Furthermore, therapeutic modulation of this gene may be useful in the treatment of melanoma and lung cancer.

O. CG104251-01: Type III membrane protein

Expression of gene CG104251-01 was assessed using the primer-probe set Ag4280, described in Table OA. Results of the RTQ-PCR runs are shown in Tables OB, OC and OD.

Table OA. Probe Name Ag4280

Table OB. CNS_neurodegeneration_vl .0

Table OC. General_screening_panel_vl.4

Table OD. Panel 4.1D

CNS_neurodegeneration_vl.O Summary: Ag4280 Very low levels of expression of the CG 104251-01 gene is seen in the brains of an independent group of individuals, with highest expression in hippocampus of an Alzeimer patient (CT=34.3). However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag4280 Highest expression of the

CG104251-01 gene is detected in a colon cancer HCT-116 cell line (CT=30). Significant expression of this gene is also seen in clusters of cancer cell lines derived from pancreatic, gastric, colon, renal, lung, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be useful as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene product may be effective in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at low levels in pancreas, adrenal gland, thyroid, pituitary gland, fetal skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT =32.7) when compared to adult liver (CT=36). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.

In addition, low expression of this gene is also seen in brain (thalamus). Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of neurological disorders.

Panel 4.1D Summary: Ag4280 Highest expression of the CG104251-01 gene is detected in kidney (CT=31.8). This gene is expressed at low levels in a wide range of cell types of significance in the immxrne response in health and disease. These cells include members of the T-cell, B-cell, and endothelial cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by lung, thymus and kidney. This pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

P. CG104934-01: POTENTIAL PHOSPHOLIPID-TRANSPORTING ATPASE IH

Expression of gene CGI 04934-01 was assessed using the primer-probe set Ag4274, described in Table PA. Results of the RTQ-PCR runs are shown in Tables PB, PC and PD.

Table PA. Probe Name Ag4274

Table PB. CNS_neurodegeneration_vl .0

Table PC. General_screeningjpanel_vl.4

Table PP. Panel 4. ID

HUVEC none 1 28.1 Kidney 51.1

HUVEC starved j 45.7

CNS_neurodegeneration_vl.0 Summary: Ag4274 This panel confirms the expression of the CGI 04934-01 gene at low levels in the brain in an independent group of individuals. This gene is found to be upregulated in the temporal cortex of Alzheimer's disease patients. Blockade of this receptor may be of use in the treatment of this disease and decrease neuronal death.

Generaι_screening_panel_vl.4 Summary: Ag4274 Highest expression of the CG104934-01 gene is detected in fetal lung (CT=23.5). Interestingly, this gene is expressed at much higher levels in fetal (CT=23.5) when compared to adult lung (CT=29.5). This observation suggests that expression of this gene can be used to distinguish fetal from adult lung. In addition, the relative overexpression of this gene in fetal lung suggests that the protein product may enhance lung growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of lung related diseases.

Significant expression of this gene is also seen in clusters of cancer cell lines derived from pancreatic, gastric, colon, renal, lung, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene may be used as a diagnostic marker for detection of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of pancreatic, gastric, colon, renal, lung, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at high levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

The CG104934-01 gene codes for a variant of potential phospholipid-transporting ATPase, a P-type ATPase with phospholipid transporting activity. In mice, a P-type ATPase (p- locus fat-associated ATPase) was mapped to locus that deletion of which results in increase in the body fat of the mice (Dhar et al, 2000, Physiol Genomics 4(1):93-100, PMID: 11074018). Therefore, based on functional homology, the CG104934-01 gene may also play a role in modulation of the body fat in human and therapeutic modulation of this protein may be useful in the treatment of obesity and diabetes.

Mutations in the FIC1 gene, a member of phospholipid-transporting ATPase, is shown to constitute the molecular defect in familial intrahepatic cholestasis I (Byler's disease) and benign recurrent intrahepatic cholestasis (Ujhazy et al., 2001, Hepatology 34:768-75, PMID: 11584374). Thus, based on homology, potential phospholipid-transporting ATPase encoded by this gene may also play a role in pathology of Byler's disease and intrahepatic cholestasis and therapeutic modulation of this protein may be useful in the treatment of these diseases.

In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4274 Highest expression of the CG104934-01 gene is detected in monocytes (CTs=28.4). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Q. CG105463-01 and CG105463-02: Meningioma-Expressed Antigen

6/11 (MEA6) (MEA11) Expression of gene CGI 05463-01 and CGI 05463-02 was assessed using the primer-probe set Ag4288, described in Table QA. Results of the RTQ-PCR runs are shown in Tables QB, QC and QD. Please note that CGI 05463-02 represents a full-length physical clone of the CGI 05463-01 gene, validating the prediction of the gene sequence.

Table OA. Probe Name Ag4288

Table QB. CNS_neurodegeneration_vl .0

Table QC. General_screening_panel_vl.4

Table OP. Panel 4. ID

CNS_neurodegeneration_vl.O Summary: Ag4288 This panel confirms the expression of the CG105463-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders. General_screeningjpanel_vl.4 Summary: Ag4288 Highest expression of the CGI 05463-01 gene is detected in colon cancer CaCo-2 cell line (CT=30). Significant expression is also seen in number of cancer cell lines derived from colon, renal, lung, liver, breast, ovarian, and brain cancers. Thus, expression of this gene as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of colon, renal, lung, liver, breast, ovarian, and brain cancers.

The CG105463-01 gene codes for a homolog of meningioma-expressed antigen 6/11 (MEA6). MGEA6 is overexpressed in meningioma and glioma tumor cells. Furthermore, the immune response to MGEA6/11 is frequent in both meningioma and glioma patients (Comtesse et al., 2002, Oncogene 21(2):239-47, PMID: 11803467). Thus, based on the homology, MEA6 like protein encoded by the CG105463-01 gene may play a role in pathology of meningioma and glioma and therapeutic modulation of this gene may be beneficial in the treatment of these tumors.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adipose, skeletal muscle, fetal heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CTs=31 -32) when compared to adult liver and heart(CTs>37). This observation suggests that expression of this gene can be used to distinguish fetal heart and liver from corresponding adult tissues. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance growth or development of heart and liver in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of MEA6 like protein encoded by this gene could be useful in treatment of heart and liver related diseases.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4288 Highest expression of the CG105463-01 gene is detected in kidney (CT=29.3). Therefore, expression of this gene may be used to distinguish kidney from other samples used in this panel. Furthermore, therapeutic modulation of this gene product may be useful in the treatment of autoimmune and inflammatory disease that affect kidney, including lupus and glomerulonephritis.

In addition, moderate to low expression of this gene is also seen in TNFalpha + ILlbeta treated bronchial epithelium, basophils, NCI-H292, resting neutrophils and normal tissues represented by colon and thymus. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, lupus erythematosus, or psoriasis.

R. CG105491-01: Serine protease

Expression of gene CG105491-01 was assessed using the primer-probe sets Ag4348,

Ag4302 and Ag6953, described in Tables RA, RB and RC. Results of the RTQ-PCR runs are shown in Tables RD, RE and RF.

Table RA. Probe Name Ag4348

Table RB. Probe Name Ag4302

Table RC. Probe Name Ag6953

Table RD. CNS_neurodegeneration_vl.O

Table RE. General_screening_panel_vl.6

Table RF. Panel 4. IP

CNS_neurodegeneration_vl.O Summary: Ag4348 This panel confirms the expression of the CGI 05491-01 gene at low levels in the brain in an independent group of individuals. This gene is found to be slightly down-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, up-regulation of this gene or its protein product, or treatment with specific agonists for this protein may be of use in reversing the dementia/memory loss associated with this disease and neuronal death.

The CGI 05491-01 gene codes for a serine protease. Plasmin, a member of serine protease family, is shown to increase the processing of human APP preferentially at the alpha- cleavage site, and efficiently degrades secreted amyloidogenic and non-amyloidogenic APP fragments. Brain tissue from Alzheimer's disease patients was shown to contain reduced levels of plasmin, implying that plasmin downregulation may cause amyloid plaque deposition accompanying sporadic Alzheimer's disease (Ledesma et al., 2000, EMBO Rep l(6):530-5, PMIP: 11263499). Thus, based on functional homology and also, on expression pattern, the serine protease encoded by this gene may also play a role in degradation of amyloidogenic and non-amyloidogenic APP fragments. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of Alzheimer's disease.

General_screeningjpanel_vl.6 Summary: Ag6953 Highest expression of this gene is detected in testis and a breast cancer MPA-MB-231 cell line (CTs=33.1). Therefore, expression of this gene may be used to distinguish these samples from other samples in this panel. In addition, low expression of this gene is detected in pancreatic, a gastric, and squamous cell cancer cell lines. Therefore, expression of this gene may be used as diagnostic marker for detection of squamous cell carcinoma, breast, pancreatic, and gastric cancers. In additon, therapeutic modulation of this gene product may be useful in the treatment of these cancers.

In addition to testis, low levels of expression of this gene is also seen in normal tissues represented by thymus, lymphnode, bladder, colon and small intestine. Therefore, therapeutic modulation of this gene may be useful in the treatment of disease associated with these tissues.

Low levels of expression of this gene is also detected in fetal skeletal muscle. Interestingly, this gene is expressed at much higher levels in fetal (CT=34.5) when compared to adult skeletal muscle (CT= 0). This observation suggests that expression of this gene can be used to distinguish fetal from adult skeletal muscle. In addition, the relative overexpression of this gene in fetal skeletal muscle suggests that the protein product may enhance muscular growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of muscle related diseases. More specifically, treatment of weak or dystrophic muscle with the protein encoded by this gene could restore muscle mass or function.

Panel 4.1D Summary: Ag4348 Moderate level of expression of the CG105491-01 gene is detected only in kidney sample (CT=31.2). Therefore, expression of this gene may be used to distinguish kidney from other samples used in this panel. In addition, therapeutic modulation of this gene product may be beneficial in the treatment of autoimmune and inflammatory diseases that affect kidney, including lupus and glomerulonephritis.

S. CG105954-01: human ortholog of chicken NEUROFASCIN PRECURSOR

Expression of gene CGI 05954-01 was assessed using the primer-probe set Ag4311 , described in Table SA.

Table SA. Probe Name Ag4311

Primers! Sequences jLengthl Start SEQ ID Position No

ForwardlS ' -aatgggatcatgattggataca-3 22 2890 210

ITET-5 ' -aatatgtggcctgtacgttctcccca-3 '

Probe 26 2918 211 TA RA

Reverse|5 ' -ttcσtactttggtcccgttaac-3 ' 22 2944 212

T. CG105963-01: Novel cadherin

Expression of gene CG 105963-01 was assessed using the primer-probe set Ag4312, described in Table TA. Results of the RTQ-PCR runs are shown in Tables TB and TC.

Table TA. Probe Name Ag4312

Primersi jLength; Start SEQ ID

Sequences Position No

Forwardfs ' -cagccctcatctatgactacga-3 ' 22 2219 213 jTET-5 ' -acgctgagctccatcctgtccag-3

Probe 23 2263 214 TAMRA

ReversejS ' -agtcgtagtcctggtcctcatc-3 ' 22 2293 215

Table TB. General_screening_panel_vl.4

Renal ca. ACHN 0.0 Pancreatic ca. CAPAN2 0.0

Renal ca. UO-31 0.0 {Pancreas Pool 0.2

Table TC. Panel 4. IP

General_screening_panel_vl.4 Summary: Ag4312 Highest expression of the CG105963-01 gene is detected in brain (cerebellum) (Ct=28.8). In addition, moderate expression of this gene is also seen in whole brain sample. The CG105963-01 gene codes for a variant of cadherin-15 (M-cadherin). Cadherins are calcium-dependent, transmembrane intercellular adhesion proteins with morphoregulatory functions in the development and maintenance of tissues. Cadherins can act as axon guidance and cell adhesion proteins, specifically during development and in the response to injury (Ranscht B., 2000, Int. J. Pev. Neurosci. 18: 643-651, PMIP: 10978842). In addition, M-cadherin is involved in muscle cell, Schwann cell, and motoneuron interactions and also in differentiation during neuromuscular development (Padilla et al., 1998, Mol Cell Neurosci 11(4):217-33, PMIP: 9675053). Therefore, therapeutic modulation of this protein may be useful in inducing a compensatory synaptogenic response to neuronal death in Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, ALS, head trauma, stroke, or any other disease/condition associated with neuronal loss. In addition, low to moderate levels of expression of this gene is also^' seen in number ot cancer cell lines including CNS cancer, colon, renal, liver, lung, breast, ovarian and prostate cancer cell lines. Therefore, therapeutic modulation of this gene product may be useful in the treatment of these cancers.

Moderate expression of this gene is also seen in skeletal muscle. M-cadherin is shown to be important for skeletal muscle development, in particular the fusion of myoblasts into myotubes (Kaufmann et al., 1999, J Cell Sci 112:55-68, PMIP: 9841904). Therefore, therapeutic modulation of this gene may be beneficial in the treatment of muscle related disease

Panel 4.1D Summary: Ag4312 Highest expression of the CG105963-01 gene is detected in kidney (CT=28.3). Therefore, expression of this gene may be used to distinguish kidney sample from other samples used in this panel. In addition, moderate to low expression of this gene is also seen in thymus, lung, TNF alpha + IL-1 beta treated Ixmg fibroblasts and endothelial cells represent by HPAEC and HUVEC, coronery artery, and lung microvascular EC. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of autoimmune and inflammatory diseases affecting kidney and lung including lupus erythematosus, asthma, emphysema, Crohn's disease, ulcerative colitis, rheumatoid arthritis, osteoarthritis, and psoriasis.

U. CG105973-01 and CG105973-02: INTEGRIN ALPHA-8

Expression of gene CGI 05973-01 and CG105973-02 was assessed using the primer-probe sets Ag4305 and Ag4313, described in Tables UA and UB. Results of the RTQ-PCR runs are shown in Tables UC, UD, UE, UF and UG. Please note that CGI 05973-02 represents a full-length physical clone of the CGI 05973-01 gene, validating the prediction of the gene sequence.

Table UA. Probe Name Ag4305

Table UB. Probe Name Ag4313

Table UC. AI_comprehensive panel_vl .0

Table UP. CNS_neurodegeneration_vl.O

Table UE. General_screening_panel_vl.4

359

Table UF. Panel 4. IP

361

Table UG. Panel 5 Islet

AI_comprehensive panel_vl.0 Summary: Ag4305 Highest expression of the CG105973- 01 gene is detected in Crohn's sample (CT=28.8). Low to moderate levels of expression of this gene are detected in samples derived from osteoarthritic (OA) bone and adjacent bone as well as OA cartilage, OA synovium and OA synovial fluid samples, and in cartilage, bone, synovium and synovial fluid samples from rheumatoid arthritis patients. Low level expression is also detected in samples derived from normal lung samples, COPO lung, emphysema, atopic asthma, asthma, allergy, Crohn's disease (normal matched control and diseased), ulcerative colitisfnormal matched control and diseased), and psoriasis (normal matched control and diseased). Therefore, therapeutic modulation of this gene product may ameliorate symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis

CNS_neurodegeneration_vl.0 Summary: Ag4305/Ag4313 Two experiments with same primer and probe set are in excellent agreements, with highest expression of the CGI 05973-01 gene in a hippocampus sample from Alzheimer's patient (CTs=31). This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag4305/Ag4313 Two experiments with same primer and probe set are in excellent agreements, with highest expression of the CGI 05973-01 gene in fetal lung (Cts=27.7). Although, this gene appears to be expressed mainly in the normal tissues used in this panel, significant expression of this gene is also seen in two melanoma and three CNS cancer cell lines and colon cancer tissue. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression and therapeutic modulation of this gene product may be useful in the treatment of these neurological disorders.

Panel 4.1D Summary: Ag4305/Ag4313 Two experiments with same primer and probe set are in excellent agreements, with highest expression of the CGI 05973 -01 gene in lung (CTs=31-32). In addition, moderate to low levels of expression of this gene is also seen in liver cirrhosis, dermal fibroblasts and normal tissues represented by colon, thymus, and kidney. Therefore, therapeutic modulation of this gene may be useful in the treatment of autoimmune and inflammatory diseases that affect lung,colon and kidney, such as lupus erythematosus, asthma, emphysema, Crohn's disease, ulcerative colitis, and psoriasis.

The CG105973-01 gene codes for a variant of integrin aIpha-8. In the kidney, the alphaδ integrin chain is expressed in glomerular mesangial cells and it plays a role in early nephrogenesis. In mice the alphaδ integrin chain maintains the integrity of the glomerular capillary tuft during mechanical stress, eg, in hypertension (Hartner et al., 2002, Am J Pathol 160 :861-7, PMIP: 11891185). Therefore, therapeutic modulation of this gene may be useful in the treatment of glomerular mesangial cell related diseases such as glomerulonephritis. Panel 5 Islet Summary: Ag4305 Highest expression of the CG105973-01 gene is detected in uterus (CT=31). This gene is expressed at moderate to low levels in tissues with metabolic or endocrine function including adipose, uterus, small intestine and kidney. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at low levels (CT=34) in human islets. Integrins are found at the insulin-secreting beta cell surface in situ. Insulin secretagogues upregulate the beta cell-surface expression of some classes of integrins (Bosco et al., 2000, Piabetes 49(2):233-43, PMIP: 10868940). Thus, therapeutic modulation of this gene product may increase beta cell insulin secretion and may be useful in the treatment of Type 2 diabetes.

V. CG106915-01 and CG106924-01: Novel Nogo receptor isoform-2

Expression of gene CGI 06924-01 was assessed using the primer-probe sets Ag4329, Ag4330 and Ag6865, described in Tables VA, VB and VC. Results of the RTQ-PCR runs are shown in Tables VP, VE and VF. Please note that probe Ag4330 is specific for the variant CGI 06924-01.

Table VA. Probe Name Ag4329

Table VB. Probe Name Ag4330

Table VC. Probe Name Ag6865

Start SEQ ID

Primersi Sequences Length! Position No

Forward 5 ' -gctgcacttgtgatctccat-3 ' 20 662 228

Table VP. CNS_neurodegeneration_vl.O

Table VE. General_screening__panel_vl.4

Table VF. General_screeningjpanel_vl .6

Liver 0.0 (Brain (Thalamus) Pool j 7.9

Fetal Liver 0.6 Brain (whole) | 1.1

Liver ca. HepG2 0.0 Spinal Cord Pool j 2.4

Kidney Pool 5.9 Adrenal Gland j 0.0

Fetal Kidney 1.8 (Pituitary gland Pool j 1.2

Renal ca. 786-0 0.0 (Salivary Gland ] 0.0 Renal ca. A498 1.7 (Thyroid (female) j 0.0

Renal ca. ACHN 0.0 (Pancreatic ca. CAPAN2 j 0.0

Renal ca. UO-31 0.0 (Pancreas Pool j 0.0

CNS_neurodegeneration_vl.O Summary: Ag4329/Ag4330 Two experiments with two different probe and primer sets are in good agreement with significant expression of the CGI 06924-01 gene in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4329/Ag4330 Two experiment with different probe and primer sets are in excellent agreements with highest expression of the CG106924-01 gene in fetal heart (CT=30.5-32). Interestingly, expression of this gene is higher in fetal as compared to the adult heart (CT=33.8-34.6). Therefore, expression of this gene may be used to distinguish fetal heart from adult tissue and also from other samples used in this panel. In addition, the relative overexpression of this gene in fetal heart suggests that the protein product may enhance heart growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of heart related diseases.

In addition, this gene is expressed at low levels in some of the regions of the central nervous system examined, including substantia nigra, thalamus, and cerebral cortex. This gene encodes a leucine-rich repeat protein. Leucine rich repeats (LRR) mediate reversible protein-protein interactions and have diverse cellular functions, including cellular adhesion and signaling. Several of these proteins, such as connectin, slit, chaoptin, and Toll have been shown to have a pivotal role in neuronal development in Prosophila, as well as a distinct role in neural development and in the adult nervous system of humans (Battye R., 2001, J. Neurosci. 21 : 4290-4298; Itoh A., 1998, Brain Res. Mol. Brain Res. 62: 175-186). In Prosophilia, the LRR region of axon guidance proteins has been shown to be critical for their function (especially in axon repulsion). Since the leucine-rich-repeat protein encoded by this gene shows significant expression in the cerebral cortex, it is an excellent candidate neuronal guidance protein for axons, dendrites and/or growth cones in general. Therefore, therapeutic modulation of the levels of this protein, or possible signaling via this protein, may be of utility in enhancing/directing compensatory synaptogenesis and fiber growth in the CNS in response to neuronal death (stroke, head trauma), axon lesion (spinal cord injury), or neurodegeneration (Alzheimer's, Parkinson's, Huntington's, vascular dementia or any neurodegenerative disease).

General_screening_panel_vl.6 Summary: Ag6865 Highest expression of the

CGI 06915-01 gene is detected in fetal heart (CT=30.2). Interestingly, expression of this gene is higher in fetal as compared to the adult heart (CT=33.3). Therefore, expression of this gene may be used to distinguish fetal heart from adult tissue and also from other samples used in this panel. In addition, the relative overexpression of this gene in fetal heart suggests that the protein product may enhance heart growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of heart related diseases.

In addition, this gene is expressed at low levels in some of the regions of the central nervous system examined, including thalamus, and cerebral cortex. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders.

Low expression of this gene is also seen in a lung cancer SHP-77 cell line. Therefore, expression of this gene may be used as a marker to detect the presence of lung cancer and therapeutic modulation of this gene may be useful in the treatment of this cancer.

Low expression of this gene is also seen in kidney, testis and adipose tissue. Therefore, therapeutic modulation of this gene may be useful in the treatment of diseases associated with these tissues including obesity, diabetes, lupus, glomerulonephritis, fertility and hypogonadism.

W. CG106942-01: Nramp-Iike membrane protein Expression of gene CGI 06942-01 was assessed using the primer-probe set Ag4331, described in Table WA. Results of the RTQ-PCR runs are shown in Tables WB, WC and WP.

Table WA. Probe Name Ag4331

Table WB. CNS_neurodegeneration_vl .0

Table WC. General_screening_panel_vl.4

Table WP. Panel 4. IP

CNS_neurodegeneration_vl.O Summary: Ag4331 This panel confirms the expression of the CGI 06942-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders. General_screening__panel_vl.4 Summary: Ag4331 Highest expression of the CGI 06942-01 gene is detected in a lung cancer SHP-77 cell line (CT=28.5). High to moderate levels of expression of this gene is also seen in cluster of cancer cell lines including CNS, colon, renal, liver, breast, ovarian and melanoma cancer cell lines. Therefore, expression of this gene may be used as diagnostic marker for detection of these cancers and therapeutic modulation of this gene product may be beneficial in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adrenal gland, thyroid, pituitary gland, fetal heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, expression of this gene is higher in fetal (CT=33.8) as compared to adult liver (CT=37). Therefore, expression of this gene may be used to distinguish the fetal tissue from the adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.

In addition, this gene is expressed at high to moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4331 Highest expression of the CG106942-01 gene is detected in IL4 treated NCI-H292 cells (CT=33.4). In addition, moderate to low expression of this gene is also seen in activated primary and secondary Th2 cells, activated CD45RA CP4 lymphocytes, PWM/PHA-L treated PBMC cells, resting astrocytes, untreated and cytokine treated NCI-H292 cells, TNF alpha + IL-1 beta treated lung fibroblasts. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of T cells and B cells mediated diseases such as systemic lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, or psoriasis.

X. CG107513-01: Syntaxin domain containing protein

Expression of gene CG107513-01 was assessed using the primer-probe set Ag4339, described in Table XA. Results of the RTQ-PCR runs are shown in Tables XB, XC and XP.

Table XA. Probe Name Ag4339

Table XB. CNS_neurodegeneration_vl.O

Table XC. General_screening_panel_vl .4

Table XP. Panel 4. IP

CNS_neurodegeneration_vl.O Summary: Ag4339 This panel confirms the expression of the CG107513-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag4339 Highest expression of the

CGI 07513-01 gene is detected in fetal liver (CT=24). Interestingly, this gene is expressed at much higher levels in fetal (CT= 24) when compared to adult liver(CT=34.9). Thus expression of this gene can be used to distinguish fetal from adult liver and also from other samples used in this panel. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may enhance liver growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the membrane protein encoded by this gene may be useful in treatment of liver related diseases.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of the membrane protein encoded by this gene may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag4339 Highest expression of the CG107513-01 gene is detected in activated secondary Thl cells (CT=30.7). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation of the gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Y. CG107533-02: TUMOR NECROSIS FACTOR (LIGAND) SUPERFAMILY, MEMBER 7

Expression of gene CG107533-02 was assessed using the primer-probe set Ag6859, described in Table YA. Results of the RTQ-PCR runs are shown in Table YB.

Table YA. Probe Name Ag6859

Table YB. General j.creening_panel_vl .6

General_screening_panel_vl.6 Summary: Ag6859 Highest expression of the CGI 07533-02 gene is detected in breast cancer BT 549 cell line (CT=29.4). In addition, moderate to low levels of expression of this gene is also seen in number of cancer cell lines derived from colon, lung, renal, breast, ovarian, melanoma and brain cancers. Interestingly, expression of this gene is low or undectable in the samples derived from normal tissues. Thus, expression of this gene may be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of colon, lung, renal, breast, ovarian, melanoma and brain cancers.

Z. CG107562-01 and CG107562-02: TM LRR Ig Fnlll domains

Expression of gene CGI 07562-01 and CGI 07562-02 was assessed using the primer-probe set Ag4340, described in Table ZA. Results of the RTQ-PCR rxms are shown in Tables ZB, ZC, ZP and ZE.

Table ZA. Probe Name Ag4340

Table ZB. CNS neurodegeneration vl.O

Table ZC. General jscreening_panel_v 1.4

Table ZP. Panel 4. IP

Table ZE. general oncology screening panel_v_2.4

CNS_neurodegeneration_vl.O Summary: Ag4340 Two experiments with the same probe and primer set produce results that are in excellent agreement. Highest expression of this gene is seen in the hippocampus of a patient with Alzheimer's disease (CTs=30). The hippocampus is a critical brain region for the formation of long-term memory. This gene encodes a putative LRR/Ig/FNII containing protein. Fibronectin repeat regions are often involved in cell surface binding and in this protein may be involved in the formation and maintenance of specific neuronal networks in the brain. Therefore, this gene product is therefore an excellent drug target for the treatment of dementia (Alzheimer's, vascular, etc) or for memory enhancement.

General_screening_panel_vl.4 Summary: Ag4340 Highest expression of this gene is seen in the fetal brain (CT=28.7). In addition, this gene is expressed at moderate levels in thalamus, substantia nigra, cerebral cortex, hippocampus, and amygdala, with low, but significant expression in the cerebellum. This gene encodes a novel transmembrane protein that contains a putative leucine rich repeat region. Leucine rich repeats (LRR) mediate reversible protein-protein interactions and have diverse cellular functions, including cellular adhesion and signaling. Several of these proteins, such as connectin, slit, chaoptin, and Toll have pivotal roles in neuronal development in Prosophila and may play significant but distinct roles in neural development and in the adult nervous system of humans (Battye R. (2001) J. Neurosci. 21 : 4290-4298. Itoh A. (1998) Brain Res. Mol. Brain Res. 62: 175- 186). In Prosophilia, the LRR region of axon guidance proteins has been shown to be critical for their function (especially in axon repulsion). (Taniguchi H, Shishido E, Takeichi M, Nose A. (2000) J Neurobiol. 42:104-116.) Since the leucine-rich-repeat protein encoded by this gene shows high expression in the cerebral cortex, it is an excellent candidate neuronal guidance protein for axons, dendrites and/or growth cones in general. Therefore, therapeutic modulation of the levels of this protein, or possible signaling via this protein, may be of utility in enhancing/directing compensatory synaptogenesis and fiber growth in the CNS in response to neuronal death (stroke, head trauma), axon lesion (spinal cord injury), or neurodegeneration (Alzheimer's, Parkinson's, Huntington's, vascular dementia or any neurodegenerative disease).

Among tissues with metabolic function, this gene is expressed at low but significant levels in pituitary, adipose, adrenal gland, pancreas, fetal skeletal muscle, and adult and fetal heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

Moderate levels of expression are also seen in colon cancer and some brain, breast, lung, renal, ovarian and melanoma cancer cell lines. Therefore, therapeutic modulation of this gene product may be useful in the treatment of these cancers.

Panel 4.1D Summary: Ag4340 Highest expression of this gene is seen in the kidney (CT=32). In addition, low but significant levels of expression are seen in activated lung and dermal fibroblasts, suggesting a role for this gene product in pathological and inflammatory conditions of the lung and skin.

general oncology screening panel_v_2.4 Summary: Ag4340 Two experiments with the same probe and primer set produce results that are in excellent agreement. Highest expression of the gene is seen in prostate and lung cancer (CTs=29.3-30). In addition, this gene is more highly expressed in lung and prostate cancer than in the corresponding normal adjacent tissue. Thus, expression of this gene could be used as a marker of these cancers. Furthemore, therapeutic modulation of the expression or function of this gene product may be useful in the treatment of lung and prostate cancer.

AA. CG108184-01 and CG108184-02: novel transmembrane protein Tm7

Expression of gene CGI 08184-01 and CGI 08184-02 was assessed using the primer-probe set Ag4350, described in Table AAA. Results of the RTQ-PCR runs are shown in Tables AAB, AAC and AAP. Please note that CGI 08184-02 represents a full-length physical clone of the CGI 08184-01 gene, validating the prediction of the gene sequence. Table AAA. Probe Name Ag4350

Table AAB. CNS_neurodegeneration_vl .0

Table AAC. General_screening_panel_vl .4

Table AAP. Panel 4. IP

CNS_neurodegeneration_vl.O Summary: Ag4350 This panel confirms the expression of the CGI 08184-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential use of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag4350 Higest expression of the CGI 08184- 01 gene is detected in brain (CTs=28.1). High expression of this gene is seen mainly in all the brain regions examined. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. Moderate to low levels of expression of this gene is also seen in cluster of cancer cell lines derived from pancreas, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, therapeutic modulation of the expression or function of this gene may be effective in the treatment of pancreas, gastric, colon, lung, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adipose, thyroid, pituitary gland, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CTs=30.7-33.7) when compared to adult lung and liver (CTs=34-37). This observation suggests that expression of this gene can be used to distinguish fetal lung and liver from corresponding adult tissues. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance growth or development of lung and liver in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the membrane protein encoded by this gene could be useful in treatment of lung and liver related diseases.

Panel 4.1D Summary: Ag4350 Higest expression of the CG108184-01 gene is detected in kidney (CT=27.8). Therefore, expression of this gene may be used to distinguish kidney from other samples used in this panel. Furthermore, therapeutic modulation of this gene product may be useful in the treatment of autoimmune and inflammatory disease that affect kidney, including lupus and glomerulonephritis.

In addition, moderate to low expression of this gene is also seen in CP45RA CP4 lymphocyte act, anti-CP95 CHI 1 treated secondary Thl/Th2/Trl cells, IL-2 treated LAK and NK cells, two way MLR, PWM treated PBMC, microvascular dermal EC, NCI-H292 and normal tissues represented by colon, lung and thymus. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, lupus erythematosus, or psoriasis.

AB. CG108238-01: Sialic acid binding immunoglobulin-like lectin Expression of gene CGI 08238-01 was assessed using the primer-probe set Ag4352, described in Table ABA. Results of the RTQ-PCR runs are shown in Tables ABB, ABC and ABP.

Table ABA. Probe Name Ag4352

Table ABB. CNS neurodegeneration vl.O

Table ABC. General_screening_panel_vl.4

Table ABP. Panel 4. IP

CNS_neurodegeneration_vl.0 Summary: Ag4352 This panel confirms the expression of the CG108238-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Expression of this gene in brain suggests that this gene may play a role in central nervous system disorders such as Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

General_screening_panel_vl.4 Summary: Ag4352 Low levels of expression of the CG108238-01 gene is seen only in testis (CT=34.5). Therefore, expression of this gene may be used to distinguish testis from other samples used in the panel. In addition, therapeutic modulation of this gene product may a beneficial in the treatment of testis related diseases including fertility and hypogonadism.

Panel 4.1D Summary: Ag4352 Low levels of expression of the CGI 08238-01 gene is seen only in kidney (CT=33.6). Therefore, expression of this gene may be used to distinguish kidney from other samples used in the panel. In addition, therapeutic modulation of this gene product may a beneficial in the treatment of autoimmune and inflammatory diseases that affect kidney including lupus and glomerulonephritis.

AC. CG109505-01: Aldehyde dehydrogenase

Expression of gene CG109505-01 was assessed using the primer-probe set Ag4387, described in Table ACA. Results of the RTQ-PCR runs are shown in Tables ACB and ACC.

Table ACA. Probe Name Ag4387

Primers! Sequences ILength Start SEQ ID Position No

Forward j5 ' -tgtatccacagactgccagact-3 22 744 249

Probe JTET-5 ' -tcgtccgaaacatacagtcctttcaca-3 ' -

27 767 250 TAMRA

ReversejS ' -atgtcacaaaagttccgtgtgt-3 ' 22 797 251

Table ACB. General_screening_panel_vl.4

Table ACC. Panel 4. ID

General_screening_panel_vl.4 Summary: Ag4387 Highest expression of the CG109505-01 gene is detected in bone marrow (CT=30.6). Therefore, expression of this gene may be used to distinguish this sample from other samples used in this panel. In addition, therapeutic modulation of this gene product may be useful in the bone marrow related diseases such as leukemia.

Panel 4.1D Summary: Ag4387 Highest expression of the CG109505-01 gene is detected in kidney (CT=30.9). Therefore, expression of this gene may be used to distinguish kidney from other samples used in this panel. In addition, therapeutic modulation of this gene may be beneficial in the treatment of autoimmune of inflammatory disease that affect kidney including lupus and glomeralonephritis.

Moderate to low levels of expression of this gene is also seen in thymus, basophils, and small airway epithelium. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of asthma, allergies, COPP, and emphysema, inflammatory bowel disease, and autoimmune diseases.

AD. CG109742-01: LATENT TRANSFORMING GROWTH FACTOR BETA BINDING PROTEIN 3 like Expression of gene CG109742-01 was assessed using the pπmer-probe sets Agl 112 and Ag25, described in Tables APA. Results of the RTQ-PCR runs are shown in Table APB.

Table APA. Probe Name Ag25

Table APB. Panel 1

Panel 1 Summary: Ag25 Highest expression of the CG109742-01 gene is detected in a lung cancer SW 900 cell line (CT=21.5). High expression of this gene is seen in cluster of cancer cell lines including melanoma, ovarian, breast, lung, renal, colon, gastric, pancreatic and CNS cancer cell lines. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at high levels in pancreas, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

AE. CG109844-01: C4B-BINDING PROTEIN

Expression of gene CGI 09844-01 was assessed using the primer-probe sets Ag4406 and Ag4446, described in Tables AEA and AEB. Results of the RTQ-PCR runs are shown in Table AEC.

Table AEA. Probe Name Ag4406

Table AEB. Probe Name Ag4446

Table AEC. General_screening_panel_vl.4

General_screeningjpanel_vl.4 Summary: Ag4406 Low levels of expression of the CG109844-01 gene is seen only in a colon cancer HCT-116 cell line (CT=34.9). Therefore, express on o t s gene may e use to st ngu s t s sample from other samples used n this panel and also as diagnostic marker for colon cancer. In addition, therapeutic modulation of this gene product may be beneficial for the treatment of colon cancer.

AF. CG110014-03: Protein Tyrosine Kinase-7

Expression of gene CGI 10014-03 was assessed using the primer-probe set Ag6098, described in Table AFA. Results of the RTQ-PCR runs are shown in Table AFB.

Table AFA. Probe Name Ag6098

Start

Primers! Sequences iLengthj SEQ ID Position No

Forwardlδ ' -gcaccctcgatgaaagct-3 ' .1 18 482 261

TET-5' -atacctcgctactaccacgtcctggg-3 ' - )

Probe 26 521 262 TA RA

Reverse 5 ' -agaactggcaatggaacatg-3 ' 20 555 263

Table AFB. General_screeningjpanel_vl .5

General_screeningjpanel_vl.5 Summary: Ag6098 Highest expression of the CGI 10014-03 gene is detected in colon cancer HCT-116 cell line (CT=32.9). In addition, low to moderate expression of this gene is also seen in number of cancer cell lines including CNS, colon, liver, lung, breast, ovarain and melanoma cancer cell lines. This gene codes for a splice variant of tyrosine protein kinase -like 7 precursor (colon carcinoma kinase 4, CCK-4; PTK7), belonging to protein-tyrosine kinases (PTKs) family. PTKs play important role in regulating cell proliferation and differentiation during development. Mossie et al. (1995, Oncogene 11(10):2179-84, PMID: 7478540) showed a varied expression of CCK-4 in colon cancer cell lines and suggested a tumor-characteristic role for CCK-4 as a signal amplifier or modulator. Therefore, therapeutic modulation of this gene product may be beneficial in the treatment of melanoma, CNS, colon, liver, lung, breast, and ovarian cancers.

Moderate expression of this gene is also seen in spinal cord sample. Therefore, therapeutic modulation of this gene product may be useful in the treatment of spinal cord related diseases.

Low expression of this gene is also detected in fetal lung. Interestingly, expression of this gene is higher in fetal (CT=34.3) as compared to adult lung (CT=40). Therefore, the expression of this gene may be used to distinguish the fetal from adult lung. In addition, the relative overexpression of this gene in fetal lung suggests that the protein product may enhance lung growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the CCK-4 protein encoded by this gene could be useful in treatment of Ixmg related diseases.

AG. CG110014-04: Protein Tyrosine Kinase-7

Expression of gene CGI 10014-04 was assessed using the primer-probe set Ag6687, described in Table AGA. Results of the RTQ-PCR runs are shown in Table AGB.

Table AGA. Probe Name Ag6687

Table AGB. General_screening_panel_vl.6

General_screening_panel_vl.6 Summary: Ag6687 Highest expression of the CGI 10014-04 gene is detected in CNS cancer cell line SNB-75 (CT=32.6). In additioi moderate to low levels of expression of this gene is also seen in number of cancer cell lines derived from gastric, colon, lung, renal, breast, ovarian, melanoma and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of gastric, colon, lung, renal, breast, ovarian, melanoma and brain cancers.

Low levels of expression of this gene is also seen in kidney and fetal lung. Interestingly, this gene is expressed at much higher levels in fetal (CT=34.7) when compared to adult lung (CT=38). This observation suggests that expression of this gene can be used to distinguish fetal from adult lung. In addition, the relative overexpression of this gene in fetal lung suggests that the protein product may enhance lung growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of lung and kidney related diseases.

AH. CG110187-01: Novel alpha Cl-like protocadherin

Expression of gene CGI 10187-01 was assessed using the primer-probe set Ag4412, described in Table AHA. Results of the RTQ-PCR runs are shown in Tables AHB, AHC, AHO, AHE and AHF.

Table AHA. Probe Name Ag4412

Table AHB. CNS_neurodegeneration_vl .O

Table AHC. General_screening_panel_vl.4

Table AHP. Oncology_cel ine_screeningjpanel_v3.2

Tissue Name Rel. Tissue Name Rel.

Table AHE. Panel 4. IP

, Rel. Exp.(%) Ag4412,

Tissue Name Rel. Exp.(%) Ag4412

Tissue Name Run 190413471 Run 190413471

Secondary Thl act 0.0 HUVEC IL-lbeta 0.0

Table AHF. general oncology screening panel_v_2.4

CNS neurodegeneration vl.O Summary: Ag4412 This panel does not show differential expression of the CGI 10187-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of use of this gene in the central nervous system.

General_screeningjpanel_vl.4 Summary: Ag4412 Highest expression of the

CGI 10187-01 gene is seen in the fetal brain (CT=29.8). This gene is also expressed at moderate to low levels in all CNS regions examined, including the hippocampus, thalamus, substantia nigra, amygdala, cerebellum and cerebral cortex. The cadherins have been shown to be critical for CNS development, specifically for the guidance of axons, dendrites and/or growth cones in general. Therapeutic modulation of the levels of this protein, or possible signaling via this protein may be of utility in enhancing/directing compensatory synaptogenesis and fiber growth in the CNS in response to neuronal death (stroke, head trauma), axon lesion (spinal cord injury), or neurodegeneration (Alzheimer's, Parkinson's, Huntington's, vascular dementia or any neurodegenerative disease). Since protocadherins play an important role in synaptogenesis, this gene product may also be involved in depression, schizophrenia, which also involve synaptogeneisis. (Hilschmann N. Naturwissenschaften 2001 Jan;88(l):2-12)

Moderate levels of expression are also seen in prostate, ovarian, lung and brain cancer cell lines. Thus, expression of this gene could be used to as a marker to detect the presence of these cancers. This gene encodes a protien that is homologous to cadherin which is involved in cellular adhesion. Oysregulation of cadherins has been observed in cancer, including renal cell carcinomas (Stassar, MJ. Br J Cancer 2001 Nov 2;85(9): 1372-82). Therefore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of prostate, ovarian, lung and brain cancers.

Oncology_cell_line_screeningjpanel_v3.2 Summary: Ag4412 Significant expression of the CGI 10817-01 gene is restricted to lung cancer cell lines and the cerebellum, with highest expression in a small cell lung cancer cell line (CT=32.4). This expression is in agreement with expression in Panel 1.4, where significant levels of expression are detected in the brain and cancer cell lines. Thus, expression of this gene could be used as a marker for lung cancer. Furthermore, therapeutic modulation of the expression or function oft gene may be effective in the treatment of lung cancer.

Panel 4.1D Summary: Ag4412 Significant expression of the CGI 10817-01 gene is restricted to untreated muco-epidermoid NCI-H292 cells (CT=34.9). Thus, the protein could be used to identify certain lung tumors similar to NCI-H292. This expression is in agreement with the previous panels, where significant levels of expression are detected in lung cancer cell lines. The encoded protein may also contribute to the normal function of the goblet cells within the lung. Therefore, designing therapeutics to this protein may be important for the treatment of emphysema and asthma as well as other Ixmg diseases in which goblet cells or the mucus they produce have pathological consequences.

general oncology screening panel_v_2.4 Summary: Ag4412 Highest expression of the CGI 10817-01 gene is seen in kidney cancer (CT=32.2). In addition, significant levels of expression are also seen in kidney cancer and lung cancer when compared to expression in the normal adjacent tissue. Thus, expression of this gene could be used as a marker of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of lung cancer.

Al. CG110205-01 and CG110205-02: A DISINTEGRIN-LIKE AND METALLOPROTEASE (REPROLYSIN TYPE) WITH THROMBOSPONDIN

Expression of gene CGI 10205-01 and CGI 10205-02 was assessed using the primer-probe sets Ag2430, Ag4413, Ag6546, Ag6645, Ag7012 and Ag7058, described in Tables AIA, AIB, AIC, AIO, AIE and AIF. Results of the RTQ-PCR runs are shown in Tables AIG, AIH, All, AIJ, AIK, AIL, AIM, AIN and AIO. Please note that CGI 10205-02 is the peptide containing reprolysin and thrombospondin type 1 domains of CGI 10205-01 and only recognized by probes Ag2430, and Ag4413.

Table AIA. Probe Name Ag2430

jTET-5 ' -catgatcatgccatcttactaacagga-3 '

Probe 27 1231 271

TAMRA

|Reversej5 ' -tcacatggttcattcttccaa-3 ' 21 1272 272

Table AIB. Probe Name Ag4413

Table AIC. Probe Name Ag6546

Start SEQ ID

Primers Sequences JLength! Position No

Forwardj5 ' -ggatagcttggaagtatgcactt- 3 ' 23 2633 276

TET- 5 ' - caaggtcatgaatggaactccaccag- 3 ' -

Probe 26 2658 277 TAMRA jReversejS ' - ctggcatccagcaggtatag-3 20 2700 278

Table AIP. Probe Name Ag6645

Start SEQ ID

Primers Sequences jLength| Position No

ForwardjS ' -ggatagcttggaagtatgcactt-3 ' JL: 23 2633 279

STET-5 ' -caaggtcatgaatggaactccaccag-3 '

Probe ITAMRA 26 I 2658 280

Reversej5 ' -ctggcatccagcaggtatag-3 ' 20 2700 281

Table AIE. Probe Name Ag7012

Table AIF. Probe Name Ag7058

Table AIG. AI_comprehensive panel__vl .0

Table AIH. CNS_neurodegeneration_vl.O

Table AIL General_screening_panel_vl.4

Table AIJ. Oncology_cell_line_screeningjpanel_v3.2

Table AIK. Panel 1.3P

Table AIL. Panel 2P

Rel. Exp.(%) Ag2430, Rel. Exp.(%) Ag2430,

Tissue Name Tissue Name Run 159505825 Run 159505825

Normal Colon 15.4 JKidney Margin 8120608 0.6

Table AIM. Panel 4. IP

Table AIN. Panel 4P

Table AIO. Panel CNS 1

AI_comprehensive panel_vl.O Summary: Ag4413 Highest expression of this gene is seen in a sample from a patient with Crohn's disease (CT=29.4). Moderate levels of expression are also seen in a cluster of tissues derived from patients with asthma and OA. This gene encodes a protein with homology to members of the APAMTS family. APAMTS proteins have been implicated in extracellular proteolysis and may play a critical role in the tissue degradation seen in arthritis and other inflammatory conditions. (Martel- Pelletier J. (2001) Best Pract Res Clin Rheumatol 15(5): 805-29 ) Therefore, therapeutic modulation of the expression or function of this gene through the use of human monoclonal antibodies or small molecule drugs may be effective in the treatment of osteoarthritis and other autoimmune diseases.

CNS_neurodegeneration_vl.O Summary: Ag2430/Ag4413 Two experiments with two different probe and primer sets produce results that are in excellent agreement, with highest expression in the temporal cortex of an Alzheimer's patient (CTs=30-32.7). These results confirm the expression of this gene at low levels in the brain in an independent group of individuals. This gene is found to be upregulated in the temporal cortex of Alzheimer's disease patients. Therefore, therapeutic modulation of the expression or function of this gene may decrease neuronal death and be of use in the treatment of this disease.

General_screeningjpanel__vl.4 Summary: Ag4413 Highest expression of this gene is seen in the cerebellum (CT=_7). In addition, this gene is expressed at moderate to low levels in all regions of the CNS examined. The high levels of expression in the cerebellum suggest that this gene product may be a useful and specific target for the treatment of CNS disorders that originate in this region, such as autism and the ataxias.

Among tissues with metabolic function, this gene is expressed at moderate to low levels in adipose, pancreas, heart, and fetal skeletal muscle and liver. This expression suggests that this gene product may play a role in normal neuroendocrine and metabolic function and ^' that disregulated expression of this gene may contribute to neuroendocrine disorders c metabolic diseases, such as obesity and diabetes.

In addition, this gene is expressed at much higher levels in fetal kidney tissue (CT=29.6) when compared to expression in the adult counterpart (CT=30.6). Thus, expression of this gene may be used to differentiate between the fetal and adult source of this tissue.

Moderate levels of expression are also seen in cell lines from brain, colon, lung, renal and melanoma cancers. Thus, expression of this gene may potentially be used as a marker of these cancers. Therapeutic modulation of this gene product may also be useful in the treatment of these cancers.

OncoIogy_ceII_Iine_screening_panel_v3.2 Summary: Ag2430 Expression of the gene on this panel is limited to cerebellum and lung cancer cell lines. This is in agreement with the expression seen in Panels 1.3P and 1.4. Thus, expression of this gene could be used as a marker of cerebellar tissue and lung cancer and to differentiate these samples from other samples on this panel.

Panel 1.3D Summary: Ag2430 Expression of the gene in this panel is in agreement with expression in Panel 1.4. Highest expression is seen in the cerebellxxm (CT=31), with low but significant expression detected in the amygdala, hippocampus, substantia nigra and thalamus. Moderate to low levels of expression are seen in fetal skeletal muscle, adipose, and cancer cell lines derived from melanoma, breast, lung, renal, colon and brain cancers. Please see Panel 1.4 for further discussion of utility of this gene in human disease.

Panel 2D Summary: Ag2430 Highest expression of this gene is seen in lung cancer (CT=31). In addition, expression of this gene appears to be upregulated in lung, thyroid, gastric and ovarian cancer when compared to expression in the corresponding normal adjacent tissue. This protein is homologous to members of the family of APAMTS proteins that are characterized by disintegrin, metalloproteinase and thrombospondin domains. This domain structure alone leads one to speculate that the expression of these genes in the context of cancer might play a role in the progression of the disease, as both metalloproteinases and thrombospondins have been demonstrated to be important to tumor progression. Specifically, the metalloproteinase domain may play a role in cell invasion and metastasis, and the thrombospondin domain may play a role in angiogenesis. (Masui T. Clin Cancer Res 2001 Nov;7(l l):3437-4)

Based on the expression profile of this gene and the role played by APAMTS proteins in tumor progression, this gene in the correct context might play a role in tumor angiogeneis. Furthermore, therapeutic targeting with antibodies or small molecule drugs directed against this gene product may block the angiogenic and invasion/metastasis promoting activities of this molecule especially in those cancer types where the gene is overexpressed in the tumor compared to the normal adjacent tissue.

Panel 4.1D Summary: Ag4413/Ag7012 Three experiments with two different probe and primer set produce results that are in excellent agreement. Highest expression is seen in TNF-a and IL-1 beta treated HPAECs. This gene appears to be preferentially expressed in endothelial cells, including microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells and human umbilical vein endothelial cells. Endothelial cells are known to play important roles in inflammatory responses by altering the expression of surface proteins that are involved in activation and recruiting of effector inflammatory cells. The expression of this gene in dermal microvascular endothelial cells suggests that this protein product may be involved in inflammatory responses to skin disorders, including psoriasis. Expression in lung microvascular endothelial cells suggests that the protein encoded by this gene may also be involved in lung disorders including asthma, allergies, chronic obstructive pulmonary disease, and emphysema. The protein encoded by this gene has homology to APAMTS family of molecules suggesting that it may function as an enzyme. Based on its homology, it may contribute to the tissue destruction and remodeling processes associated with asthma, ulcerative colitis, emphysema and osteoarthritis. (Kuno K. J Biol Chem 1997 Jan 3;272(l):556-62;) Therefore, blocking the function of the protein encoded by this gene with human nonoclonal antibody therapeutics or small molecule therapeutics may reduce or inhibit tissue destruction in the lungs, intestine, or joints due to emphysema, allergy, asthma, colitis, or osteoarthritis.

Panel 4D Summary: Ag2430 Highest expression of the gene in this panel is seen in HUVECs (CT=28). Expression in this panel is in agreement with expression in Panel 4. IP, with preferential expression seen in endothelial cells, including HPAECs, lung and dermal microvascular ECs, and a cluster of HUVEC samples. Please see Panel 4P for discussion of this gene in inflammation.

Panel CNS_1 Summary: Ag2430 This panel confirms the presence of this gene in the brain. Please see Panels 1.4 and CNS_neurodegeneration for discussion of this gene in the central nervous system.

AJ. CG110242-01: Ebnerin

Expression of gene CGI 10242-01 was assessed using the primer-probe sets Agl 000 and Ag855, described in Tables AJA and AJB. Results of the RTQ-PCR runs are shown in Table AJC.

Table AJA. Probe Name Agl 000

Table AJB. Probe Name Ag855

Table AJC. General_screening_panel_vl.5

General_screening_panel_vl.5 Summary: Ag855 Highest expression of the CGI 10242- 01 gene is seen in the bladder (CT=31). Thus, expression of this gene could be used tc differentiate this sample from other samples on this panel and as a marker of bladder tissue. In addition, low but significant levels of expression are also seen in testis, thalamus, substantia nigra, and whole brain samples. Thus, therapeutic modulation of the expression or function of this gene may be useful in the treatment of neurologic disorders, such as Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, stroke and epilepsy.

AK. CG99598-01: Endosomal Glycoprotein

Expression of gene CG99598-01 was assessed using the primer-probe sets Ag4149 and Ag4806, described in Tables AKA and AKB. Results of the RTQ-PCR runs are shown in Table AKC.

Table AKA. Probe Name Ag4149

Table AKB. Probe Name Ag4806

Primers Start

Sequences SEQ ID iLengthi Position No

Forward! 5 ' -ctacgtggctctggatgatct-3 ' 21 2829 297

TET-5 ' -cctgccctcagccaggttcctgt-3 '

Probe 23 2867 298 TAMRA

Reverse! 5 ' -acacaggccagactcaaaatc-3 ' 21 2890 299

Table AKC. General_screening__panel_v 1.4

Renal ca. UO-31 Pancreas Pool 1 11.7

General_screeningjpanel_vl.4 Summary: Ag4806 Expression of this gene is highest in a breast cancer cell line (CT=31.5). This gene is also expressed in breast, ovarian and colon cancer cell lines at higher levels when compared to normal tissue samples. Hence, expression of this gene might be used as a marker to identify normal tissue from cancerous tissue in these organs.

There is relatively low level of expression in most endocrine (metabolic)-related tissues except for liver. Modulation of this gene or gene-product may therefore be beneficial in treating various abnormalities related to liver function. The higher levels of expression in adult liver (CT=32.7) when compared to fetal liver suggest that expression of this gene can also be used to differentiate fetal vs adult liver tissue. Conversely, higher levels of expression in fetal lung (CT=33) when compared to adult lung (CT=40) suggest involvement of this gene in the development of the lung. Expression of this gene could also therefore be used to differentiate between fetal and adult lung tissue.

Example D: Identification of Single Nucleotide Polymorphisms in NOVX nucleic acid sequences

Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cPNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration of the amino acid encoded by the gene at the position of the SNP. Intragenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result of the redxindancy of the genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation of the expression pattern. Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message.

SeqCalling assemblies produced by the exon linking process were selected and extended using the following criteria. Genomic clones having regions with 98% identity to all or part of the initial or extended sequence were identified by BLASTN searches using the relevant sequence to query human genomic databases. The genomic clones that resulted were selected for further analysis because this identity indicates that these clones contain the genomic locus for these SeqCalling assemblies. These sequences were analyzed for putative coding regions as well as for similarity to the known PNA and protein sequences. Programs used for these analyses include Grail, Genscan, BLAST, HMMER, FASTA, Hybrid and other relevant programs.

Some additional genomic regions may have also been identified because selected SeqCalling assemblies map to those regions. Such SeqCalling sequences may have overlapped with regions defined by homology or exon prediction. They may also be included because the location of the fragment was in the vicinity of genomic regions identified by similarity or exon prediction that had been included in the original predicted sequence. The sequence so identified was manually assembled and then may have been extended using one or more additional sequences taken from CuraGen Corporation's human SeqCalling database. SeqCalling fragments suitable for inclusion were identified by the CuraTools™ program SeqExtend or by identifying SeqCalling fragments mapping to the appropriate regions of the genomic clones analyzed.

The regions defined by the procedures described above were then manually integrated and corrected for apparent inconsistencies that may have arisen, for example, from miscalled bases in the original fragments or from discrepancies between predicted exon junctions, EST locations and regions of sequence similarity, to derive the final sequence disclosed herein. When necessary, the process to identify and analyze SeqCalling assemblies and genomic clones was reiterated to derive the full length sequence (Alderborn et al., Petermination of Single Nucleotide Polymorphisms by Real-time Pyrophosphate PNA Sequencing. Genome Research. 10 (8) 1249-1265, 2000). Variants are reported individually but any combination of all or a select subset of variants are also included as contemplated NOVX embodiments of the invention.

NOVla SNP Data

One polymorphic variant of NOVla has been identified and is shown in Table 42 A. Table 42A

NOV2a SNP Data

One polymorphic variant of NOV2a has been identified and is shown in Table 42B.

Table 42B

NO 5a SNP Data

One polymorphic variant of NOV5a has been identified and is shown in Table 42C. Table 42C

NOV6a SNP Data

Seven polymorphic variants of NOV6a have been identified and are shown in Table 42P.

Table 42D

NOV9a SNP Data

Two polymorphic variants of NOV9a have been identified and are shown in Table 42E. Table 42E

NOV9b SNP Data

Three polymorphic variants of NOV9b have been identified and are shown in Table 42F. Table 42F

NOVlOa SNP Data

Eight polymorphic variants of NOVlOa have been identified and are shown in Table 42G. Table 42G

NOVlla SNP Data

Two polymorphic variants of NOVl la have been identified and are shown in Table 42H. Table 42H

NOV15a SNP Data

Three polymorphic variants of NOVl 5a have been identified and are shown in Table 421. Table 421

NOVlόa SNP Data

One polymoφhic variant of NOVl 6a has been identified and is shown in Table 42 J. Table 42 J

NOV17a SNP Data

One polymoφhic variant of NO VI 7a has been identified and is shown in Table 42K.

Table 42K

NOV19a SNP Data

Two polymoφhic variants of NOVl 9a have been identified and are shown in Table 42L. Table 42L

NO 27a SNP Data

One polymoφhic variant of NOV27a has been identified and is shown in Table 42M. Table 42M

NOV29a SNP Data One polymoφhic variant of NOV29a has been identified and is shown in Table 42N. Table 42N

NOV31a SNP Data One polymoφhic variant of NOV31 a has been identified and is shown in Table 420. Table 42O

NOV35a SNP Data

One polymoφhic variant of NOV35a has been identified and is shown in Table 42P. Table 42P

NOV39a SNP Data

Five polymoφhic variants of NOV39a have been identified and are shown in Table 42Q. Table 42Q

Example E: Potential Role(s) of CGI 02615-01 in Tumorgenesis

The NOV13a gene (CG102615-01) is known to mediate chloride flow, affecting the membrane potential of the cell. Changes in membrane potential can affect tumor cell and associated smooth muscle cells (therefore tumor-induced vasculature) growth and motility. In this respect, the strong expression in fetal muscle is an indication of a role for NOVl 3a in muscle growth/development.

Therapeutic targeting of NOVl 3a with a human monoclonal antibody is anticipated to limit or block the extent of tumor cell growth and motility and tumor associated angiogenesis, preferably in breast, ovarian bladder, lung tumors.

SAGE data is present for NOV13a in Table 43.

Table 43. NOV13a SAGE data

Hs 301350 : FXYD dora_-n-cont_ning ion transport regulator _

SAGE librarv data and reliable tap summary

Reliable tags found m SAGE libraries

JLi-CCSAMJ. Tagspβr tag - i mηiϊKum mWiou ounts TotalJtigit_j

SAGE Caco 2 16 1 61601

SAGE Chen LNCaP 32 2 62267

SAGE Chen LNCaP no-DUT 15 64631

SAGE Chen TumDr Pr 14 68384

SAGE CAPAN 1 52 37926

SAGE Duke GBM Hl l lO 14 70061

SAGE S S37 16 60986

SAGE PR317 normal prostate 16 59419

SAGE PR317 prostate tumor 46 65109

SAGEoooled GBM 16 61841

SAGE NHAβtiϊ) 19 52196

SAGE NCI 19 50115

SAGE NC2 141 7 49552

SAGE Pane 91-16113 88 3 33941

SAGETul02 34 2 57636

SAGETOB 61 3 49005

SAGE SciencePar MCF7 163 10 61079 Control Oh

SAGE SciencePark MCF7 estradiol 3h 33 2 59978

SAGE 95-259 25 1 39473

SAGE 95-260 22 1 45179

SAGE 95-348 33 2 60484

SAGE Medul 3871 115 5 43274

SAGE MousePδ PGCP 1 61240

SAGE MDA453 52 1 18924

SAGE Duke HMVEC VEGr 17 1 57928

SAGE DCIS 218 9 41230

SAGE OVT-S 29 1 33575

SAGE DCIS 2 34 1 2SSSS

Tagsgar I filimiyntmte miWenl <xn mmts Ttmit S

SAGE Caco 2 16 1 61601

SAGE Chen LNCaP 208 13 62267

SAGE Chen LNCaP no-DHT 278 18 64631

SAGE Chen Normal Pr 196 13 66193

SAGE Chen Tumor Pr 102 7 68384

SAGE CAPAH1 632 24 37926

SAGECAPAN2 473 11 23222

SAGE SW837 196 12 60986

SAGE CPDR NCaP-C 48 2 41590

SAGE PR317 normal prostate 521 31 59419

SAGE PR317 prostate tumor 2042 -t - 133 65109

SAGE NCI 2554 *mr 128 50115

SAGE NC2 3329 *• 165 49552

SAGE Pane 91-16113 824 &r* 28 33941

SAGE Pane 96-6252 111 4 35745

SAGE OV1063-3 154 6 38938

SAGETul02 884 ' - 51 57636

SAGETu98 938 " 46 49005

SAGE SciencePark MCF7 control 3h 677 -«'■» 4 5903

SAGE SciencePark MCF7

343 21 61079 Control Oh

OTHER EMBODIMENTS

Although particular embodiments have been disclosed herein in detail, this has been done by way of example for proposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the embodiments described herein. The claims presented are representative of the inventions disclosed herein. Other, unclaimed inventions are also contemplated. Applicants reserve the right to pxirsue such inventions in later claims.

Claims

CLAIMSWhat is claimed is:

1. An isolated polypeptide comprising the mature form of an amino acid sequence selected from the group consisting of SEQ IP NO:2n, wherein n is an integer between 1 and 73.

2. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ IP NO:2n, wherein n is an integer between 1 and 73.

3. An isolated polypeptide comprising an amino acid sequence which is at least 95%> identical to an amino acid sequence selected from the group consisting of SEQ IO NO:2n, wherein n is an integer between 1 and 73.

4. An isolated polypeptide, wherein the polypeptide comprises an amino acid sequence comprising one or more conservative substitutions in the amino acid sequence selected from the group consisting of SEQ IP NO:2n, wherein n is an integer between 1 and 73.

5. The polypeptide of claim 1 wherein said polypeptide is naturally occurring.

6. A composition comprising the polypeptide of claim 1 and a carrier.

7. A kit comprising, in one or more containers, the composition of claim 6.

8. The use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1, wherein the therapeutic comprises the polypeptide of claim 1.

9. A method for determining the presence or amount of the polypeptide of claim 1 in a sample, the method comprising: (a) providing said sample;

(b) introducing said sample to an antibody that binds immunospecifically tι polypeptide; and

(c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.

10. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the polypeptide of claim 1 in a first mammalian subject, the method comprising: a) measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and b) comparing the expression of said polypeptide in the sample of step (a) to the expression of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease, wherein an alteration in the level of expression of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.

11. A method of identifying an agent that binds to the polypeptide of claim 1 , the method comprising:

(a) introducing said polypeptide to said agent; and

(b) determining whether said agent binds to said polypeptide.

12. The method of claim 11 wherein the agent is a cellular receptor or a downstream effector.

13. A method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of the polypeptide of claim 1, the method comprising:

(a) providing a cell expressing the polypeptide of claim 1 and having a property or function ascribable to the polypeptide;

(b) contacting the cell with a composition comprising a candidate substance; and (c) determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition in the absence of the substance, the substance is identified as a potential therapeutic agent.

14. A method for screening for a modulator of activity of or of latency or predisposition to a pathology associated with the polypeptide of claim 1, said method comprising:

(a) administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of claim 1, wherein said test animal recombinantly expresses the polypeptide of claim 1;

(b) measuring the activity of said polypeptide in said test animal after administering the compound of step (a); and

(c) comparing the activity of said polypeptide in said test animal with the activity of said polypeptide in a control animal not administered said polypeptide, wherein a change in the activity of said polypeptide in said test animal relative to said control animal indicates the test compound is a modulator activity of or latency or predisposition to, a pathology associated with the polypeptide of claim 1.

15. The method of claim 14, wherein said test animal is a recombinant test animal that expresses a test protein transgene or expresses said transgene under the control of a promoter at an increased level relative to a wild-type test animal, and wherein said promoter is not the native gene promoter of said transgene.

16. A method for modulating the activity of the polypeptide of claim 1 , the method comprising contacting a cell sample expressing the polypeptide of claim 1 with a compound that binds to said polypeptide in an amount sufficient to modulate the activity of the polypeptide.

17. A method of treating or preventing a pathology associated with the pol peptide of claim 1, the method comprising administering the polypeptide of claim 1 to a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject.

18. The method of claim 17, wherein the subject is a human.

19. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ IO NO:2n, wherein n is an integer between 1 and 73 or a biologically active fragment thereof.

20. An isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ IP NO:2n-l, wherein n is an integer between 1 and 73.

21. The nucleic acid molecule of claim 20, wherein the nucleic acid molecule is naturally occurring.

22. A nucleic acid molecule, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ IO NO: 2n-l, wherein n is an integer between 1 and 73.

23. An isolated nucleic acid molecule encoding the mature form of a polypeptide having an amino acid sequence selected from the group consisting of SEQ IO NO:2n, wherein n is an integer between 1 and 73.

24. An isolated nucleic acid molecule comprising a nucleic acid selected from the group consisting of 2n-l, wherein n is an integer between 1 and 73.

25. The nucleic acid molecule of claim 20, wherein said nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ IO NO: 2n-l, wherein n is an integer between 1 and 73, or a complement of said nucleotide sequence.

26. A vector comprising the nucleic acid molecule of claim 20.

27. The vector of claim 26, further comprising a promoter operably linked to said nucleic acid molecule.

28. A cell comprising the vector of claim 26.

29. An antibody that immunospecifically binds to the polypeptide of claim 1.

30. The antibody of claim 29, wherein the antibody is a monoclonal antibody.

31. The antibody of claim 29, wherein the antibody is a humanized antibody.

32. The antibody of claim 29, wherein the antibody is a fully human antibody.

33. The antibody of claim 29, wherein the dissociation constant for the binding of the polypeptide to the antibody is less than 1 x IO^"9 M.

34. The antibody of claim 29, wherein the antibody neutralizes an activity of the polypeptide.

35. A method of treating or preventing a NOVX-associated disorder, the method comprising administering to a subject in which such treatment or prevention is desired the antibody of claim 29 in an amount sufficient to treat or prevent the pathology in the subject.

36. The method of claim 35, wherein the subject is human.

37. A method for determining the presence or amount of the nucleic acid molecule of claim 20 in a sample, the method comprising:

(a) providing said sample;

(b) introducing said sample to a probe that binds to said nucleic acid molecule; and

(c) determining the presence or amount of said probe bound to said nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in said sample.

38. The method of claim 37 wherein presence or amount of the nucleic acid moleci used as a marker for cell or tissue type.

39. The method of claim 38 wherein the cell or tissue type is cancerous.

40. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the nucleic acid molecule of claim 20 in a first mammalian subject, the method comprising: a) measuring the level of expression of the nucleic acid in a sample from the first mammalian subject; and b) comparing the level of expression of said nucleic acid in the sample of step (a) to the level of expression of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of expression of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

41. A method of producing the polypeptide of claim 1, the method comprising culturing a cell under conditions that lead to expression of the polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-l, wherein n is an integer between 1 and 73.

42. The method of claim 41 wherein the cell is a bacterial cell.

43. The method of claim 41 wherein the cell is an insect cell.

44. The method of claim 41 wherein the cell is a yeast cell.

45. The method of claim 41 wherein the cell is a mammalian cell.

46. A method of producing the polypeptide of claim 2, the method comprising culturing a cell under conditions that lead to expression of the polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-l, wherein n is an integer between 1 and 73.

47. The method of claim 46 wherein the cell is a bacterial cell.

48. The method of claim 46 wherein the cell is an insect cell.

49. The method of claim 46 wherein the cell is a yeast cell.

50. The method of claim 46 wherein the cell is a mammalian cell.