AU2003287228A8 - Methods of identifying compounds that modulate protein activity - Google Patents

Description

WO 2004/056961 PCT/US2003/034114 METHODS OF IDENTIFYING COMPOUNDS THAT MODULATE PROTEIN ACTIVITY TECHNICAL FIELD The present invention relates to novel polypeptides that are targets of small molecule drugs and 5 that have properties related to stimulation of biochemical or physiological responses in a cell, a tissue, an organ or an organism. More particularly, the novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use encompass screening, diagnostic, and prognostic assay procedures as well as methods of treating diverse pathological conditions. 10 1 WO 2004/056961 PCT/US2003/034114 METHODS OF IDENTIFYING COMPOUNDS THAT MODULATE PROTEIN ACTIVITY FIELD OF THE INVENTION The present invention relates to novel polypeptides that are targets of small molecule drugs and that have properties related to stimulation of biochemical or physiological responses in a cell, a tissue, an organ or an organism. More particularly, the novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use encompass screening, diagnostic and prognostic assay procedures as well as methods of treating diverse pathological conditions. BACKGROUND Obesity and diabetes are major public health concerns in the developed and developing world. It is estimated that over half of the adult US population is overweight. This includes those with a body mass index (BMI) greater than the upper limit of normal (25) where the BMI is defined as the weight (Kg) / [height (M)] 2 . A common consequence of being overweight is hyperlipidemia and the development of insulin resistance. This is followed by the development of hyperglycemia, a hallmark of Type 11 diabetes. Left untreated, the hyperglycemia leads to microvascular disease and end organ damage that includes retinopathy, renal disease, cardiac disease, peripheral neuropathy and peripheral vascular compromise. Currently, over 16 million adults in the US are affected by Type 11 diabetes and the condition has now become rampant among school-age children as a consequence of the epidemic of obesity in that age group. Diabetes mellitus is a disorder in which blood levels of glucose (a simple sugar) are abnormally high because the body doesn't release or respond to insulin adequately. Blood sugar (glucose) levels vary throughout the day, rising after a meal and returning to normal within 2 hours. Blood sugar levels are normally between 70 and 110 milligrams per deciliter (mg/dL) of blood in the morning after an overnight fast. They are usually lower than 120 to 140 mg/dL 2 hours after eating foods or drinking liquids containing sugar or other carbohydrates. Insulin, a hormone released from the pancreas, is the primary substance responsible for maintaining appropriate blood sugar levels. Insulin allows glucose to be transported into cells so that they can produce energy or store glucose-derived enrgy until it's needed. The rise in blood sugar levels after eating or drinking stimulates the pancreas to produce insulin, preventing a greater rise in blood sugar levels and causing them to fall gradually. Because muscles use glucose for energy, blood sugar levels can also fall during physical activity. Diabetes results when the body doesn't produce enough insulin to maintain normal blood sugar levels or when cells don't respond appropriately to insulin. In type 11 diabetes mellitus, the 2 WO 2004/056961 PCT/US2003/034114 pancreas continues to manufacture insulin, sometimes even at higher than normal levels. However, the body develops resistance to its effects, resulting in a relative insulin deficiency. The main goal of diabetes treatment is to keep blood sugar levels within the normal range as much as possible. Completely normal levels are difficult to maintain, but the more closely they can be kept within the normal range, the less likely that temporary or long-term complications will develop. Therefore, a therapeutic that decreases insulin resistance and/or enhances insulin secretion would be beneficial in treatment of obesity and/or diabetes. Additionally, such a therapeutic would be beneficial in treatment of insulin resistance, a condition that often leads to the development of diabetes. In order to treat diseases, pathologies and other abnormal states or conditions in which a mammalian organism has been diagnosed as being, or as being at risk for becoming, other than in a normal state or condition, it is important to identify new therapeutic agents. 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 diminished or suppressed level of synthesis and secretion of protein effectors. In other classes of pathologies the 3 WO 2004/056961 PCT/US2003/034114 dysregulation is manifested as increased or up-regulated level of synthesis and secretion of protein effectors. In a clinical setting a subject may be suspected of suffering from a condition brought on by altered or mis-regulated levels of a protein effector of interest. Therefore there is a need to assay for the level of the protein effector of interest in a biological sample from such a subject, and to compare the level with that characteristic of a nonpathological condition. There also is a need to provide the protein effector as a product of manufacture. Administration of the effector to a subject in need thereof is useful in treatment of the pathological condition. Accordingly, there is a need for a method of treatment of a pathological condition brought on by a diminished or suppressed levels of the protein effector of interest. In addition, there is a need for a method of treatment of a pathological condition brought on by a increased or up-regulated levels of the protein effector of interest. Small molecule targets have been implicated in various disease states or pathologies. These targets may be proteins, and particularly enzymatic proteins, which are acted upon by small molecule drugs for the purpose of altering target function and achieving a desired result. Cellular, animal and clinical studies can be performed to elucidate the genetic contribution to the etiology and pathogenesis-of conditions in which small molecule targets are implicated in a variety of physiologic, pharmacologic or native states. These studies utilize the core technologies at CuraGen Corporation to look at differential gene expression, protein-protein interactions, large-scale sequencing of expressed genes and the association of genetic variations such as, but not limited to, single nucleotide polymorphisms (SNPs) or splice variants in and between biological samples from experimental and control groups. The goal of such studies is to identify potential avenues for therapeutic intervention in order to prevent, treat the consequences or cure the conditions. In order to treat diseases, pathologies and other abnormal states or conditions in which a mammalian organism has been diagnosed as being, or as being at risk for becoming, other than in a normal state or condition, it is important to identify new therapeutic agents. Such a procedure includes at least the steps of identifying a target component within an affected tissue or organ, and identifying a candidate therapeutic agent that modulates the functional attributes of the target. The target component may be any biological macromolecule implicated in the disease or pathology. Commonly the target is a polypeptide or protein with specific functional attributes. Other classes of macromolecule may be a nucleic acid, a polysaccharide, a lipid such as a complex lipid or a glycolipid; in addition a target may be a sub-cellular structure or extra-cellular structure that is comprised of more than one of these classes of macromolecule. Once such a target has been identified, it may be employed in a screening assay in order to identify favorable candidate therapeutic agents from among a large population of substances or compounds. In many cases the objective of such screening assays is to identify small molecule candidates; this is commonly approached by the use of combinatorial methodologies to develop the population of substances to be tested. The implementation of high throughput screening methodologies is advantageous when working with large, combinatorial libraries of compounds. DEFINITIONS As used herein, the terms and phrases "nucleic acid-molecule", "probe", "isolated", "oligonucleotide", "complementary", "fragment", "homologous nucleic acid sequence", "homologous 4 WO 2004/056961 PCT/US2003/034114 amino acid sequence", "polypeptide having a biologically active portion of NOVX", "gene", "recombinant gene", "hybaridizes under stringent conditions", "stringent hybridization conditions", "coding region", "noncoding region", "PNAs", "peptide nucleic acids", "isolated", "purified", "derivative", analog", "homolog", "substantially free if chemical precursors or other chemicals", "sequence identity", "chimeric protein", "fusion protein", "operatively linked", "antibody", and "monoclonal antibody" are as defined in United States Patent 6,600,019 in columns 68 to 81, the definitions of which are incorporated in toto herein. SUMMARY OF THE INVENTION The invention includes nucleic acid sequences and the novel polypeptides they encode. The novel nucleic acids and polypeptides are referred to herein as NOVX, or NOVI, 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, which represents the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 47, or polypeptide sequences, which represents the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 47. In one aspect, the invention provides an isolated polypeptide comprising a mature form of a NOVX amino acid. One example is a variant of a mature form of a NOVX amino acid sequence, 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. The amino acid 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 changed. The invention also includes fragments of any of these. 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 allelic variant of a NOVX sequence. In one embodiment, the allelic 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 one embodiment, the invention discloses a method for determining the presence or amount of the NOVX polypeptide in a sample. The method involves the steps of: 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 another embodiment, the invention provides a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide in a mammalian subject. This method involves the steps of: 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 5 WO 2004/056961 PCT/US2003/034114 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, wherein 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 a further embodiment, the invention includes a method of identifying an agent that modulates a NOVX polypeptide. This method can involve the steps of: introducing the polypeptide to the agent; and determining whether the agent binds to the polypeptide. In various embodiments, the agent is a cellular receptor or a downstream effector. In another aspect, the invention provides 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 a NOVX polypeptide. The method involves the steps of: providing a cell expressing the NOVX polypeptide and having a property or function ascribable to the polypeptide; contacting the cell with a composition comprising a candidate substance; and 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 devoid of the substance, the substance is identified as a potential therapeutic agent. In another aspect, the invention describes a method for screening for a modulator of activity or of latency or predisposition to a pathology associated with the NOVX polypeptide. This method involves the following steps: administering a test compound to a test animal at increased risk for a pathology associated with the NOVX polypeptide, wherein the test animal recombinantly expresses the NOVX polypeptide. This method involves the steps of measuring the activity of the NOVX polypeptide in the test animal after administering the compound of step; and comparing the activity of the protein in the test animal with the activity of the NOVX polypeptide in a control animal not administered the polypeptide, wherein a change in the activity of the NOVX polypeptide in the test animal relative to the control animal indicates that the test compound is a modulator of latency of, or predisposition to, a pathology associated with the NOVX polypeptide. In one embodiment, the test animal is a recombinant test animal that expresses a test protein transgene or expresses the transgene under the control of a promoter at an increased level relative to a wild-type test animal, and wherein the promoter is not the native gene promoter of the transgene. In another aspect, the invention includes a method for modulating the activity of the NOVX polypeptide, the method comprising introducing a cell sample expressing the NOVX polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide. In order to treat diseases, pathologies and other abnormal states or conditions in which a mammalian organism has been diagnosed as being, or as being at risk for becoming, other than in a normal state or condition, it is important to identify new therapeutic agents. Such a procedure includes at least the steps of identifying a target component within an affected tissue or organ, and identifying a candidate therapeutic agent that modulates the functional attributes of the target. The target component may be any biological macromolecule implicated in the disease or pathology. Commonly the target is a polypeptide or protein with specific functional attributes. Other classes of macromolecule may be a nucleic acid, a polysaccharide, a lipid such as a complex lipid or a 6 WO 2004/056961 PCT/US2003/034114 glycolipid; in addition a target may be a sub-cellular structure or extra-cellular structure that is comprised of more than one of these classes of macromolecule. Once such a target has been identified, it may be employed in a screening assay in order to identify favorable candidate therapeutic agents from among a large population of substances or compounds. In many cases the purpose of such screening assays is to identify small molecule candidates; this is commonly approached by the use of combinatorial methodologies to develop the population of substances to be tested. The implementation of high throughput screening methodologies is advantageous when working with large, combinatorial libraries of compounds. It is a purpose of this invention to provide cell lines that recombinantly or endogenously express the target biopolymer or an isolated target biopolymer that is intended to serve as the macromolecular component in a screening assay for identifying candidate pharmaceutical agents. It is another purpose of the present invention to provide screening assays that positively identify candidate pharmaceutical agents from among a combinatorial library of low molecular weight substances or compounds. It is still a further aspect of this invention to employ the candidate pharmaceutical agents in any of a variety of in vitro, ex vivo and in vivo assays in order to identify pharmaceutical agents with advantageous therapeutic applications in the treatment of a disease, pathology, or abnormal state or condition in a mammal. In another aspect, the present invention provides a method of identifying a test compound as a candidate therapeutic agent, for treating a disease, pathology, or an abnormal state or condition using a target polypeptide (NOVX) having a specific association with the disease. This method includes: (a) combining a test compound with a target polypeptide and a substrate of the target polypeptide; and (b) determining whether the test compound modulates the activity of the target polypeptide. In one embodiment of this method, the chemical compound is a member of a combinatorial library of compounds; the combining in step (a) is conducted on one or more replicate samples of the biopolymer; and the replicate sample is contacted with at least one member of the combinatorial library. In additional embodiments of this method, the biopolymer is included within a cell and is functionally expressed therein. In still a further embodiment, the binding of the compound modulates the function of the biopolymer, and it is the modulation that provides the identification that the compound is a potential therapeutic agent. In yet further embodiments of this method, the target biopolymer is a polypeptide. As used herein, a "substrate" includes any compound capable of binding to or interacting with a target polypeptide, including but not limited to a peptide, a polypeptide, a nucleic acid, a carbohydrate moiety, a lipid, a small molecule (e.g., cyclic AMP, ATP), an agonist, an antagonist, and an inhibitor. In another aspect of the invention, a method for identifying a pharmaceutical agent for treating a disease, pathology, or an abnormal state or condition is provided. The method includes the steps of: 7 WO 2004/056961 PCT/US2003/034114 (1) identifying a candidate therapeutic agent for treating said disease, pathology, or abnormal state or condition by the method described in the preceding paragraphs; (2) contacting a biological sample associated with the disease, pathology, or abnormal state or condition with the candidate therapeutic agent; (3) determining whether the candidate induces an effect on the biological sample associated with a therapeutic response therein; and (4) identifying a candidate exerting such an effect as a pharmaceutical agent. In significant embodiments of the method, the biological sample includes a cell, a tissue or organ, or is a nonhuman mammal. Several cellular, animal and clinical studies were performed to elucidate the genetic contribution to the etiology and pathogenesis of these conditions in a variety of physiologic, pharmacologic or native states. These studies utilized the core technologies at CuraGen Corporation to look at differential gene expression, protein-protein interactions, large-scale sequencing of expressed genes and the association of genetic variations such as, but not limited to, single nucleotide polymorphisms (SNPs) or splice variants in and between biological samples from experimental and control groups. The goal of such studies is to identify various therapeutic interventions in order to prevent, treat the consequences or cure the conditions of obesity and/or diabetes. The present invention discloses novel associations of proteins and polypeptides and the nucleic acids that encode them with various diseases or pathologies. The proteins and related proteins that are similar to them, are encoded by a cDNA and/or by genomic DNA. The proteins, polypeptides and their cognate nucleic acids were identified by the inventors in certain cases. Additionally, the current invention embodies the use of recombinantly expressed and/or endogenously expressed protein in various screens to identify therapeutic antibodies and/or therapeutic small molecules which modulate activity of the disclosed NOVX polypeptides. 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-1, wherein n is an integer between 1 and 47, or a complement of the nucleotide sequence. In another aspect, the invention provides a vector or a cell expressing a NOVX nucleotide sequence. In one embodiment, the invention discloses a method for modulating the activity of a NOVX polypeptide. The method includes the steps of: introducing a cell sample expressing the NOVX polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide. In another embodiment, the invention includes an isolated NOVX nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising a NOVX amino 8 WO 2004/056961 PCT/US2003/034114 acid sequence or a variant of a mature form of the NOVX amino acid sequence, 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. In another embodiment, the invention includes an amino acid sequence that is a variant of the NOVX amino acid sequence, 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. In one embodiment, the invention discloses a NOVX nucleic acid fragment encoding at least a portion of a NOVX polypeptide or any variant of the 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. In another embodiment, the invention includes the complement of any of the NOVX nucleic acid molecules or a naturally occurring allelic nucleic acid variant. In another embodiment, the invention discloses a NOVX nucleic acid molecule that encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant. In another embodiment, the invention discloses a NOVX nucleic acid, wherein the nucleic acid molecule differs by a single nucleotide from a NOVX nucleic acid sequence. In another aspect, the invention includes a NOVX nucleic acid, wherein one or more nucleotides in the NOVX nucleotide sequence is changed to a different nucleotide provided that no more than 15% of the nucleotides are so changed. In one embodiment, the invention discloses a nucleic acid fragment of the NOVX nucleotide sequence and a nucleic acid fragment wherein one or more nucleotides in the NOVX nucleotide sequence 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. In another embodiment, the invention includes a nucleic acid molecule wherein the nucleic acid molecule hybridizes under stringent conditions to a NOVX nucleotide sequence or a complement of the NOVX nucleotide sequence. In one embodiment, the invention includes a nucleic acid molecule, wherein the sequence is changed such that no more than 15% of the nucleotides in the coding sequence differ from the NOVX nucleotide sequence or a fragment thereof. In a further aspect, the invention includes a method for determining the presence or amount of the NOVX nucleic acid in a sample. The method involves the steps of: providing the sample; introducing the sample to a probe that binds to the nucleic acid molecule; and determining the presence or amount of the probe bound to the NOVX nucleic acid molecule, thereby determining the presence or amount of the NOVX nucleic acid molecule in the sample. In one embodiment, the presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type. In another aspect, the invention discloses a method for determining the presence of or predisposition to a disease associated with altered levels of the NOVX nucleic acid molecule of in a first mammalian subject. The method involves the steps of: measuring the amount of NOVX nucleic acid in a sample from the first mammalian subject; and comparing the amount of the nucleic acid in the sample of step (a) to the amount of NOVX 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 9 WO 2004/056961 PCT/US2003/034114 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. 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. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF THE FIGURES Figure Al illustrates how alterations in expression of Long chain acyl-CoA synthetase 2 (LACS) affect the etiology and pathogenesis of obesity and/or diabetes. Figure El is a diagram of the biochemical components in the purine nucleotide cycle. 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 compounds. 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. Sequences and Corresponding SEQ ID Numbers SEQ ID NO NOVX Internal (nucleic SEQ ID NO Assignment Identification acid) (amino acid) Homology NOVI a CG93648-01 1 2 Long-chain-fatty-acid--CoA ligase 2 (EC 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens NOVI b CG93648-02 3 4 Long-chain-fatty-acid--CoA ligase 2 (EC 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens NOV1c CG93648-03 5 6 Long-chain-fatty-acid--CoA ligase 2 (EC 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens NOVI d CG93648-04 7 8 Long-chain-fatty-acid--CoA ligase 2 (EC 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens NOVIe CG93648-05 9 10 Long-chain-fatty-acid-CoA ligase 2 (EC 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens 10 WO 2004/056961 PCT/US2003/034114 NOV1f CG93648-06 11 12 Long-chain-fatty-acid--CoA ligase 2 (EC 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens NOV1g CG93648-07 13 14 Long-chain-fatty-acid--CoA ligase 2 (EC 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens NOV1 h 306395308 15 16 Long-chain-fatty-acid--CoA ligase 2 (EC 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens NOV1 i SNP 13375590 of 17 18 Long-chain-fatty-acid--CoA ligase 2 (EC CG93648-01 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens NOV1j SNP 13378188 of 19 20 Long-chain-fatty-acid--CoA ligase 2 (EC CG93648-01 6.2.1.3) (Long-chain acyl-CoA synthetase 2) (LACS 2) - Homo sapiens NOV2a CG190178-02 21 22 Membrane copper amine oxidase (EC 1.4.3.6) (Vascular adhesion protein- 1) (VAP-1) (HPAO) - Homo sapiens NOV2b CG190178-01 23 24 Membrane copper amine oxidase (EC 1.4.3.6) (Vascular adhesion protein- 1) (VAP-1) (HPAO) - Homo sapiens NOV2c CG190178-03 25 26 Membrane copper amine oxidase (EC 1.4.3.6) (Vascular adhesion protein- 1) (VAP-1) (HPAO) - Homo sapiens NOV2d CG190178-04 27 28 Membrane copper amine oxidase (EC 1.4.3.6) (Vascular adhesion protein- 1) (VAP-1) (HPAO) - Homo sapiens NOV2e 318008675 29 30 Membrane copper amine oxidase (EC 1.4.3.6) (Vascular adhesion protein- 1) (VAP-1) (HPAO) - Homo sapiens NOV2f 318351920 31 32 Membrane copper amine oxidase (EC 1.4.3.6) (Vascular adhesion protein- 1) (VAP-1) (HPAO) - Homo sapiens NOV3a CG186525-01 33 34 MAPK-activated protein kinase (EC 2.7.1.

) 2 NOV3b CG186525-02 35 36 MAPK-activated protein kinase (EC 2.7.1.

)2 WO 2004/056961 PCT/US2003/034114 NOV3c CG186525-03 37 38 MAPK-activated protein kinase (EC 2.7.1.

) 2 NOV3d CG186525-04 39 40 MAPK-activated protein kinase (EC 2.7.1.

)2 NOV3e CG186525-05 41 42 MAPK-activated protein kinase (EC 2.7.1.

)2 NOV3f CG186525-06 43 44 MAPK-activated protein kinase (EC 2.7.1.

)2 NOV3g 317973998 45 46 MAPK-activated protein kinase (EC 2.7.1.

)2 NOV4a CG91149-01 47 48 5'-AMP-activated protein kinase, catalytic alpha-1 chain (EC 2.7.1.-) (AMPK alpha-1 chain) - Homo sapiens NOV4b CG91149-02 49 50 5'-AMP-activated protein kinase, catalytic alpha-1 chain (EC 2.7.1.-) (AMPK alpha-1 chain) - Homo sapiens NOV4c CG91149-03 51 52 5'-AMP-activated protein kinase, catalytic alpha-1 chain (EC 2.7.1.-) (AMPK alpha-1 chain) - Homo sapiens NOV5a CG186855-01 53 54 AMP-activated protein kinase NOV5b CG186855-02 55 56 AMP-activated protein kinase NOV5c CG186855-03 57 58 AMP-activated protein kinase NOV6a CG127397-01 59 60 5'-AMP-activated protein kinase, beta-1 subunit (AMPK beta-1 chain) (AMPKb) Homo sapiens NOV7a CG186873-01 61 62 5'-AMP-activated protein kinase, beta-2 subunit (AMPK beta-2 chain) - Homo sapiens 12 WO 2004/056961 PCT/US2003/034114 NOV8a CG186882-01 63 64 5'-AMP-activated protein kinase, gamma-1 subunit (AMPK gamma-1 chain) (AMPKg) - Homo sapiens NOV8b SNP 13382600 of 65 66 5'-AMP-activated protein kinase, gamma-1 CG186882-01 subunit (AMPK gamma-1 chain) (AMPKg) - Homo sapiens NOV9a CG186895-01 67 68 Protein kinase, AMP-activated, gamma 2 non-catalytic subunit - Homo sapiens NOV9b SNP 13382598 of 69 70 Protein kinase, AMP-activated, gamma 2 CG186895-01 non-catalytic subunit - Homo sapiens NOV9c SNP 13382599 of 71 72 Protein kinase, AMP-activated, gamma 2 CG186895-01 non-catalytic subunit - Homo sapiens NOVI0a CG186913-02 73 74 Sequence 5 from Patent WO0177305 Homo sapiens NOVIOb CG186913-01 75 76 Sequence 5 from Patent W00177305 Homo sapiens NOV11 a CG192154-01 77 78 AMP deaminase 1 (EC 3.5.4.6) (Myoadenylate deaminase) (AMP deaminase isoform M) - Homo sapiens NOV11b CG192154-02 79 80 AMP deaminase 1 (EC 3.5.4.6) (Myoadenylate deaminase) (AMP deaminase isoform M) - Homo sapiens NOV11c CG192154-03 81 82 AMP deaminase 1 (EC 3.5.4.6) (Myoadenylate deaminase) (AMP deaminase isoform M) - Homo sapiens NOV11 d CG192154-04 83 84 AMP deaminase 1 (EC 3.5.4.6) (Myoadenylate deaminase) (AMP deaminase isoform M) - Homo sapiens NOVIle CG192154-05 85 86 AMP deaminase 1 (EC 3.5.4.6) (Myoadenylate deaminase) (AMP deaminase isoform M) - Homo sapiens NOV11f CG192154-06 87 88 AMP deaminase 1 (EC 3.5.4.6) (Myoadenylate deaminase) (AMP deaminase isoform M) - Homo sapiens 13 WO 2004/056961 PCT/US2003/034114 NOV11 g 319077055 89 90 AMP deaminase .1 (EC 3.5.4.6) (Myoadenylate deaminase) (AMP deaminase isoform M) - Homo sapiens NOV11 h 319077084 91 92 AMP deaminase 1 (EC 3.5.4.6) (Myoadenylate deaminase) (AMP deaminase isoform M) - Homo sapiens NOV11 i 320155888 93 94 AMP deaminase 1 (EC 3.5.4.6) (Myoadenylate deaminase) (AMP deaminase isoform M) - Homo sapiens 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. Pathologies, diseases, disorders and condition and the like that are associated with NOVX sequences include, but are not limited to, e.g., 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, metabolic disturbances associated with obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, diabetes, metabolic disorders, 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, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers, as well as conditions such as transplantation and fertility. 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 Examples for identification of human sequence in individual sections for each NOVX polypeptide. 14 WO 2004/056961 PCT/US2003/034114 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 Examples showing expression profiles in individual sections for each NOVX polypeptide. 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. SNP analysis for each NOVX, if applicable, is presented in SNP Examples in individual sections for each NOVX polypeptide. 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 a research tool. 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 47; (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 47, 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 15 WO 2004/056961 PCT/US2003/034114 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 47; (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 47 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 47; (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 47 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 47; (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 47, 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 47 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-1, wherein n is an integer between 1 and 47; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 47 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-1, wherein n is an integer between 1 and 47; 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-1, wherein n is an integer between 1 and 47 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., 16 WO 2004/056961 PCT/US2003/034114 NOVX mRNAs) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. 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, by way of nonlimiting example, as a result of one or more naturally occurring processing steps that may take place within the cell (e.g., 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+1 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. Isolated NOVX nucleic acid molecules as used herein 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, or of chemical precursors or other chemicals. A nucleic acid molecule of the invention, e.g., a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, or a complement of this 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:2n-1, wherein n is an integer between 1 and 47, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g., see Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2n Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausubel, et al., (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 with appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized 17 WO 2004/056961 PCT/US2003/034114 by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer. 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:2n-1, wherein n is an integer between 1 and 47, 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 shown in SEQ ID NO:2n-1, wherein n is an integer between I and 47, 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:2n-1, wherein n is an integer between 1 and 47, is one that is sufficiently complementary to the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, that it can hydrogen bond with few or no mismatches to the nucleotide sequence shown in SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, thereby forming a stable duplex. 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. 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 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. In the present invention, homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, 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 18 WO 2004/056961 PCT/US2003/034114 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 bona fide 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:2n-1, wherein n is an integer between 1 and 47; or an anti-sense strand nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47; or of a naturally occurring mutant of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47. 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 has a detectable label attached, e.g., the label 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 nucleic acid fragment encoding a "biologically-active portion of NOVX" according to the present invention can be prepared by isolating a portion of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, 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:2n-1, wherein n is an integer between 1 and 47, 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:2n-1, wherein n is an integer between 1 and 47. 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:2n, wherein n is an integer between 1 and 47. In addition to the human NOVX nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, 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. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. 19 WO 2004/056961 PCT/US2003/034114 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 a human SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, 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:2n-1, wherein n is an integer between 1 and 47. 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. Stringent conditions, as used in the present invention, 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-HCI (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/mI denatured salmon sperm DNA at 650C, followed by one or more washes in 0.2X SSC, 0.01% BSA at 500C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to a sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, 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-1, wherein n is an integer between 1 and 47, 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/mI denatured salmon sperm DNA at 55 *C, followed by one or more washes in 1X SSC, 0.1% SDS at 37 0 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:2n-1, wherein n is an integer between 1 and 47, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A 20 WO 2004/056961 PCT/US2003/034114 non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5X SSC, 50 mM Tris-HCI (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/mI denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40'C, followed by one or more washes in 2X SSC, 25 mM Tris-HCI (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; and. PNAS USA 78: 6789 (1981). 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:2n-1, wherein n is an integer between 1 and 47, thereby leading to changes in the amino acid sequences of the encoded NOVX protein, without altering the functional ability of that NOVX protein. 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:2n, wherein n is an integer between 1 and 47. 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 not particularly 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 SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, 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 40% homologous to the amino acid sequences of SEQ ID NO:2n, wherein n is an integer between 1 and 47. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 47; more preferably at least about 70% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 47; still more preferably at least about 80% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 47; even more preferably at least about 90% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 47; and most preferably at least about 95% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 47. An isolated nucleic acid molecule encoding a NOVX protein homologous to the protein of SEQ ID NO:2n, wherein n is an integer between 1 and 47, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein. 21 WO 2004/056961 PCT/US2003/034114 Mutations can be introduced any one of SEQ ID NO:2nl-1, wherein n is an integer between 1 and 47, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more 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 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 a nucleic acid of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, 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 protein:protein interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (i) complex formation between a mutant NOVX protein and a NOVX ligand; or (iil) 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). Interfering RNA .In one aspect of the invention, NOVX gene expression can be attenuated by RNA interference. One approach well-known in the art is short interfering RNA (siRNA) mediated gene silencing where expression products of a NOVX gene are targeted by specific double stranded NOVX derived siRNA nucleotide sequences that are complementary to at least a 19-25 nt long segment of the NOVX gene transcript, including the 5' untranslated (UT) region, the ORF, or the 3' UT region [see PCT applications WOOO/44895, W099/32619, WO01/75164, WO01/92513, WO 01/29058, 22 WO 2004/056961 PCT/US2003/034114 WO01/89304, W002/16620, and WO02/29858]. Targeted genes can be a NOVX gene, or an upstream or downstream modulator of the NOVX gene. Nonlimiting examples of upstream or downstream modulators of a NOVX gene include, e.g., a transcription factor that binds the NOVX gene promoter, a kinase or phosphatase that interacts with a NOVX polypeptide, and polypeptides involved in a NOVX regulatory pathway. According to the methods of the present invention, NOVX gene expression is silenced using short interfering RNA. A NOVX polynucleotide according to the invention includes a siRNA polynucleotide. Such a NOVX siRNA can be obtained using a NOVX polynucleotide sequence, for example, by processing the NOVX ribopolynucleotide sequence in a cell-free system, such as but not limited to a Drosophila extract, or by transcription of recombinant double stranded NOVX RNA or by chemical synthesis of nucleotide sequences homologous to a NOVX sequence [see Genes & Dev. 13:3191 (1999)]. When synthesized, a typical 0.2 micromolar-scale RNA synthesis provides about 1 milligram of siRNA, which is sufficient for 1000 transfection experiments using a 24-well tissue culture plate format. The most efficient silencing is generally observed with siRNA duplexes composed of a 21-nt sense strand and a 21-nt antisense strand, paired in a manner to have a 2-nt 3' overhang. The sequence of the 2-nt 3' overhang makes an additional small contribution to the specificity of siRNA target recognition. The contribution to specificity is localized to the unpaired nucleotide adjacent to the first paired bases. In one embodiment, the nucleotides in the 3' overhang are ribonucleotides. In an alternative embodiment, the nucleotides in the 3' overhang are deoxyribonucleotides. Using 2'-deoxyribonucleotides in the 3' overhangs is as efficient as using ribonucleotides, but deoxyribonucleotides are often cheaper to synthesize and are most likely more nuclease resistant. A contemplated recombinant expression vector of the invention comprises a NOVX DNA molecule cloned into an expression vector comprising operatively-linked regulatory sequences flanking the NOVX sequence in a manner that allows for expression (by transcription of the DNA molecule) of both strands. An RNA molecule that is antisense to NOVX mRNA is transcribed by a first promoter (e.g., a promoter sequence 3' of the cloned DNA) and an RNA molecule that is the sense strand for the NOVX mRNA is transcribed by a second promoter (e.g., a promoter sequence 5' of the cloned DNA). The sense and antisense strands may hybridize in vivo to generate siRNA constructs for silencing of the NOVX gene. Alternatively, two constructs can be utilized to create the sense and anti-sense strands of a siRNA construct. Finally, cloned DNA can encode a construct having secondary structure, wherein a single transcript has both the sense and complementary antisense sequences from the target gene or genes. In an example of this embodiment, a hairpin RNAi product is homologous to all or a portion of the target gene. In another example, a hairpin RNAi product is a siRNA. The regulatory sequences flanking the NOVX sequence may be identical or may be different, such that their expression may be modulated independently, or in a temporal or spatial manner. In a specific embodiment, siRNAs are transcribed intracellularly by cloning the NOVX gene templates into a vector containing, e.g., a RNA po1 Ill transcription unit from the smaller nuclear RNA (snRNA) U6 or the human RNase P RNA H1. One example of a vector system is the GeneSuppressorTM RNA Interference kit (commercially available from lmgenex). The U6 and H1 promoters are members of 23 WO 2004/056961 PCT/US2003/034114 the type III class of Pol III promoters. The +1 nucleotide of the U6-like promoters is always guanosine, whereas the +1 for H1 promoters is adenosine. The termination signal for these promoters is defined by five consecutive thymidines. The transcript is typically cleaved after the second uridine. Cleavage at this position generates a 3' UU overhang in the expressed siRNA, which is similar to the 3' overhangs of synthetic siRNAs. Any sequence less than 400 nucleotides in length can be transcribed by these promoter, therefore they are ideally suited for the expression of around 21-nucleotide siRNAs in, e.g., an approximately 50-nucleotide RNA stem-loop transcript. A siRNA vector appears to have an advantage over synthetic siRNAs where long term knock-down of expression is desired. Cells transfected with a siRNA expression vector would experience steady, long-term mRNA inhibition. In contrast, cells transfected with exogenous synthetic siRNAs typically recover from mRNA suppression within seven days or ten rounds of cell division. The long-term gene silencing ability of siRNA expression vectors may provide for applications in gene therapy. In general, siRNAs are chopped from longer dsRNA by an ATP-dependent ribonuclease called DICER. DICER is a member of the RNase 11 family of double-stranded RNA-specific endonucleases. The siRNAs assemble with cellular proteins into an endonuclease complex. In vitro studies in Drosophila suggest that the siRNAs/protein complex (siRNP) is then transferred to a second enzyme complex, called an RNA-induced silencing complex (RISC), which contains an endoribonuclease that is distinct from DICER. RISC uses the sequence encoded by the antisense siRNA strand to find and destroy mRNAs of complementary sequence. The siRNA thus acts as a guide, restricting the ribonuclease to cleave only mRNAs complementary to one of the two siRNA strands. A NOVX mRNA region to be targeted by siRNA is generally selected from a desired NOVX sequence beginning 50 to100 nt downstream of the start codon. Alternatively, 5' or 3' UTRs and regions nearby the start codon can be used but are generally avoided, as these may be richer in regulatory protein binding sites. UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP or RISC endonuclease complex. An initial BLAST homology search for the selected siRNA sequence is done against an available nucleotide sequence library to ensure that only one gene is targeted. Specificity of target recognition by siRNA duplexes indicate that a single point mutation located in the paired region of an siRNA duplex is sufficient to abolish target mRNA degradation [see EMBO J. 20(23):6877 (2001)]. Hence, consideration should be taken to accommodate SNPs, polymorphisms, allelic variants or species-specific variations when targeting a desired gene. In one embodiment, a complete NOVX siRNA experiment includes the proper negative control. A negative control siRNA generally has the same nucleotide composition as the NOVX siRNA but lack significant sequence homology to the genome. Typically, one would scramble the nucleotide sequence of the NOVX siRNA and do a homology search to make sure it lacks homology to any other gene. Two independent NOVX siRNA duplexes can be used to knock-down a target NOVX gene. This helps to control for specificity of the silencing effect. In addition, expression of two independent genes can be simultaneously knocked down by using equal concentrations of different NOVX siRNA duplexes, e.g., a NOVX siRNA and an siRNA for a regulator of a NOVX gene or polypeptide. 24 WO 2004/056961 PCT/US2003/034114 Availability of siRNA-associating proteins is believed to be more limiting than target mRNA accessibility. A targeted NOVX region is typically a sequence of two adenines (AA) and two thymidines (TT) divided by a spacer region of nineteen (N19) residues (e.g., AA(N19)TT). A desirable spacer region has a G/C-content of approximately 30% to 70%, and more preferably of about 50%. If the sequence AA(N19)TT is not present in the target sequence, an alternative target region would be AA(N21). The sequence of the NOVX sense siRNA corresponds to (N1 9)TT or N21, respectively. In the latter case, conversion of the 3' end of the sense siRNA to TT can be performed if such a sequence does not naturally occur in the NOVX polynucleotide. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3' overhangs. Symmetric 3' overhangs may help to ensure that the siRNPs are formed with approximately equal ratios of sense and antisense target RNA-cleaving siRNPs [see Genes & Dev. 15:188 (2001)]. The modification of the overhang of the sense sequence of the siRNA duplex is not expected to affect targeted mRNA recognition, as the antisense siRNA strand guides target recognition. Alternatively, if the NOVX target mRNA does not contain a suitable AA(N21) sequence, one may search for the sequence NA(N21). Further, the sequence of the sense strand and antisense strand may still be synthesized as 5' (N19)TT, as it is believed that the sequence of the 3'-most nucleotide of the antisense siRNA does not contribute to specificity. Unlike antisense or ribozyme technology, the secondary structure of the target mRNA does not appear to have a strong effect on silencing [see J. Cell Science 114:4557 (2001)]. Transfection of NOVX siRNA duplexes can be achieved using standard nucleic acid transfection methods, for example, OLIGOFECTAMINE Reagent (available from Invitrogen). An assay for NOVX gene silencing is generally performed approximately 2 days after transfection. No NOVX gene silencing has been observed in the absence of transfection reagent, allowing for a comparative analysis of the wild-type and silenced NOVX phenotypes. In a specific embodiment, for one well of a 24-well plate, approximately 0.84 pg of the siRNA duplex is generally sufficient. Cells are typically seeded the previous day, and are transfected at about 50% confluence. The choice of cell culture media and conditions are routine to those of skill in the art, and will vary with the choice of cell type. The efficiency of transfection may depend on the cell type, but also on the passage number and the confluency of the cells. The time and the manner of formation of siRNA-liposome complexes (e.g., inversion versus vortexing) are also critical. Low transfection efficiencies are the most frequent cause of unsuccessful NOVX silencing. The efficiency of transfection needs to be carefully examined for each new cell line to be used. Preferred cell are derived from a mammal, more preferably from a rodent such as a rat or mouse, and most preferably from a human. Where used for therapeutic treatment, the cells are preferentially autologous, although non-autologous cell sources are also contemplated as within the scope of the present invention. For a control experiment, transfection of 0.84 pg single-stranded sense NOVX siRNA will have no effect on NOVX silencing, and 0.84 pg antisense siRNA has a weak silencing effect when compared to 0.84 pg of duplex siRNAs. Control experiments again allow for a comparative analysis 25 WO 2004/056961 PCT/US2003/034114 of the wild-type and silenced NOVX phenotypes. To control for transfection efficiency, targeting of common proteins is typically performed, for example targeting of lamin A/C or transfection of a CMV-driven EGFP-expression plasmid (e.g., available from Clontech). In the above example, a determination of the fraction of lamin A/C knockdown in cells is determined the next day by such techniques as immunofluorescence, Western blot, Northern blot or other similar assays for protein expression or gene expression. Lamin A/C monoclonal antibodies may be obtained from Santa Cruz Biotechnology. Depending on the abundance and the half life (or turnover) of the targeted NOVX polynucleotide in a cell, a knock-down phenotype may become apparent after 1 to 3 days, or even later. In cases where no NOVX knock-down phenotype is observed, depletion of the NOVX polynucleotide may be observed by immunofluorescence or Western blotting. If the NOVX polynucleotide is still abundant after 3 days, cells need to be split and transferred to a fresh 24-well plate for re-transfection. If no knock-down of the targeted protein is observed, it may be desirable to analyze whether the target mRNA (NOVX or a NOVX upstream or downstream gene) was effectively destroyed by the transfected siRNA duplex. Two days after transfection, total RNA is prepared, reverse transcribed using a target-specific primer, and PCR-amplified with a primer pair covering at least one exon-exon junction in order to control for amplification of pre-mRNAs. RT/PCR of a non-targeted mRNA is also needed as control. Effective depletion of the mRNA yet undetectable reduction of target protein may indicate that a large reservoir of stable NOVX protein may exist in the cell. Multiple transfection in sufficiently long intervals may be necessary until the target protein is finally depleted to a point where a phenotype may become apparent. If multiple transfection steps are required, cells are split 2 to 3 days after transfection. The cells may be transfected immediately after splitting. An inventive therapeutic method of the invention contemplates administering a NOVX siRNA construct as therapy to compensate for increased or aberrant NOVX expression or activity. The NOVX ribopolynucleotide is obtained and processed into siRNA fragments, or a NOVX siRNA is synthesized, as described above. The NOVX siRNA is administered to cells or tissues using known nucleic acid transfection techniques, as described above. A NOVX siRNA specific for a NOVX gene will decrease or knockdown NOVX transcription products, which will lead to reduced NOVX polypeptide production, resulting in reduced NOVX polypeptide activity in the cells or tissues. The present invention also encompasses a method of treating a disease or condition associated with the presence of a NOVX protein in an individual comprising administering to the individual an RNAi construct that targets the mRNA of the protein (the mRNA that encodes the protein) for degradation. A specific RNAi construct includes a siRNA or a double stranded gene transcript that is processed into siRNAs. Upon treatment, the target protein is not produced or is not produced to the extent it would be in the absence of the treatment. Where the NOVX gene function is not correlated with a known phenotype, a control sample of cells or tissues from healthy individuals provides a reference standard for determining NOVX expression levels. Expression levels are detected using the assays described, e.g., RT-PCR, Northern blotting, Western blotting, ELISA, and the like. A subject sample of cells or tissues is taken 26 WO 2004/056961 PCT/US2003/034114 from a mammal, preferably a human subject, suffering from a disease state. The NOVX ribopolynucleotide is used to produce siRNA constructs, that are specific for the NOVX gene product. These cells or tissues are treated by administering NOVX siRNA's to the cells or tissues by methods described for the transfection of nucleic acids into a cell or tissue, and a change in NOVX polypeptide or polynucleotide expression is observed in the subject sample relative to the control sample, using the assays described. This NOVX gene knockdown approach provides a rapid method for determination of a NOVX minus (NOVX~) phenotype in the treated subject sample. The NOVX~ phenotype observed in the treated subject sample thus serves as a marker for monitoring the course of a disease state during treatment. In specific embodiments, a NOVX siRNA is used in therapy. Methods for the generation and use of a NOVX siRNA are known to those skilled in the art. Example techniques are provided below. Production of RNAs Sense RNA (ssRNA) and antisense RNA (asRNA) of NOVX are produced using known methods such as transcription in RNA expression vectors. In the initial experiments, the sense and antisense RNA are about 500 bases in length each. The produced ssRNA and asRNA (0.5 ElM) in 10 mM Tris-HCI (pH 7.5) with 20 mM NaCI were heated to 950 C for 1 min then cooled and annealed at room temperature for 12 to 16 h. The RNAs are precipitated and resuspended in lysis buffer (below). To monitor annealing, RNAs are electrophoresed in a 2% agarose gel in TBE buffer and stained with ethidium bromide. See, e.g., Sambrook et al., supra. Lysate Preparation Untreated rabbit reticulocyte lysate (Ambion) are assembled according to the manufacturer's directions. dsRNA is incubated in the lysate at 30* C for 10 min prior to the addition of mRNAs. Then NOVX mRNAs are added and the incubation continued for an additional 60 min. The molar ratio of double stranded RNA and mRNA is about 200:1. The NOVX mRNA is radiolabeled (using known techniques) and its stability is monitored by gel electrophoresis. In a parallel experiment made with the same conditions, the double stranded RNA is internally radiolabeled with a 3P-ATP. Reactions are stopped by the addition of 2X-proteinase-K buffer and deproteinized as described previously [see Genes Dev., 13:3191 (1999)]. Products are analyzed by electrophoresis in 15% or 18% polyacrylamide sequencing gels using appropriate RNA standards. By monitoring the gels for radioactivity, the natural production of 10 to 25 nt RNAs from the double stranded RNA can be determined. The band of double stranded RNA, about 21-23 bps, is eluded. The efficacy of these 21-23 mers for suppressing NOVX transcription is assayed in vitro using the same rabbit reticulocyte assay described above using 50 nanomolar of double stranded 21-23 mer for each assay. The sequence of these 21-23 mers is then determined using standard nucleic acid sequencing techniques. RNA Preparation 21 nt RNAs, based on the sequence determined above, are chemically synthesized using Expedite RNA phosphoramidites and thymidine phosphoramidite. Synthetic oligonucleotides are 27 WO 2004/056961 PCT/US2003/034114 deprotected and gel-purified (see Genes & Dev. 15:188 (2001)], followed by Sep-Pak C18 cartridge (Waters, Milford, A) purification (Biochemistry, 32:11658 (1993)). These RNAs (20 DIM) single strands are incubated in annealing buffer (100 mM potassium acetate, 30 mM HEPES-KOH at pH 7.4, 2 mM magnesium acetate) for 1 min at 90* C followed by 1 h at 37* C. Cell Culture A cell culture known in the art to regularly express NOVX is propagated using standard conditions. 24 hours before transfection, at approx. 80% confluency, the cells are trypsinized and diluted 1:5 with fresh medium without antibiotics (1-3 X 105 cells/ml) and transferred to 24-well plates (500 ml/well). Transfection is performed using a commercially available lipofection kit and NOVX expression is monitored using standard techniques with positive and negative control. A positive control is cells that naturally express NOVX while a negative control is cells that do not express NOVX. Base-paired 21 and 22 nt siRNAs with overhanging 3' ends mediate efficient sequence-specific mRNA degradation in lysates and in cell culture. Different concentrations of siRNAs are used. An efficient concentration for suppression in vitro in mammalian culture is between 25 nM to 100 nM final concentration. This indicates that siRNAs are effective at concentrations that are several orders of magnitude below the concentrations applied in conventional antisense or ribozyme gene targeting experiments. The above method provides a way both for the deduction of NOVX siRNA sequence and the use of such siRNA for in vitro suppression. In vivo suppression may be performed using the same siRNA using well known in-vivo transfection or gene therapy transfection techniques. 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:2n-1, wherein n is an integer between 1 and 47, 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:2n, wherein n is an integer between 1 and 47, or antisense nucleic acids complementary to a NOVX nucleic acid sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, 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. 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. 28 WO 2004/056961 PCT/US2003/034114 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-carboxymethylaminomethyl-2-thiouridine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 5-methoxyuracil, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, 2-thiouracil, 4-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 2-methylthio-N6- isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, 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 29 WO 2004/056961 PCT/US2003/034114 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 11 or po 111I promoter are preferred. In yet another embodiment, the antisense nucleic acid molecule of the invention is an O-anomeric nucleic acid molecule. An Oi-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual 0-units, the strands run parallel to each other [see Nuci. Acids Res. 15:6625 (1987)]. The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide [see Nuci. Acids Res. 15:6131 (1987)] or a chimeric RNA-DNA analogue [see FEBS Lett. 215:327 (1987)]. 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., SEQ ID NO:2n-1, wherein n is an integer between 1 and 47). For example, a derivative of a Tetrahymena L-1 9 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. Patents 4,987,071 and 5,116,742. NOVX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules [see Science 261:1411]. 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 Anticancer Drug Des. 6:569 (1991); Ann. N. Y. Acad. Sci. 660:27 (1992); and Bioassays 14: 807 (1992)]. 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 Bioorg Med Chem 4: 5 (1996]. 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 30 WO 2004/056961 PCT/US2003/034114 used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S1 nucleases, or as probes or primers for DNA sequence and hybridization. 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. The synthesis of PNA-DNA chimeras can be performed as described in Nucl Acids Res 24:3357 (1996). 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 Nuc/ Acid Res 17:5973 (1989)]. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment. Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment [see Bioorg. Med. Chem. Lett. 5:1119 (1975)] 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 PNAS U.S.A. 86:6553 (1989); PNAS 84: 648 (1987), or PCT Publication No. W088/0981 0] or the blood-brain barrier (PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents [see BioTechniques 6:958 (1988)] or intercalating agents [see Pharm. Res. 5:539 (1988)].. 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:2n, wherein n is an integer between 1 and 47. 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:2n, wherein n is an integer between 1 and 47, 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. 31 WO 2004/056961 PCT/US2003/034114 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. 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 and 47) 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:2n, wherein n is an integer between 1 and 47. In other embodiments, the NOVX protein is substantially homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 47, and retains the functional activity of the protein of SEQ ID NO:2n, wherein n is an integer between 1 and 47, 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:2n, wherein n is an integer between 1 and 47, and retains the functional activity of the NOVX proteins of SEQ ID NO:2n, wherein n is an integer between 1 and 47. 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 Bio/ 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence 32 WO 2004/056961 PCT/US2003/034114 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:2n-1, wherein n is an integer between 1 and 47. 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 at 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. An "NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1 and 47, 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. 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-imrmunoglobulin 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 polypeptide sequences are 33 WO 2004/056961 PCT/US2003/034114 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.), supra. 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 (i.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 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 Tetrahedron 39: (1983), Annu. Rev. Biochem. 53:323 (1984), and Nucl. Acids Res. 11:477(1983)]. 34 WO 2004/056961 PCT/US2003/034114 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 S1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal 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 PNAS USA 89:7811 (1992); Protein Engineering 6:327 (1993)].. Anti-NOVX Antibodies Included in the invention are antibodies to NOVX proteins, or fragments of NOVX proteins. 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 residues of the amino acid sequence of the full length protein, such as an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 47, 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, are likely to encode surface residues useful for 35 WO 2004/056961 PCT/US2003/034114 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 polypeptide 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 gM, preferably 5 100 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, homolog 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 (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., lysolecithin, 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 36 WO 2004/056961 PCT/US2003/034114 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 that 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 discussed, for 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 Monoclonal antibodies according to the present invention can be prepared using hybridoma methods, such as those described in 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 fuse 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, and the American Type Culture Collection. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [see for example J. Immunol., 133:3001 (1984]. 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 37 WO 2004/056961 PCT/US2003/034114 antibody can, for example, be determined by the Scatchard analysis of 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. 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 cells such as simian COS 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 (see U.S. Patent No. 4,816,567; Nature 368:812 (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 immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 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 methods described in Nature, 321:522 (1986); Nature, 332:323-327 (1988); or 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 38 WO 2004/056961 PCT/US2003/034114 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.. 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. 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. PNAS 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 (J. Mol. Biol., 227:381 (1991); J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals. For example, 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; and 5,661,016; Nature 368:856 (1994); Nature 368:812 (1994); Nature Biotechnology 14, 845 (1996); and Intern. Rev. Immunol. 13:65 (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 (PCT publication W094/02602). 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 Xenomousem [see 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 39 WO 2004/056961 PCT/US2003/034114 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 (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 (PCT publication WO 99/53049). Fab 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 (U.S. Patent No. 4,946,778). In addition, methods can be adapted for the construction of Fab expression libraries [see Science 246:1275 (1989)] to allow rapid and effective identification of monoclonal Fab 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 Fab fragment generated by reducing the disulfide bridges of an F(ab') 2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) Fv 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 (Nature, 305:537 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these 40 WO 2004/056961 PCT/US2003/034114 hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography. Similar procedures are disclosed in WO 93/08829, and EMBO J., 10:3655 (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 (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain 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, 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 that 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') 2 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. 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. J. Exp. Med. 175:217(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. 41 WO 2004/056961 PCT/US2003/034114 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 in PNAS USA (90:6444 (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 (VL) by a linker that is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL 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 J. Immunol. 152:5368 (1994)]. Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared [see 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 (FcyR), such as FcyRI (CD64), FcyRlI (CD32) and FcyRlIl (CD16) 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 infection (WO 91/00360; 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 42 WO 2004/056961 PCT/US2003/034114 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 J. Exp Med., 176:1191 (1992) and J. Immunol., 148:2918 (1992)]. Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers [see Cancer Research, 53:2560 (1993)]. Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities [see Anti-Cancer Drug Design, 3:219 (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 tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 2Bi, 1I, 1In, 9 0 Y, and 1 86 Re. Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) 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 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Science, 238: 1098 (1987). Carbon-1 4-labeled 1 -isothiocyanatobenzyl-3 methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody [see W094/11026]. 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 [see PNAS USA, 82:3688 (1985); 43 WO 2004/056961 PCT/US2003/034114 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 J. Biol. Chem., 257: 286-288 (1982) via a disulf ide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome [see J. National Cancer inst., 81(19):1484 (1989)]. Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention In one embodiment, methods for the screening of antibodies that possess the desired specificity include, but are not limited to, enzyme linked immunosorbent assay (ELISA) and other immunologically mediated techniques known within the art. In a specific embodiment, selection of antibodies that are specific to a particular domain of an NOVX protein is facilitated by generation of hybridomas that bind to the fragment of an NOVX protein possessing such a domain. Thus, antibodies that are specific for a desired domain within an NOVX protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein. Antibodies directed against a NOVX protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of a NOVX protein (e.g., for use in measuring levels of the NOVX protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies specific to a NOVX protein, or derivative, fragment, analog or homolog thereof, that contain the antibody derived antigen binding domain, are utilized as pharmacologically active compounds (referred to hereinafter as "Therapeutics"). An antibody specific for a NOVX protein of the invention (e.g., a monoclonal antibody or a polyclonal antibody) can be used to isolate a NOVX polypeptide by standard techniques, such as immunoaffinity, chromatography or immunoprecipitation. An antibody to a NOVX polypeptide can facilitate the purification of a natural NOVX antigen from cells, or of a recombinantly produced NOVX antigen expressed in host cells. Moreover, such an anti-NOVX antibody can be used to detect the antigenic NOVX protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic NOVX protein. Antibodies directed against a NOVX 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, L-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 44 WO 2004/056961 PCT/US2003/034114 material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 12, 1311, 3 5 S or 3H. Antibody Therapeutics Antibodies of the invention, including polyclonal, monoclonal, humanized and fully human antibodies, may be 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 that 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: The 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. 45 WO 2004/056961 PCT/US2003/034114 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 PNAS 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 y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT Tm (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-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., 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 46 WO 2004/056961 PCT/US2003/034114 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 Theory 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, useful expression vectors 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 47 WO 2004/056961 PCT/US2003/034114 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 coliwith 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; (i) to increase the solubility of the recombinant protein; and (iil) 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 (Gene 67:31 (1998)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmaciathat fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coliexpression vectors include pTrc [see Gene 69:301 (1988)], and pET 11d [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 48 WO 2004/056961 PCT/US2003/034114 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 Nucl. Acids Res. 20: 2111 (1992)]. 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 [ EMBO J. 6:229 (1987)], pMFa [Cell 30: 933 (1982)], pJRY88 [Gene 54:113 (1987)], pYES2 (invitrogen Corporation, San Diego, Calif.), and picZ (InVitrogen Corp). 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 [see Mol. Cell. Biol. 3:2156 (1983)], and the pVL series [see Virology 170:31 (1989)]. 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 (Nature 329:840 (1987)) and pMT2PC (EMBO J. 6:187 (1987)). 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., supra. 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; Genes Dev. 1:268 (1987), lymphoid-specific promoters (Adv. Immunol. 43:235 (1988), in particular promoters of T cell receptors (EMBO J. 8:729 (1989) and immunoglobulins (Cell 33: 729 (1983); Cell 33: 741 (1988)), neuron-specific promoters (e.g., the neurofilament promoter; PNAS USA 86: 5473 (1989)), pancreas-specific promoters (Science 230: 912 (1985), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Science 249:374 (1990)) and the E-fetoprotein promoter (Genes Dev. 3:537 (1989)). 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 49 WO 2004/056961 PCT/US2003/034114 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 herein. It is 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, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. supra. 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 50 WO 2004/056961 PCT/US2003/034114 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 a NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral 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-1, wherein n is an integer between 1 and 47, 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 expression of NOVX protein to particular 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:2n-1, wherein n is an integer between 1 and 47), 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:2n-1, wherein n is an integer between 1 and 47, can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse 51 WO 2004/056961 PCT/US2003/034114 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 after 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 Cell 51:503 (1987)] for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced NOVX gene has homologously-recombined with the endogenous NOVX gene are selected [see Cell, 69:915 (1992)]. 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 Curr. Opin. Biotechnol. 2: 823 (1991) and 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 P1. For a description of the cre/loxP recombinase system, see,. PNAS USA 89: 6232 (1992). Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae [see Science 251:1351 (1991)]-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 Nature 385: 810 (1997). 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 Go 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 52 WO 2004/056961 PCT/US2003/034114 transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone 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

T

' (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, 53 WO 2004/056961 PCT/US2003/034114 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 that 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 that 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. 54 WO 2004/056961 PCT/US2003/034114 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, U.S. Patent No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al., 1994. PNAS 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., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system. 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 55 WO 2004/056961 PCT/US2003/034114 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 that 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 PNAS U.S.A. 90:6909 (1993); PNAS U.S.A. 91:11422 (1994); J. Med. Chem. 37:2678 (1994); Science 261:1303 (1993); Angew. Chem. Int. Ed. Eng. 33:2059 (1994); and J. Med. Chem. 37:1233 (1994). Libraries of compounds may also be presented in solution (Biotechniques 13: 412 (1992)), or on beads (Nature 354:82 (1991), on chips (Nature 364:555 (1993), bacteria (U.S. Patent No. 5,223,409), spores (U.S. Patent 5,233,409), plasmids (PNAS USA 89:1865 (1992) or on phage (Science 249: 386 (1990); PNAS U.S.A. 87:6378 (1990); and 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 be 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, 1 4 C, or 3 H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by 56 WO 2004/056961 PCT/US2003/034114 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 Ca 2 , diacylglycerol, IP 3 , 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 57 WO 2004/056961 PCT/US2003/034114 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 of 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-1 14, Thesit*, Isotridecypoly(ethylene glycol ether)n, N-dodecyl--N,N-dimethyl-3-ammonio-1 -propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1 -propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane 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 test compound to 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, 58 WO 2004/056961 PCT/US2003/034114 GST-NOVX 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, Ill.), 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 59 WO 2004/056961 PCT/US2003/034114 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. In yet another aspect of the invention a method for identifying compounds that modulate target polypeptide (NOVX) activity is disclosed wherein the method comprises: (a) combining a test compound with a target polypeptide and a substrate of the target polypeptide; and (b) determining whether the test compound modulates the activity of the target polypeptide; wherein the target polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 47, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n. The method further comprising a step of identifying the test compound that modulates the target polypeptide activity by modulating the target polypeptide activity as modulator of the target polypetide. Such modulator could be an inhibitor, an activator, an antagonist, or an agonist of NOVX target polypeptide. The method also further comprising a step of identifying the test compound that modulates the target polypeptide activity as an enhancer of insulin secretion, or as a therapeutic for treatment of insulin resistance, obesity and/or diabetes. In the above described method, the target polypeptide (NOVX) could be an isolated polypetide. The target polypeptide could be produced by a process comprising culturing a recombinant host cell, the recombinant host cell comprising a nucleic acid encoding the target polypeptide, under conditions promoting expression of the target polypeptide. In such a method, the nucleic acid comprises a nucleotide sequence selected from the group consisting of: (a) SEQ ID NO:2n-1, wherein n is an integer between 1 and 47; (b) nucleotides encoding an amino acid sequence of the at least one domain of SEQ ID NO:2n; and (c) a nucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n. 60 WO 2004/056961 PCT/US2003/034114 Alternatively, the target polypeptide could be produced by expression of a recombinant vector comprising a nucleic acid, the nucleic acid encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 47, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n. Here, the test compound could be combined with the target polypeptide in a mammalian cell grown in culture. Also, the test compound could be combined with the target polypeptide in vitro. In this method, the nucleic acid comprises a nucleotide sequence selected from the group consisting of: (a) SEQ ID NO:2n-1, wherein n is an integer between 1 and 47; (b) nucleotides encoding an amino acid sequence of the at least one domain of SEQ ID NO:2n; and (c) a nucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n. In yet another embodiment, the target polypeptide is produced by expression of an endogenous nucleic acid, the endogenous nucleic acid encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 47, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n. Here as well, the test compound could be combined with the target polypeptide in a mammalian cell grown in culture. Also, the test compound could be combined with the target polypeptide in vitro. In this method, the nucleic acid comprises a nucleotide sequence selected from the group consisting of: (a) SEQ ID NO:2n-1, wherein n is an integer between 1 and 47; (b) nucleotides encoding an amino acid sequence of the at least one domain of SEQ ID NO:2n; and (c) a nucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n. 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: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (i) identify an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below. 61 WO 2004/056961 PCT/US2003/034114 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:2n-1, wherein n is an integer between 1 and 47, 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). 62 WO 2004/056961 PCT/US2003/034114 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). 63 WO 2004/056961 PCT/US2003/034114 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-1, wherein n is an integer between 1 and 47, 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, pharmacogenomics, 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. 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, 64 WO 2004/056961 PCT/US2003/034114 a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NO:2n-1, wherein n is an integer between 1 and 47, 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. 65 WO 2004/056961 PCT/US2003/034114 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: (J) a deletion of one or more nucleotides from a NOVX gene; (i) an addition of one or more nucleotides to a NOVX gene; (ii) 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, (v) aberrant modification of a NOVX gene, such as of the methylation pattern of the genomic DNA, (vi) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of a NOVX gene, (vii) 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. 66 WO 2004/056961 PCT/US2003/034114 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; (i) an addition of one or more nucleotides to a NOVX gene; (ii) 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, (v) 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. 66 WO 2004/056961 PCT/US2003/034114 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) (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) (Science 241:1077 (1988); and PNAS USA 91: 360 (1994)), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (Nuc/. Acids Res. 23: 675 (1995)). 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 (PNAS USA 87:1874 (1990)), transcriptional amplification system (PNAS USA 86:1173 (1989)); 0 Replicase (BioTechnology 6: 197 (1988)), 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 (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 Human Mutation 7:244 (1996); Nat. Med. 2:753 (1996) . For example, genetic mutations in NOVX can be identified in two dimensional arrays containing light-generated DNA. 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. 67 WO 2004/056961 PCT/US2003/034114 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, PNAS USA 74:560 (1997) or Sanger PNAS USA 74: 5463 (1977). It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays [see Biotechniques 19:448 (1995)], including sequencing by mass spectrometry [see PCT Publication. WO 94/16101; Adv. Chromatography 36:127 (1996); or -Appl. Biochem. Biotechnol. 38:147 (1993)].. 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 Science 230:1242 (1985)]. 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 S 1 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 PNAS USA 85:4397 (1988); Methods Enzymol. 217: 286 (1992)]. 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. co/icleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches (Carcinogenesis 15: 1657 (1994)).. 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 U.S. Patent No. 5,459,039). In other embodiments, alterations in electrophoretic mobility may 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., PNAS USA: 86: 2766 (1989 Mutat. Res. 285: 125 (1993)]. 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. 68 WO 2004/056961 PCT/US2003/034114 In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility [see Trends Genet. 7:5 (1991)]. In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant may be assayed using denaturing gradient gel electrophoresis (DGGE) [see Nature 313:495 (1985)]. When DGGE 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 may used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA [see Biophys. Chem. 265:12753 (1987)].. 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 a 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., Nature 324:163 (1986); and PNAS USA 86: 6230 (1989)]. 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 Nucl. Acids Res. 17:2437 (1989)] or at the extreme 3'-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension [see Tibtech. 11: 238 (1993)]. In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification [see PNAS USA 88:189 (1991)]. 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 but are not 69 WO 2004/056961 PCT/US2003/034114 limited to, e.g., those diseases, disorders and conditions listed above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table 1. 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 drug disposition and abnormal action in affected persons (e.g., Clin. Exp. Pharmacol. Physio., 23: 983 (1996) or Clin. Chem., 43:254 (1997)). In general, two types of pharnacogenetic 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 drug 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 70 WO 2004/056961 PCT/US2003/034114 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 (J) obtaining a pre-administration sample from a subject prior to administration of the agent; (it) detecting the level of expression of a NOVX protein, mRNA, or genomic DNA in the preadministration sample; (iii) 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 (v) altering the 71 WO 2004/056961 PCT/US2003/034114 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 but are not limited to, e.g., those diseases, disorders and conditions listed above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table 1. Diseases 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: (J) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (il) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) 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). 72 WO 2004/056961 PCT/US2003/034114 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 situations in which NOVX is abnormally downregulated and/or in which increased NOVX activity is likely to have 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). 73 WO 2004/056961 PCT/US2003/034114 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. The disorders include but are not limited to, e.g., those diseases, disorders and conditions listed above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table 1. 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 diseases, disorders, conditions and the like, including but not limited to those listed herein. 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 anti-bacterial 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. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. NOVX Polypeptides The following sections describe in detail the NOVX polypeptides of the invention and methods of screening for modulators of NOVX polypeptides. A. NOVI - Long chain acyl-CoA synthetase 2 Long chain acyl-CoA synthetase 2 (LACS2, CuraGen Acc. No.: CG93648-01) is a microsomal enzyme involved in fatty acid esterification. The first step in the usage of long chain fatty acid in mammals requires the ligation of fatty acid with coenzyme A (CoA). This reaction, catalyzed by acyl CoA synthetase, produces acyl-CoAs, which are primary substrates for energy use via beta-oxidation, as well as for the synthesis of triacylglycerol, phospholipids, and other lipid-based molecules. 74 WO 2004/056961 - PCT/US2003/034114 (Diabetes. Jan;48(1):121 (1999), PMID: 9892232; Horm Metab Res. Feb;26(2):85 (1994). PMID: 8200619) Inhibition studies with acyl-CoA synthetase inhibitors, triacsin and troglitazone, have shown that long chain acyl-CoAs are functionally channeled towards specific metabolic fates through acyl CoA synthetases (LACS) which have different subcellular localizations. In humans, five different LACS homologs have been identified, LACS1, LACS2, LACS3, LACS4, and LACS5. (J Biol Chem. Jul 6;276(27):24667 (2001). PMID: 11319222). LACS1 and LACS2 seem to be two very closely related genes that are over 95% identical. They are the orthologues of rat and mouse ACS1/LACS2. It has been shown through subcellular fractionation studies that rat LACS2 is localized in the cytosol and microsomes and is likely to play a role in the esterification of fatty acids to produce triglycerides in adipose and liver. The rat long chain acyl-CoA synthetase 5 (ACS5), which is unique for rodents, is localized in the mitochondrial fraction and may be involved in channeling of fatty acids towards beta-oxidation. (Atherosclerosis. Apr; 137 Suppl:S75 (1998). Review. PMID: 9694545). Not to be limited by mechanism of action, the inventors have proposed a scheme which suggests how alterations in expression of the human Long chain acyl-CoA synthetase 2 and associated gene products function in the etiology and pathogenesis of obesity and/or diabetes, as shown in Figure Al. Inhibition of the human Long chain acyl-CoA synthetase 2 would result in decrease of fatty acid esterification and triglyceride storage and would drive beta-oxidation though other members of the LACS family. The inventors have discovered the upregulation of this gene in liver after TZD treatment, and the downregulation of the gene in brown adipose under high fat conditions, a tissue which is known to have higher thermogenesis induced by diet. Therefore the downregulation of the enzyme is linked to higher beta-oxidation. It is know that the family of ACS/LACS proteins is involved in esterification of fatty acids. It is unknown where the fate lies of the coupled fatty acids once they are in the cell. It is known from subcellular localization studies of ACS1 (which is in fact ACS2), ACS4 and ACS5 in rat liver ACS1 is associated with the ER, cytosol but not with mitochondria, while ACS4/5 are associated with mitochondria. The inventors suggest that fatty acids esterified by ACS1 have a different fate than fatty acids esterified by ACS4/5. ACS1 is more likely to be esterified, ACS4/5 is more likely to be oxidized (i.e. beta-oxidation of fatty acids takes place in the mitochondria). Published literature shows that after re feeding rats after a fasting period, ACS1 and ACS4 proteins go up (J Biol Chem. Jul 6;276(27):24674 (2001). PMID: 11319232). Therefore, the literature suggests that ACS1 and ACS4 may be linked to triacylglycerol synthesis in rat. The outcome of inhibiting the action of the human Long chain acyl-CoA synthetase 2 would be a way to decrease fatty acid esterification and triglyceride storage and drive beta-oxidation though other members of the LACS family. Based on the disclosed differential gene expression studies we postulate that LACS2 is contributing to the increase in adiposity, which has been well demonstrated to occur during TZD treatment. Moreover, in the diet-induced obesity study ACS1 was found to be downregulated in brown adipose of diet-induced obese hyperinsulinemic mice compared to brown adipose tissue of control 75 WO 2004/056961 PCT/US2003/034114 mice. In contrast, it was not downregulated in white adipose tissue of obese hyperinsulinemic mice. Brown adipose fat differs significantly from white adipose: it has more fat utilization for energy and heat production in mitochondria, which exceeds fat storage. It is suggested that through inhibition of LACS2, the brown adipose may be able to shift more fatty acids through the other LACSs members like LACS5 and promote fatty acid oxidation. The selective downregulation of LACS2 in brown adipose may therefore be part of a compensation mechanism against the high fat conditions which may be linked to the reported increase in heat production (diet-induced thermogenesis) demonstrated predominantly in brown adipose. It would be very beneficial to mimic this compensation mechanisms in white adipose, the predominant adipose form in humans, with a specific inhibitor of LACS2. This may prevent Acyl-CoA from becoming re-esterified in white adipose and liver and promote beta oxidation, which would be a good treatment for obesity. Furthermore, our results indicate that a modulator of Long chain acyl-CoA synthetase 2 activity, such as an inhibitor, activator, antagonist, or agonist of Long chain acyl-CoA synthetase 2 may be useful for treatment of such disorders as obesity, diabetes, and insulin resistance, as well as for enhancement of insulin secretion. Thus, Long chain acyl-CoA synthetase 2 (CG93648-01 thru -07) nucleic acids and proteins are useful for screening for an inhibitor/antagonist of Long chain acyl-CoA synthetase 2 for the treatment of obesity and or diabetes. These materials are further useful in the generation of antibodies that bind immunospecifically to the substances of the invention for use in diagnostic and/or therapeutic methods. Discovery Process The following sections describe the study design(s) used to identify the Long chain acyl-CoA synthetase 2 protein and any variants thereof, as being suitable as diagnostic markers, targets for an antibody therapeutic and targets for a small molecule drugs for Obesity and Diabetes. Example Al. Insulin Resistance Study The spontaneously hypertensive rat (SHR) is a strain exhibiting features of the human Metabolic Syndrome X. The phenotypic features include obesity, hyperglycemia, hypertension, dyslipidemia and dysfibrinolysis. Tissues were removed from adult male rats and a control strain (Wistar - Kyoto) to identify the gene expression differences that underlie the pathologic state in the SHR and in animals treated with various anti-hyperglycemic agents such as troglitizone. Tissues included sub-cutaneous adipose, visceral adipose and liver. The protocol for Insulin Resistance Study is disclosed in Example Q5. A fragment of Long chain acyl-CoA synthetase 2 gene was initially found to be up-regulated by 6.5 fold in troglitazone LD10/72 h treated liver tissue compared to the 0.02% DMSO/72 h untreated liver tissue of WKY rats using CuraGen's GeneCalling m method of differential gene expression (described in Example Q7). A differentially expressed rat gene fragment migrating, at approximately 431 nucleotides in length was definitively identified as a component of the rat Long chain acyl-CoA synthetase 2 cDNA in the troglitazone LD10/72 h treated liver tissue and the 0.02% DMSO/72 h untreated liver tissue of WKY rats. The method of competitive PCR was used for confirmation of the gene assessment. The electropherographic peaks corresponding to the gene fragment of the rat Long 76 WO 2004/056961 PCT/US2003/034114 chain acyl-CoA synthetase 2 were ablated when a gene-specific primer (shown in Table Al) competes with primers in the linker-adaptors during the PCR amplification. The peaks at 431 nt in length were ablated in the sample from both the troglitazone LD1 0/72 h treated liver tissue and the 0.02% DMSO/72 h untreated liver tissue. The same gene fragment of 431 nucleotides was identified to be upregulated 2.6 fold in troglitazone LD10/72 h treated liver tissue compared to the 0.02% DMSO/72 h untreated liver tissue of SHR rats using CuraGen's GeneCalling TM method of differential gene expression. By comparison, this band is likely to represent a gene fragment of rat Long chain acyl-CoA synthetase 2. Table Al. Gene Sequence identified in WKY Troglitazone LD1 0/72 h liver tissue vs. 0.02% DMSO/72 h liver tissue. Identified fragment from 347 to 777 in bold. band size: 431; gene length is 3657, only region from 1 to 1257 is shown (SEQ ID NO:95). 1 CCAACACAGA ACTATGGAAG TCCACGAATT GTTCCGGTAT TTTCGAATGC CAGAGCTGAT 61 TGACATTCGG CAGTACGTGC GTACCCTTCC AACCAACACA CTCATGGGCT TCGGGGCTTT 121 TGCAGCGCTC ACCACCTTCT GGTATGCCAC CCGGCCGAAG GCCCTGAAGC CACCATGTGA 181 TCTGTCCATG CAGTCTGTGG AAGTAACGGG TACTACTGAG GGTGTCCGAA GATCAGCAGT 241 CCTTGAGGAC GACAAGCTCT TGCTGTACTA CTACGACGAT GTCAGAACGA TGTACGATGG 301 CTTCCAGAGG GGGATTCAGG TGTCAAATGA TGGCCCTTGT TTAGGTTCTA GAAAGCCAAA 361 CCAGCCATAT GAGTGGATTT CTTACAAACA GGTTGCAGAA ATGGCTGAGT GCATAGGCTC 421 GGCGCTGATC CAGAAGGGTT TCAAACCTTG CTCAGAGCAG TTCATCGGCA TCTTTTCTCA 481 GAACAGACCT GAGTGGGTGA CCATCGAGCA GGGGTGCTTC ACTTACTCCA TGGTGGTTGT 541 TCCGCTCTAT GACACGCTTG GAACCGACGC CATCACCTAC ATAGTGAACA AAGCTGAACT 601 CTCTGTGATT TTTGCTGACA AGCCAGAAAA AGCCAAACTC TTATTAGAAG GTGTAGAAAA 661 TAAGTTAACA CCATGCCTTA AAATCATAGT CATCATGGAC TCCTACGACA ATGATCTGGT 721 GGAACGCGGC CAGAAGTGTG GGGTGGAAAT CATCGGCCTA AAAGCTCTGG AGGATCTTGG 781 AAGAGTGAAC AGAACGAAAC CCAAGCCTCC AGAACCTGAA GATCTTGCGA TAATCTGTTT 841 CACAAGTGGA ACTACAGGCA ACCCCAAAGG AGCAATGGTC ACCCACCAAA ACATTATGAA 901 CGATTGCTCC GGTTTTATAA AAGCGACGGA GAGTGCATTC ATCGCTTCCC CAGAGGATGT 961 TCTGATATCT TTCTTGCCTC TCGCCCATAT GTTTGAGACC GTTGTAGAGT GTGTAATGCT 1021 ATGTCATGGA GCTAAGATAG GATTTTTCCA AGGAGACATC AGGCTGCTTA TGGATGACCT 1081 CAAGGTGCTT CAGCCTACCA TCTTCCCTGT GGTTCCGAGA CTGCTAAACC GGATGTTTGA 1141 CAGAATTTTT GGACAAGCAA ACACGTCAGT GAAGCGATGG CTGTTGGATT TTGCCTCCAA 1201 AAGGAAAGAG GCGGAGCTTC GCAGTGGCAT CGTCAGAAAC AACAGCCTGT GGGATAA 77 WO 2004/056961 PCT/US2003/034114 Example A2. Mouse Dietary - Induced Obesity Study The predominant cause for obesity in clinical populations is excess caloric intake. This so called diet-induced obesity (DIO) is mimicked in animal models by feeding high fat diets of greater than 40% fat content. The DIO study was established to identify the gene expression changes contributing to the development and progression of diet-induced obesity. In addition, the study design seeks to identify the factors that lead to the ability of certain individuals to resist the effects of a high fat diet and thereby prevent obesity. The sample groups for the study were selected from C57BL/6J mice and had body weights +1 S.D. (sdl), + 4 S.D. (sd4) and + 7 S.D. of the chow-fed controls. In addition, the biochemical profile of the + 7 S.D. mice revealed a further stratification of these animals into mice that retained a normal glycemic profile in spite of obesity (ngsd7) and mice that demonstrated hyperglycemia (hgsd7). Tissues examined included hypothalamus, brainstem, liver, retroperitoneal white adipose tissue (WAT), epididymal WAT, brown adipose tissue (BAT), gastrocnemius muscle (fast twitch skeletal muscle) and soleus muscle (slow twitch skeletal muscle). The differential gene expression profiles for these tissues revealed genes and pathways that can be used as therapeutic targets for obesity. The protocol for Mouse Dietary-Induced Obesity is disclosed in Example Q1. This specific study examined differential gene expression in C57B11/6 obese euglycemic sd7 brown adipose tissue versus chow brown adipose tissue. A gene fragment of the mouse Long chain acyl-CoA synthetase 2 was found to be down regulated by 1.6 fold in the brown fat pad of the obese euglycemic sd7 mice relative to the chow-fed mice using CuraGen's GeneCallingTM method of differential gene expression (described in Example Q7). A differentially expressed mouse gene fragment migrating, at approximately 293 nucleotides in length was definitively identified as a component of the mouse Long chain acyl-CoA synthetase 2 cDNA. The method of competitive PCR was used for confirmation of the gene assessment. The electropherographic peaks corresponding to the gene fragment of the mouse Long chain acyl-CoA synthetase 2 were ablated when a gene-specific primer (shown in Table A2) competes with primers in the linker-adaptors during the PCR amplification. The peaks at 294 nt in length were ablated in the sample from both the obese euglycemic sd7 brown adipose and chow brown adipose tissue. Table A2. Gene Sequence identified in mouse dietary-induced obesity study. Identified fragment from 1806 to 2098 in bold, band size: 293; gene length is 2100, only region from 1325 to 2100 shown (SEQ ID NO:96). 1325 CAGTGCTGAC GTTTCTGAGG ACAGCGCTCG GCTGCCAGTT CTATGAAGGC TACGGACAGA 1385 CCGAGTGCAC TGCTGGTTGC TGCCTGAGCT TGCCCGGAGA CTGGACGGCA GGCCATGTTG 1445 GAGCCCCCAT GCCTTGCAAT TATGTAAAGC TTGTGGATGT GGAAGAAATG AATTACCTGG 1505 CATCCAAGGG CGAGGGTGAG GTGTGTGTGA AAGGGGCAAA TGTGTTCAAA GGCTACTTGA 1565 AAGACCCAGC AAGAACAGCT GAAGCCCTGG ATAAAGATGG CTGGTTACAC ACGGGGGACA 1625 TTGGAAAATG GCTGCCAAAT GGCACCTTGA AGATTATCGA CAGGAAAAAG CACATATTTA 1685 AACTAGCCCA AGGAGAGTAC ATAGCACCAG AAAAGATTGA AAATATCTAC CTGCGGAGTG 78 WO 2004/056961 PCT/US2003/034114 1745 AAGCCGTGGC CCAGGTGTTT GTCCACGGAG AAAGCTTGCA GGCCTTTCTC ATAGCAGTTG 1805 TGGTACCCGA CGTTGAGAGC CTACCGTCCT GGGCACAGAA GAGAGGCTTA CAAGGGTCCT 1865 TCGAAGAACT GTGCAGGAAC AAGGATATCA ATAAAGCTAT CCTGGACGAC TTGTTGAAAC 1925 TTGGGAAGGA AGCCGGTCTG AAGCCATTTG AACAGGTCAA AGGCATTGCT GTGCACCCGG 1985 AATTATTTTC TATTGACAAC GGCCTTCTGA CTCCAACACT GAAGGCGAAG AGGCCAGAGC 2045 TACGOAACTA TTTCAGGTCG CAGATAGATO AACTGTACGC CACCATCAAG ATCTAA Example A3. Identification of Human Long chain acyl-CoA synthetase 2 sequence The sequence of Human Long chain acyl-CoA synthetase 2 (Acc. No. CG93648-01) was 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, were 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 protocol for identification of human sequence(s) is disclosed in Example Q8. Table A3 shows an alignment of the protein sequences of the human (CG93648-01), rat, and mouse homologs of the Long chain acyl-CoA synthetase 2. Table A4 shows sequences of human (CG93648-01), rat, and mouse homologs of the Long chain acyl-CoA synthetase 2. Table A3. An alignment (ClustalW) of the protein sequences of the human (CG93648-01; SEQ ID NO:2), mouse (ACS1_mouse; MMU15977.1; SEQ ID NO:97), and rat (ACS1_rat; A36275; SEQ ID NO:98) versions of Long chain acyl-CoA synthetase 2. 79 WO 2004/056961 PCT/US2003/0341 14 AC51mow to ACO90lAC21u=' ACS1 -Mi 61 T 1 lI ACS1t 121 A~l - 5JA~uim 1j~fDjF i AM 51an 181 240UMAMRHM K M ACSL cze 121 Mhmv n I1so 009-* 0-1 :A(=2n,w 40 OLt WT A PD 0 ACSli 301 140 ACS-m 301 11 .M a300 00936480t 'ASb~~~I 20 I T 140RW 4WM=fiHfAHMV &2M Pt SM 259 301 42 CQ093a4S1.-AC2-hwjz 360 4 ACSI.Yat 421 490 421 0093643 0) 1,ACbm, 420 VMMW JM1j= 7 AS i431. 540M ACS)I 48 60 ACS31 i 54102 ACS~I 401c AtD ~ 3H~ ACSt xi~ 601 IV11IMO 009354 01 2A3 ILWRMAMM 60 5" Uin,5II AC'tni 66 f99 ACImm661 699UN~UDM~iI C340jA52ig 660 Wm~ NjIE3~I l tog Table A4 shows sequences of human (CG93648-O1), rat, and mouse homologs of the Long chain acyl-CoA synthetase 2. Mouse (ACS1 _Mouse; MMU 15977. 1; SEQ ID NO:97) Long chain acyl-CoA synthetase 2. M EVHELFRYFRMP ELI DI RQYVRTLPTNTLMG FGAFAALTTFWYATR PKALKPPCDLSMQSVEIAGTTDG I RRSAVLEDDKLLVYYYDDVRTMYDGFQRGIQVSNNG PGLGSRKPNQPYEWISYKEVAELAECIG SG LIQ KG FKPGSEQFIG LFSQNRPEWVI VEQGCFSYSMVVVPLYDTLGADAITYIVNKAELSVI FADKPEKAKLL LEGVENKLTPCLKIIVIMDSYGSDLVERGKKCGVEI ISLKALEDLGRVNRVKPKPPEPEDLAIICFTSGT TGNPKGAMITHQNI INDCSG FIKATESAFIASTDDVLISFLPLAHMFEVVECVMLCHGAKIG FFQGDIR LLMDDLKVLQPTIFPVVPRLLNRMFDRIFGQANTSLKRWLLDFASKRKEADVRSGIVRNNSLWDKLI FHK IQSSLGGKVRLMITGAAPVSATVLTFLRTALGCQFYEGYGQTECTAGCCLSLPGDWTAGHVGAPMPCNYV KLVDVEEMNYLASKG EG EVCVKGANVFKG YLKD PARTAEALDKDGWLHTG DIG KWLPNGTLKI IDRKKH I FKLAQGEYIAPEKI ENIYLRSEAVAQVFVHGESLOAFLIAVVVPDVESLPSWAQKRGLQGSFEELCRNKD INKAI LDDLLKLGKEAGLKPFEQVKGIAVHPELFSIDNGLLTPTLKAKRPELRNYFRSQIDELYATIKI Rat (ACSI-rat; A36275; SEQ ID NO:98) Long chain acyl-CoA synthetase 2. MEVHIELFRYFRMPELIDIRQYVRTLPTNTLMGFGAFAALTTFWYATRPKALKPPCDLsmQsVEVTGTTEG VRRSAVLEDDKLLLYYYDDVRTMYDGFQRGIQVSNDG PCLGSRKPNQPYEWISYKQVAEMAECIGSALIQ KGFKPCSEQFIG I FSQNRPEWVTIEQGCFTYSMVVVPLYDTLGTDAITYi VNKAELSVI FADKPEKAKLL LEG VENKLTPCLKIIVIMDSYDNDLVERGQKCG VEI IG LKALEDLGRVNRTKPKPPEPEDLAI ICFTSGT TGNPKGAMVTHQNIMNDCSGFI KATESAFIASPEDVLISFLPLAHMFETVVECVMLCHGAKIGFFQG DIR LLMDDLKVLQPTI FPVVPRLLNRMFDRI FGOANTSVKRWLLDFASKRKEAELRSGIVRNNSLWDKLI FHK IQSSLGGKVRLMITGAAPVSATVLTFLRAALGCQFYEGYGQTEOTAGCCLSLPGDWTAGHVGAPMPCNYI KLVDVEOMNYQAAKGEGEVCVKGANVFKGYLKDPARTAEALDKDGWLHTG DIGKWLPNGTLKIIDRKKHI 80 WO 2004/056961 PCT/US2003/034114 FKLAQGEYAPEKIENIYLRSEAVAQVFVHG ESLQAFLIAIVVPDVEILPSWAQKRGFQGSFEELCRNKD INKAILEDMVKLGKNAGLKPFEQVKGIAVHPELFSIDNGLLTPTLKAKRPELRNYFRSQIDELYSTIKI The laboratory cloning was performed using one or more of the methods summarized in Example 08. The NOV1 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table A5. Table A5. NOVI Sequence Analysis INOVIa, 0'9'3648-01-""- iSEQiD NO: 1 '3634 bp______ DNA Sequence ORF Start: ATG at 14 ORF Stop: TAG at 2108 TCAACACAGGACAATGCAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACTTCC GACAGTACGTGCGTACTCTTCCGACCAACACGCTTATGGGCTTCGGAGCTTTTGCAGCACTCACCACC TTCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGAAGT GGCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCTATG ATGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGTTTA GGCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGAGTG CATAGGCTCAGCACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTGCTC AAAATAGACCTGAGTGGGTGATTATTGAACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCACTT TATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGGT1TTTGT TGACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAAGTTAATACCAGGCCTTAAAA TCATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAAGTC ACCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACCTGA AGATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTCACC GAAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAACAGAGAATACAGTCAATCCTTGCCCAGAT GATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTGTGTAATGCTGTG TCATGGAGCTAAAATCGGATTTTCCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGCTTC AACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTTTCGGACAAGCA AACACCACGCTGAAGCGATGGCTCTTGGACTTTGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAGCGG CATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCGGAA GAGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCAGCC CTGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTAACCATGCC TGGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATGTGG AAGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTTCAG GGCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGGGGA CATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAAAAAGCACATATTTAAGCTGG CACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCTCAG GTGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGACATT ATGTTCCTGGGCCCAAAAGAGAGGATTTGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATGTCA AAAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAGGTC AAAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAAGGC GAAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGGTTT AGTGTGAAGAAGAAAGCTCAGAGGAAATGGCACAGTTCCACAATCTCTTCTCCTGCTGATGGCCTTCA TGTTGTTAATTTTGAATACAGCAAGTGTAGGGAAGGAAGCGTTCGTGTTTGACTTGTCCATTCGGGGT TCTTCTCATAGGAATGCTAGAGGAAACAGAACACCGCCTTACAGTCACCTCATGTTGCAGACCATGTT TATGGTAATACACACTTTCCAAAATGAGCCTTAAAAATTGTAAAGGGGATACTATAAATGTGCTAAGT TATTTGAGACTTCCTCAGTTTAAAAAGTGGGTTTTAAATCTTCTGTCTCCCTGCTTTTCTAATCAAGG GGTTAGGACTTTGCTATCTCTGAGATGTCTGCTACTTGCTGCAAATTCTGCAGCTGTCTGCTGCTCTA AAGAGTACAGTGCACTAGAGGGAAGTGTrCCCTTTAAAAATAAGAACAACTGTCCTGGCTGGAGAATC TCACAAGCGGACCAGAGATCTT1TTAAATCCCTGCTACTGTCCCTTCTCACAGGCATTCACAGAACCC TTCTGATTCGTAAGGGTTACGAAACTCATGTTCTTCTCCAGTCCCCTGTGGTTTCTGTTGGAGCATAA GGTTTCCAGTAAGCGGGAGGGCAGATCCAACTCAGAACCATGCAGATAAGGAGCCTCTGGCAAATGGG TGCTCATCAGAACGCGTGGATTCTCTTTCATGGCAGAATGCTCTTGGACTCGGTTCTCCAGGCCTGAT TCCCCGACTCCATCC111TCAGGGGTTATTTAAAAATCTGCCTTAGATTCTATAGTGAAGACAAGCA TTTCAAGAAAGAGTTACCTGGATCAGCCATGCTCAGCTGTGACGCCTGAATAACTGTCTACTTTATCT TCACTGAACCACTCACTCTGTGTAAAGGCCAACAGATTTTTAATGTGGTTTTCATATCAAAAGATCAT GTTGGGATrAACTTGCCTTTTTCCCCAAAAAATAAACTCTCAGGCAAGCATTTCTTTAAAGCTATTAA GGGAGTATATACTTGAGTACTTATTGAAATGGACAGTAATAAGCAAATGTTCTTATAATGCTACCTGA 81 WO 2004/056961 PCT/US2003/034114 YTTCTATGAAATGTGTTTGACAAGCCAAAATTCTAGGATGTAGAAATCTGGAAAGTTCATTTCCTGGG ATTCACTTCTCCAGGGATTTTTTAAAGTTAATTTGGGAAATTAACAGCAGTTCACTATTGTGAGTC TTTGCCACATTTGACTGAATTGAGCTGTCATTTGTACATTTAAAGCAGCTGTTTTGGGGTCTGTGAGA GTACATGTATTATATACAAGCACAACAGGGCTTGCACTAAAGAATTGTCATTGTAATAACACTACTTG GTAGCCTAACTTCATATATGTATTCTTAATTGCACAAAAAGTCAATAATTTGTCACCTTGGGGTTTTG AATGTTTGCTTTAAGTGTTGGCTATTTCTATGTTTTATAAACCAAAACAAAATTTCCAAAAACAATGA AGGAAACCAAAATAAATATTTCTGCATTTC NOVi a, CG93648-01 ISEQ ID NO: 2 '698 aa MWat 77942.5kD Protein Sequence I__ I______ ___ ______ MQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVEVAGSG GARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCLGSRKPDQPYEWLSYKQVAELSECIGSA LIQKG FKTAPDQFIG I FAQNRPEWVIIEQGCFAYSMVIVPLYDTLGNEAITYVNKAELSLVFVDKPE KAKLLLEGVENKLIPGLKI IVVMDAYGSELVERGQRCGVEVTSMKAMEDLG RANRRKPKPPAPEDLAV ICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAK IGFFQGDIRLLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRN NSLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTMPGDWT AGHVGAPMPCNLIKLVDVEEMNYMAAEG EG EVCVKG PNVFQGYLKDPAKTAEALDKDGWLHTG DIG KW LPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVETLCSWA QKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTPTMKAKRPE LRNYFRSQIDDLYSTIKV ______________ NOVib, CG93648-02 :SEQ ID NO: 3 2127 bp DNA Sequence .ORE Start: at 1 JORF Stop: TAG at 2107 CGCGGATCCACCATGCAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACTTCCG ACAGTACGTGCGTACTCTTCCGACCAACACGCTTATGGGCTTCGGAGCTTTTGCAGCACTCACCACCT TCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGAAGTG GCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCTATGA TGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGTTTAG GCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGAGTGC ATAGGCTCAGCACTGATACAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTGCTCA AAATAGACCTGAGTGGGTGATTATTGAACAAGGATGTTTTGCTTATTCGATGGTGATCGTTCCACTTT ATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGGTTUT GTT GACAAGCCAGAGAAGGCCAAACTCTTATTAGAAGGTGTAGAAAATAAGTTAATACCAGGCCTTAAAAT CATAGTTGTCATGGATGCCAACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAAGTCA CCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACCTGAA GATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTCACCG AAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAACAGAGAAAGCACTTCCCTTGAGTGCCAGTG ACACACACATTTCATATTTACCACTTGCTCACATTTATGAACAGTTATTGAAGTGTGTAATGCTGTGT CATGGAGCTAAAATCGGA1T1TTCCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGCTTCA ACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTCGGACAAGCAA ACACCACGCTGAAGCGATGGCTCTTGGACTTTGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAGCGGC ATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCGGAAG AGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCAGCCC TGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTGACCATGCCT GGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATGTGGA AGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTTCAGG GCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGGGGAC ATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAAAAAGCACATATTTAAGCTGGC ACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCTCAGG TGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGACATTA TGTTCCTGGGCCCAAAAGAGAGGATTTGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATGTCAA AAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAGGTCA AAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAAGGCG AAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGGTTTA GGCGGCCGCTFITfTCCTT NOVib, CG93648-02 SEQ ID NO: 4 1702 aa MW at 78258.8kD Protein Sequence RGSTMQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVEV 82 WO 2004/056961 PCT/US2003/034114 AGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCLGSRKPDQPYEWLSYKQVAELSEC IGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFAYSMVIVPLYDTLGNEAITYVNKAELSLVFV DKPEKAKLLLEGVENKLIPGLKIIVVMDANGSELVERGQRCGVEVTSMKAMEDLG RANRRKPKPPAPE DLAVICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATEKALPLSASDTHISYLPLAHIYEQLLKCVMLC HGAKIGFFQGDIRLLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSG IIRNNSLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTMP GDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEALDKDGWLHTGD IGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVETL CSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTPTMKA KRPELRNYFRSQIDDLYSTIKV NO10 C9648-03 0SQI O 5 f2120 bp DNA Sequence ORF Start: at 1 ORFStop:rAG at 2107 ACGGGATCCACCATGCAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACTTCCG ACAGTACGTGCGAACTCTTCCGACCAACACGCTTATGGGCTTCGGAGCTTTTGCAGCACTCACCACCT TCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGAAGTG GCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCTATGA TGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGTTTAG GCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGAGTGC ATAGGCTCAGCACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTGCTCA AAATAGACCTGAGTGGGTGATTATTGAACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCACTTT ATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGGTTTTTGTT GACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAAGCTAATACCAGGCCTTAAAAT CATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAAGTCA CCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACCTGAA GATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTCACCG AAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAACAGAGAATACAGTCAATCCTTGCCCAGATG ATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTGTGTAATGCTGTGT CATGGAGCTAAAATCGGAT1TF1CCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGCTTCA ACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATG1TTGACCGAATTTTCGGACAAGCAA ACACCACGCTGAAGCGATGGCTCTTGGACTTTGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAGCGGC ATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCGGAAG AGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCAGCCC TGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTGACCATGCCT GGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATGTGGA AGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTTCAGG GCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGGGGAC ATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAAAAAGCACATA1TAAGCTGGC ACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCTCAGG TGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGACATTA TGTTCCTGGGCCCAAAAGAGAGGATJTGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATGTCAA AAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAGGTCA AAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAAGGCG AAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGGTTTA GGCGGCCGCAAG NOVic, CG93648-03 ISEQ ID NO: 6 72aa - Wat 78288.8kD Protein Sequence TGSTMQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVEV AGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCLGSRKPDQPYEWLSYKQVAELSEC IGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFAYSMVIVPLYDTLGNEAITYVNKAELSLVFV DKPEKAKLLLEGVENKLIPGLKIIVVMDAYGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPE DLAVICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLC HGAKIGFFQGDIRLLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSG IIRNNSLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTMP GDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEALDKDGWLHTGD IGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVETL CSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTPTMKA KRPELRNYFRSQIDDLYSTIKV NOVid. CG93648-04 SEQ ID NO: 7 12141 bp 83 WO 2004/056961 PCT/US2003/034114 DNA Sequence RFStart: at 1 IORF Stop: TAG at 2128 ACGGGATCCACCATGGGTCATCATCATCATCATCACCAAGCCCATGAGCTGTTCCGGTATTTTCGAAT GCCAGAGCTGGTTGACTTCCGACAGTACGTGCGAACTCTTCCGACCAACACGCTTATGGGCTTCGGAG CTTTTGCAGCACTCACCACCTTCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTC TCCATGCAGTCAGTGGAAGTGGCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGA GCCCTTGGTGTATTTCTATGATGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGT CAAATAATGGCCCTTGTTTAGGCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAG GTTGCAGAATTGTCGGAGTGCATAGGCTCAGCACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCA GTTCATTGGCATCTTTGCTCAAAATAGACCTGAGTGGGTGATTATTGAACAAGGATGCTTTGCTTATT CGATGGTGATCGTTCCACTTTATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCT GAACTCTCTCTGG111TrGTTGACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAA GCTAATACCAGGCCTTAAAATCATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCC AGAGGTGTGGGGTGGAAGTCACCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAG CCCAAGCCTCCAGCACCTGAAGATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAA AGGAGCAATGGTCACTCACCGAAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAACAGAGAATA CAGTCAATCCTTGCCCAGATGATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTT GTAGAGTGTGTAATGCTGTGTCATGGAGCTAAAATCGGA1TJT CCAAGGAGATATCAGGCTGCTCAT GGATGACCTCAAGGTGCTTCAACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTG ACCGAATTTTCGGACAAGCAAACACCACGCTGAAGCGATGGCTCTTGGACTTTGCCTCCAAGAGGAAA GAAGCAGAGCTTCGCAGCGGCATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGT ACAGTCGAGCCTGGGCGGAAGAGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGC TGACGTTCCTCAGAGCAGCCCTGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCC GGGTGCTGCCTGACCATGCCTGGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTT GATAAAACTTGTTGATGTGGAAGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGA AAGGGCCAAATGTATTTCAGGGCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGAC GGCTGGTTACACACAGGGGACATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAA AAAGCACATATTTAAGCTGGCACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGC GAAGTGAGCCTGTTGCTCAGGTGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTG GTACCAGATGTTGAGACATTATGTTCCTGGGCCCAAAAGAGAGGATTTGAAGGGTCGTTTGAGGAACT GTGCAGAAATAAGGATGTCAAAAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTC TGAAACCATTTGAACAGGTCAAAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTT CTGACTCCAACAATGAAGGCGAAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCT CTATTCCACTATCAAGGTTTAGGCGGCCGCAAG NOV1 d, CG93648-04 SEQ ID NO: 8 709 aa MW at 79168.8kD Protein Sequence TGSTMGHHHHHHQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDL SMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCLGSRKPDQPYEWLSYKQ VAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVI IEQGCFAYSMVIVPLYDTLGNEATYVNKA ELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDAYGSELVERGQRCGVEVTSMKAMEDLGRANRRK PKPPAPEDLAVICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERV VECVMLCHGAKIGFFQGDIRLLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRK EAELRSGIIRNNSLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTA GCCLTMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEALDKD GWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIV VPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGL LTPTMKAKRPELRNYFRSQIDDLYSTIKV NOV1 e, CG93648-05 SEQ ID NO: 9 2138 bp DNA Sequence ORF Start: at 1 ORF Stop TAG at 2125 ACGGGATCCACCATGCAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACTTCCG ACAGTACGTGCGAACTCTTCCGACCAACACGCTTATGGGCTTCGGAGCTTTTGCAGCACTCACCACCT TCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGAAGTG GCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCTATGA TGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGTTTAG GCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGAGTGC ATAGGCTCAGCACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTGCTCA AAATAGACCTGAGTGGGTGATTATTGAACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCACTTT ATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGGIT rGTT GACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAAGCTAATACCAGGCCTTAAAAT 84 WO 2004/056961 PCT/US2003/034114 CATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAAGTCA CCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACCTGAA GATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTCACCG AAACATAGTGAGCGATTGTTCAGCTTTGTGAAAGCAACAGAGAATACAGTCAATCCTTGCCCAGATG ATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTGTGTAATGCTGTGT CATGGAGCTAAAATCGGAT1TTTCCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGCTTCA ACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTTTCGGACAAGCAA ACACCACGCTGAAGCGATGGCTCTTGGACTTTGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAGCGGC ATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCGGAAG AGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCAGCCC TGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTGACCATGCCT GGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATGTGGA AGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTTCAGG GCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGGGGAC ATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAAAAAGCACATATTTAAGCTGGC ACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCTCAGG TGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGACATTA TGTTCCTGGGCCCAAAAGAGAGGATTTGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATGTCAA AAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAGGTCA AAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAAGGCG AAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGGTTCA TCATCATCATCATCACTAGGCGGCCGCAAG NOV'e, C G93648-05 E bN 6----- - 8a t6i1'' -- -- Protein Sequence TGSTMQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVEV AGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCLGSRKPDQPYEWLSYKQVAELSEC IGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFAYSMVIVPLYDTLGNEAITYIVNKAELSLVFV DKPEKAKLLLEGVENKLI PGLKIIVVMDAYGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPE DLAVICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLC HGAKIGFFQGDIRLLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSG IIRNNSLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTMP GDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEALDKDGWLHTGD IGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVETL CSWAQKRG FEGSFEELCRNKDVKKAI LEDMVRLG KDSGLKPFEQVKGITLHPELFSI DNGLLTPTMKA KRPELRNYFRSQDDLYSTIKVHHHHHH NOVif, CG93648-06 ISEQ ID NO: 11 2127 bp IDNA Sequence [ORF Start: at 1 IORF Stop: TAG at 2092 CAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACTTCCGACAGTACGTGCGAAC TCTTCCGACCAACACGCTTATGGGCTTCGGAGCTTTTGCAGCACTCACCACCTTCTGGTACGCCACGA GACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGAAGTGGCGGGTAGTGGTGGT GCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCTATGATGATGTCACAACATT ATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGTTTAGGCTCTCGGAAACCAG ACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGAGTGCATAGGCTCAGCACTG ATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTGCTCAAAATAGACCTGAGTG GGTGATTATTGAACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCACTTTATGATACCCTTGGAA ATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGGTTTTTGTTGACAAGCCAGAGAAG GCCAAACTCTTATTAGAGGGTGTAGAAAATAAGCTAATACCAGGCCTTAAAATCATAGTTGTCATGGA TGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAAGTCACCAGCATGAAGGCGA TGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACCTGAAGATCTTGCAGTAATT TGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTCACCGAAACATAGTGAGCGA TTGTTCAGCTTTTGTGAAAGCAACAGAGAATACAGTCAATCCTTGCCCAGATGATACTTTGATATCTT TCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTGTGTAATGCTGTGTCATGGAGCTAAAATC GGA I I I I I CCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGCTTCAACCCACTGTCTTCCC CGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTTTCGGACAAGCAAACACCACGCTGAAGC GATGGCTCTTGGAC1TGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAGCGGCATCATCAGAAACAAC AGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCGGAAGAGTCCGGCTGATGGT GACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCAGCCCTGGGCTGTCAGTTTT ATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTGACCATGCCTGGAGACTGGACCGCA 85 WO 2004/056961 PCT/US2003/034114 GGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATGTGGAAGAAATGAATTACAT GGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTTCAGGGCTACTTGAAGGACC CAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGGGGACATTGGAAAATGGTTA CCAAATGGCACCTTGAAAATTATCGACCGGAAAAAGCACATATTTAAGCTGGCACAAGGAGAATACAT AGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCTCAGGTGTTGTCCACGGAG AAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGACATTATGTTCCTGGGCCCAA AAGAGAGGATTTGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATGTCAAAAAAGCTATCCTCGA AGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAGGTCAAAGGCATCACATTGC ACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAAGGCGAAAAGGCCAGAGCTG CGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGGTTTAGGCGGCCGCACTCGA GCACCACCACCACCACCAC NOV1f, CG93648-06 SEQ ID NO: 12 697 aa MW at 77811.3kD Protein Sequence______ QAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVEVAGSGG ARRSALLDSDEPLVYFYDDVTTLYEG FQRGIQVSNNG PCLGSRKPDQPYEWLSYKQVAELSECIG SAL IQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFAYSMVIVPLYDTLGNEAITYVNKAELSLVFVDKPEK AKLLLEGVENKLI PGLKIIVVMDAYGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVI CFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKI GFFQGDI RLLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSG II RNN SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTMPGDWTA GHVGAPMPCNLIKLVDVEEMNYMAAEG EGEVCVKG PNVFQGYLKDPAKTAEALDKDGWLHTGDIGKWL PNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVETLCSWAQ KRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTPTMKAKRPEL RNYFRSQIDDLYSTIKV NOVig, CG93648-07 1SEQ ID NO: 13 12146 bp DNA Sequence 0 St art at '-2 ........ R..F S.t .op -: T.A..G at '.2 :1 1 1 TCATCATCATCATCATCACCAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACT TCCGACAGTACGTGCGAACTCTTCCGACCAACACGCTTATGGGCTTCGGAGCTTTTGCAGCACTCACC ACCTTCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGA AGTGGCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCT ATGATGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGT TTAGGCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGA GTGCATAGGCTCAGCACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTG CTCAAAATAGACCTGAGTGGGTGATTATTGAACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCA CTTTATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGGTTTT TGTTGACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAAGCTAATACCAGGCCTTA AAATCATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAA GTCACCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACC TGAAGATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTC ACCGAAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAACAGAGAATACAGTCAATCCTTGCCCA GATGATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTGTGTAATGCT GTGTCATGGAGCTAAAATCGGA1T11TCCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGC TTCAACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTTTCGGACAA GCAAACACCACGCTGAAGCGATGGCTCTTGGACTTTGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAG CGGCATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCG GAAGAGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCA GCCCTGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTGACCAT GCCTGGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATG TGGAAGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTT CAGGGCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGG GGACATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAAAAAGCACATATTTAAGC TGGCACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCT CAGGTGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGAC ATTATGTTCCTGGGCCCAAAAGAGAGGATTTGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATG TCAAAAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAG GTCAAAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAA GGCGAAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGG TTTAGGCGGCCGCACTCGAGCACCACCACCACCACCAC 86 WO 2004/056961 PCT/US2003/034114 NOV1g, CG93648-07 SEQ ID NO: 14 703 aa MW at 78634.2kD Protein Sequence HHHHHHQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVE VAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCLGSRKPDQPYEWLSYKQVAELSE CIGSALIQKGFKTAPDQFIGIFAQNRPEWVIEQGCFAYSMVIVPLYDTLGNEAITYVNKAELSLVF VDKPEKAKLLLEGVENKLIPGLKIIVVMDAYGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAP EDLAVICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVML CHGAKIGFFQGDIRLLMDDLKVLOPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRS Gil RNNSLWDRLI FHKVQSSLGG RVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTM PGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEALDKDGWLHTG DIGKWLPNGTLKIIDRKKHIFKLAQG EYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVET LCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTPTMK AKRPELRNYFRSQIDDLYSTIKV jNOV1h, 30695308 SEQ ID NO: 15 2146 bp DNA Sequence ORF Start: at 2 ORF Stop: TAG at 2111 TCATCATCATCATCATCACCAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACT TCCGACAGTACGTGCGAACTCTTCCGACCAACACGCTTATGGGCTTCGGAGCTTTTGCAGCACTCACC ACCTTCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGA AGTGGCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCT ATGATGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGT TTAGGCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGA GTGCATAGGCTCAGCACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTG CTCAAAATAGACCTGAGTGGGTGATTATTGAACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCA CTTTATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGGTTTT TGTTGACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAAGCTAATACCAGGCCTTA AAATCATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAA GTCACCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACC TGAAGATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTC ACCGAAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAACAGAGAATACAGTCAATCCTTGCCCA GATGATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTGTGTAATGCT GTGTCATGGAGCTAAAATCGGAT1TrTCCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGC TTCAACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTTTCGGACAA GCAAACACCACGCTGAAGCGATGGCTCTTGGACTTTGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAG CGGCATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCG GAAGAGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCA GCCCTGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTGACCAT GCCTGGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATG TGGAAGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTT CAGGGCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGG GGACATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAAAAAGCACATATTTAAGC TGGCACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCT CAGGTGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGAC ATTATGTTCCTGGGCCCAAAAGAGAGGATTTGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATG TCAAAAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAG GTCAAAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAA GGCGAAAAGGCCAGAGCTGCGGAACTATTrCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGG TTTAGGCGGCCGCACTCGAGCACCACCACCACCACCAC NOV1h, 306395308 DNO: 16 7aa MW at 78634.2kD Protein Sequence ]SEQ ID NO: 16W HHHHHHQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVE VAGSGGARRSALLDSDEPLVYFYDDVTTLYEG FQRG IQVSNNG PCLGSRKPDQPYEWLSYKQVAELSE CIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFAYSMVIVPLYDTLGNEAITYIVNKAELSLVF VDKPEKAKLLLEGVENKLIPGLKIIVVMDAYGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAP EDLAVICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTUSFLPLAHMFERVVECVML CHGAKIG FFQG DI RLLMDDLKVLQPTVFPVVPRLLNRMFDRI FGQANTTLKRWLLDFASKRKEAELRS GilRNNSLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTM PGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEALDKDGWLHTG DIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVET 87 WO 2004/056961 PCT/US2003/034114 LCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTPTMK AKRPELRNYFRSQI DDLYSTI KV ! NOV1i, SNP 13375590 of CG93648-01 SEQ ID NO: 17 3634 bp DNA Sequence ORF Start: ATG at 14 -ORF Stop: TAG at 2108 6AACACAGGACAATGCAAGCCCATGAGCTGTTCCGGTATTTTGAATGCCAGAGCTGGTTGACTTCC GACAGTACGTGCGTACTCTTCCGACCAACACGCTTATGGGCTrCGGAGCTTTTGCAGCACTCACCACC TTCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGAAGT GGCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCTATG ATGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGTTTA GGCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGAGTG CATAGGCTCAGCACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTGCTC AAAATAGACCTGAGTGGGTGATTATTGAACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCACTT TATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGGTTTTTGT TGACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAAGTTAATACCAGGCCTTAAAA TCATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAAGTC ACCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACCTGA AGATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTCACC GAAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAACAGAGAATACAGTCAATCCTTGCCCAGAT GATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTGTGTAATGCTGTG TCATGGAGCTAAAATCGGATTTTCCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGCTTC AACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTTTCGGACAAGCA AACACCACGCTGAAGCGATGGCTCTTGGACTTTGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAGCGG CATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCGGAA GAGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCAGCC CTGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTAACCATGCC TGGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATGTGG AAGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTTCAG GGCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGGGGA CATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAAAAGGCACATATTTAAGCTGG CACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCTCAG GTGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGACATT ATGTTCCTGGGCCCAAAAGAGAGGATTrGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATGTCA AAAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAGGTC AAAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAAGGC GAAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGGTTT AGTGTGAAGAAGAAAGCTCAGAGGAAATGGCACAGTTCCACAATCTCTTCTCCTGCTGATGGCCTTCA TGTTGTTAATTTTGAATACAGCAAGTGTAGGGAAGGAAGCGTTCGTGTTTGACTTGTCCATTCGGGGT TCTTCTCATAGGAATGCTAGAGGAAACAGAACACCGCCTTACAGTCACCTCATGTTGCAGACCATGTT TATGGTAATACACACTTTCCAAAATGAGCCTTAAAAATTGTAAAGGGGATACTATAAATGTGCTAAGT TATTTGAGACTTCCTCAGTTTAAAAAGTGGGTTTTAAATCTTCTGTCTCCCTGCTTTTCTAATCAAGG GGTTAGGACTTTGCTATCTCTGAGATGTCTGCTACTTGCTGCAAATTCTGCAGCTGTCTGCTGCTCTA AAGAGTACAGTGCACTAGAGGGAAGTGTTCCCTTTAAAAATAAGAACAACTGTCCTGGCTGGAGAATC TCACAAGCGGACCAGAGATCTTTTTAAATCCCTGCTACTGTCCCTTCTCACAGGCATTCACAGAACCC TfCTGAiCGTAAGGGTTACGAAACTCATGTTCTTCTCCAGTCCCCTGTGG-TTCTGTTGGAGCATAA GGTTTCCAGTAAGCGGGAGGGCAGATCCAACTCAGAACCATGCAGATAAGGAGCCTCTGGCAAATGGG TGCTCATCAGAACGCGTGGATTCTCTTTCATGGCAGAATGCTCTTGGACTCGGTTCTCCAGGCCTGAT TCCCCGACTCCATCCTTT1TCAGGGGTTATTTAAAAATCTGCCTTAGATTCTATAGTGAAGACAAGCA TCAAGAAAGAGTTACCTGGATCAGCCATGCTCAGCTGTGACGCCTGAATAACTGTCTACTTTATCT TCACTGAACCACTCACTCTGTGTAAAGGCCAACAGATTTTTAATGTGGTTTTCATATCAAAAGATCAT GTTGGGATTAACTTGCCTT1TTCCCCAAAAAATAAACTCTCAGGCAAGCATTTCTTTAAAGCTATTAA GGGAGTATATACTTGAGTACTTATTGAAATGGACAGTAATAAGCAAATGTTCTTATAATGCTACCTGA TTTCTATGAAATGTGTTTGACAAGCCAAAATTCTAGGATGTAGAAATCTGGAAAGTTCATTTCCTGGG ATTACTTCTCCAGGGATTrTAAAGTTAATTTGGGAAATTAACAGCAGTTCACTTTATTGTGAGTC TTTGCCACATTTGACTGAATTGAGCTGTCATTTGTACATTTAAAGCAGCTGTTTTGGGGTCTGTGAGA GTACATGTATTATATACAAGCACAACAGGGCTTGCACTAAAGAATTGTCATTGTAATAACACTACTTG GTAGCCTAACTTCATATATGTATTCTTAATTGCACAAAAAGTCAATAATTTGTCACCTTGGGGTTTTG AATGTTTGCTTTAAGTGTTGGCTATTTCTATGTTTTATAAACCAAAACAAAATTTCCAAAAACAATGA AGGAAACCAAAATAAATATTTGTGCATTTC8 88 WO 2004/056961 PCT/US2003/034114 NOV1i, SNP 13375590 of CG93648-01 SEQ ID NO: 18 698 aa MW at 77970.5kD Protein Sequence MQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVEVAGSG GARRSALLDSDEPLVYFYDDVTTLYEGFORGIQVSNNGPCLGSRKPDQPYEWLSYKQVAELSECIGSA LIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFAYSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPE KAKLLLEGVENKLIPGLKIIVVMDAYGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPA PEDLAV ICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAK IGFFQGDIRLLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIlRN NSLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTMPGDWT AGHVGAPM PCNLI KLVDVEEMNYMAAEGEG EVCVKG PNVFQGYLKDPAKTAEALDKDGWLHTG DIG KW LPNGTLKIIDRKRHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVETLCSWA QKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTPTMKAKRPE LRNYFRSQIDDLYSTIKV [NOV1j, SNP13378188 of CG93648-01 - [SEQ 1~N 19 3634 bp DNA Sequence :OR Start: ATG at 14 ORF Stop: TAG at 2108 TCAACACAGGACAATGCAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACTTCC GACAGTACGTGCGTACTCTTCCGACCAACACGCTTATGGGCTTCGGAGCTTTTGCAGCACTCACCACC TTCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGAAGT GGCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCTATG ATGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGTTTA GGCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGAGTG CATAGGCTCAGCACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTGCTC AAAATAGACCTGAGTGGGTGATTATTGAACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCACTT TATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGGTTTTTGT TGACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAAGTTAATACCAGGCCTTAAAA TCATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAAGTC ACCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACCTGA AGATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTCACC GAAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAACAGAGAATACAGTCAATCCTTGCCCAGAT GATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTGTGTAATGCTGTG TCATGGAGCTAAAATCGGATTTTTCCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGCTTC AACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTTTCGGACAAGCA AACACCACGCTGAAGCGATGGCTCTTGGACTCTGCCTCCAAGAGGAAAGAAGCAGAGCTTCGCAGCGG CATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCGGAA GAGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCAGCC CTGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTAACCATGCC TGGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATGTGG AAGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTTCAG GGCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGGGGA CATTGGAAAATGGTTACCAAATGGCACCTTGAAAATTATCGACCGGAAAAAGCACATATTTAAGCTGG CACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCTCAG GTGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGACATT ATGTTCCTGGGCCCAAAAGAGAGGATTTGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATGTCA AAAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAGGTC AAAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAAGGC GAAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGGTTT AGTGTGAAGAAGAAAGCTCAGAGGAAATGGCACAGTTCCACAATCTCTTCTCCTGCTGATGGCCTTCA TGTTGTTAATTTTGAATACAGCAAGTGTAGGGAAGGAAGCGTTCGTGTTTGACTTGTCCATTCGGGGT TCTTCTCATAGGAATGCTAGAGGAAACAGAACACCGCCTTACAGTCACCTCATGTTGCAGACCATGTT TATGGTAATACACACTTTCCAAAATGAGCCTTAAAAATTGTAAAGGGGATACTATAAATGTGCTAAGT TATTTGAGACTTCCTCAGTTTAAAAAGTGGGTTTTAAATCTTCTGTCTCCCTGCTTTTCTAATCAAGG GGTTAGGACTTTGCTATCTCTGAGATGTCTGCTACTTGCTGCAAATTCTGCAGCTGTCTGCTGCTCTA AAGAGTACAGTGCACTAGAGGGAAGTGTTCCCTTTAAAAATAAGAACAACTGTCCTGGCTGGAGAATC TCACAAGCGGACCAGAGATCTTTTTAAATCCCTGCTACTGTCCCTTCTCACAGGCATTCACAGAACCC TTCTGATTCGTAAGGGTTACGAAACTCATGTTCTTCTCCAGTCCCCTGTGGTTTCTGTTGGAGCATAA GGTTTCCAGTAAGCGGGAGGGCAGATCCAACTCAGAACCATGCAGATAAGGAGCCTCTGGCAAATGGG TGCTCATCAGAACGCGTGGATTCTCTTTCATGGCAGAATGCTCTTGGACTCGGTTCTCCAGGCCTGAT TCCCCGACTCCATCCTTTTCAGGGGTTATTTAAAAATCTGCCTTAGATTCTATAGTGAAGACAAGCA TTTCAAGAAAGAGTTACCTGGATCAGCCATGCTCAGCTGTGACGCCTGAATAACTGTCTACTTTATCT 89 WO 2004/056961 PCT/US2003/034114 TCACTGAACCACTCACTCTGTGTAAAGGCCAACAGATTTTTAATGTGGTTTTCATATCAAAAGATCAT GTTGGGATTAACTTGCCTTF-TCCCCAAAAAATAAACTCTCAGGCAAGCATTTCTTTAAAGCTATAA GGGAGTATATACTTGAGTACTTATTGAAATGGACAGTAATAAGCAAATGTTCTTATAATGCTACCTGA TTTCTATGAAATGTGTTTGACAAGCCAAAATTCTAGGATGTAGAAATCTGGAAAGTTCATTTCCTGGG ATTCACTTCTCCAGGGATT11TAAAGTTAATTTGGGAAATTAACAGCAGTTCACTTTATTGTGAGTC TTTGCCACATTTGACTGAATTGAGCTGTCATTTGTACATTTAAAGCAGCTG TTIGGGGTCTGTGAGA GTACATGTATTATATACAAGCACAACAGGGCTTGCACTAAAGAATTGTCATTGTAATAACACTACTTG GTAGCCTAACTTCATATATGTATTCTTAATTGCACAAAAAGTCAATAATTTGTCACCTTGGGGTTTTG AATGTTTGCTTTAAGTGTTGGCTATTTCTATGTTTTATAAACCAAAACAAAATTTCCAAAAACAATGA AGGAAACCAAAATAAATATTTCTGCATTTC JNOV1j, SNP 13378188 of CG93648-01 SEQ ID NO: 20 698 aa MW at 77882.4kD Protein Sequence MQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVEVAGSG GARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCLGSRKPDQPYEWLSYKQVAELSECIGSA LIQKG FKTAPDQFIGI FAQNRPEWVIIEQGCFAYSMVIVPLYDTLGNEAITYVNKAELSLVFVDKPE KAKLLLEGVENKLIPGLKI IVVMDAYG SELVERGQRCGVEVTSMKAMEDLG RAN RRKPKPPAPEDLAV ICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAK IGFFQGDIRLLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDSASKRKEAELRSGIIRN NSLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTMPGDWT AGHVGAPMPCNLI KLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEALDKDGWLHTG DIG KW LPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVETLCSWA QKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTPTMKAKRPE LRNYFRSQIDDLYSTIKV A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table A6. Table A6. Comparison of the NOV1 protein sequences. NOV . a--------------.QAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOVb- --------- RGSTMQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOV1c ------- TGSTMQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOVid TGSTMGHHHHHHQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOV1e ------- TGSTMQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOVif ------------- QAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOV1g ---------- HHHHHHQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOV1h ------ HHHHHHQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOVi ----------- MQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOVi ----------- MQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPK NOV1a PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOVib PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOV1c PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOVld PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOVie PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOVif PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOVig PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOVlh PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOVi PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOV1j PLKPPCDLSMQSVEVAGSGGARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCL NOVla GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA NOVib GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA NOVic GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA NOVid GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA NOV1e GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA NOVif GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA 90 WO 2004/056961...... . _ PCT/US2003/034114 NOVlg GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA NOV1h GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA NOVli GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA NOV1j GSRKPDQPYEWLSYKQVAELSECIGSALIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFA NOVla YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOVIb YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOVic YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOVid YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOVie YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOVlf YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOVlg YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOV1h YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOV1i YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOVij YSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPEKAKLLLEGVENKLIPGLKIIVVMDA NOVla YGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOVib NGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOVlc YGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOVid YGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOVle YGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOVlf YGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOVlg YGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOV1h YGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOVli YGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOVlj YGSELVERGQRCGVEVTSMKAMEDLGRANRRKPKPPAPEDLAVICFTSGTTGNPKGAMVT NOVla HRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKIGFFQGDIR NOV1b HRNIVSDCSAFVKATEKALPLSASDTHISYLPLAHIYEQLLKCVMLCHGAKIGFFQGDIR NOVlc HRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKIGFFQGDIR NOVid HRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKIGFFQGDIR NOVle HRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKIGFFQGDIR NOVlf HRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKIGFFQGDIR NOV1g HRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKIGFFQGDIR NOV1h HRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKIGFFQGDIR NOVi HRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKIGFFQGDIR NOVij HRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAKIGFFQGDIR NOVla LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRNN NOVib LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRNN NOVIc LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRNN NOVld LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRNN NOVie LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRNN NOVif LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRNN NOVlg LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRNN NOV1h LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRNN NOV1i LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDFASKRKEAELRSGIIRNN NOVij LLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDSASKRKEAELRSGIIRNN NOVla SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL NOVib SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL NOVic SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL NOVld SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL NOVle SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL NOVIf SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL NOVIg SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL NOV1h SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL NOVli SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL NOV1j SLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCL 91 W 02004/056961 PCT/US2003/034114 NOVla TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOV1b TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOV1c TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOV1d TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOVie TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOV1f TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOV1g TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOV1h TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOV1i TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOV1j TMPGDWTAGHVGAPMPCNLIKLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEA NOVla LDKDGWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOV1b LDKDGWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOV1c LDKDGWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOV1d LDKDGWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOVle LDKDGWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOVIf LDKDGWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOV1g LDKDGWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOV1h LDKDGWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOV1i LDKDGWLHTGDIGKWLPNGTLKIIDRKRHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOV1j LDKDGWLHTGDIGKWLPNGTLKIIDRKKHIFKLAQGEYIAPEKIENIYMRSEPVAQVFVH NOVia GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP NOV1b GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP NOV1c GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP NOV1d GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP NOVie GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP NOV1f GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP NOV1g GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP NOVlh GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP NOV1i GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP 1NOV1j GESLQAFLIAIVVPDVETLCSWAQKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKP NOVla FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKV----- NOV1b FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKViNOV1c FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKV----- NOV1d FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKV----- NOVie FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKVHHHHH NOV1f FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKV----- NOV1g FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKV ---- 1NOV1h FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKV----- NOV1i FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKV----- INOV1j FEQVKGITLHPELFSIDNGLLTPTMKAKRPELRNYFRSQIDDLYSTIKV----- NOVIa (SEQ ID NO: 2) NOV1b (SEQ ID NO: 4) NOVlc (SEQ ID NO: 6) NOV1d (SEQ ID NO: 8) NOVIe (SEQ ID NO: 10) NOV1f (SEQ ID NO: 12) NOV1g (SEQ ID NO: 14) NOVih (SEQ ID NO: 16) NOV1i (SEQ ID NO: 18) NOV1j (SEQ ID NO: 20) Further analysis of the NOVia protein yielded the following properties shown in Table A7. Table A7. Protein Sequence Properties NOVIa 92 WO 2004/056961 PCT/US2003/034114 SignaiP analysis: Cleavage site between residues 49 and 50 PSORT 1I analysis: PSG: a new signal peptide prediction method N-region: length 11; pos.chg 2; neg.chg 1 H-region: length 2; peak value -9.10 PSG score: -13.50 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -3.91 possible cleavage site: between 48 and 49 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 3 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -2.28 Transmembrane 586 - 602 PERIPHERAL Likelihood= 2.92 (at 319) ALOM score: -2.28 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 593 Charge difference: -0.5 C(-1.0) - N(-0.5) N >= C: N-terminal side will be inside >>> Single TMS is located near the C-terminus >>> membrane topology: type Nt (cytoplasmic tail 1 to 585) MITDISC: discrimination of mitochondrial targeting seq R content: 2 Hyd Moment(75): 8.06 Hyd Moment(95): 9.89 G content: 0 D/E content: 2 S/T content: 0 Score: -4.51 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: RRKP (4) at 259 pat4: RKPK (4) at 260 pat4: RKKH (3) at 555 pat7: PTMKAKR (3) at 672 bipartite: none content of basic residues: 11.6% NLS Score: 0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: KKXX-like motif in the C-terminus: STIK SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none 93 WO 2004/056961 PCT/US2003/034114 RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 75 LL at 208 LL at 209 LL at 350 LL at 369 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 30.4 %: cytoplasmic 26.1 %: nuclear 13.0 %: mitochondrial 13.0 %: Golgi 8.7 %: endoplasmic reticulum 4.3 %: peroxisomal 4.3 %: vesicles of secretory system > prediction for CG93648-01 is cyt (k=23) A search of the NOVia protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table A8. Table A8. Geneseq Results for NO ViIa Geneseq Protein/Organism/Length [Patent #, NOVia Identities/ Expect Identifier Date] Residues/ Similarities for Value 94 WO 2004/056961 PCT/US2003/034114 Match the Matched Residues Region ABR47451 Breast cancer associated protein 1..698 698/698 (100%) 0.0 sequence SEQ ID NO:134 - Homo 1.698 698/698(100%) sapiens, 698 aa. [W02003004989-A2, 16 JAN-2003] AAU74393 Human cDNA encoding ovarian tumour 1..698 698/698 (100%) 0.0 protein clone OVM-65 - Homo sapiens, 1..698 698/698 (100%) 698 aa. [W0200190154-A2, 29-NOV 2001] ABP65246 Hypoxia-regulated protein #120 - Homo 1..698 698/698 (100%) 0.0 sapiens, 698 aa. [W0200246465-A2, 13- 1..698 698/698 (100%) JUN-2002] AAB42827 Human ORFX ORF2591 polypeptide 1..694 463/694 (66%) 0.0 sequence SEQ ID NO:5182 - Homo 1..694 568/694 (81%) sapiens, 697 aa. [W0200058473-A2, 05 OCT-2000] AB044460 Human secreted/transmembrane protein 25..697 414/673 (61%) 0.0 PRO1 250 - Homo sapiens, 739 aa. 68..738 527/673 (77%) [US2003044841-Al, 06-MAR-2003] In a BLAST search of public sequence databases, the NOV1 a protein was found to have homology to the proteins shown in the BLASTP data in Table A9. Table A9. Public BLASTP Results for NOV1a Protein NOV1a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion P33121 Long-chain-fatty-acid--CoA ligase 2 (EC 1..698 698/698 (100%) 0.0 6.2.1.3) (Long-chain acyl-CoA synthetase 1..698 698/698 (100%) 2) (LACS 2) - Homo sapiens (Human), 698 aa. P41215 Long-chain-fatty-acid--CoA ligase 1 (EC 1..698 678/700 (96%) 0.0 6.2.1.3) (Long-chain acyl-CoA synthetase 1..699 685/700 (97%) 1) (LACS 1) (Palmitoyl-CoA ligase) - Homo sapiens (Human), 699 aa. Q9GLP3 Long-chain fatty acid CoA ligase (EC 1..698 650/698 (93%) 0.0 6.2.1.3) - Callithrix jacchus (Common 1..698 678/698 (97%) marmoset), 698 aa. Q9JID6 Long-chain-fatty-acid--CoA ligase 1 (EC 1..698 619/698 (88%) 0.0 6.2.1.3) (Long-chain acyl-CoA synthetase 1..698 663/698 (94%) 1) (LACS 1) (Palmitoyl-CoA ligase) - Cavia porcellus (Guinea pig), 698 aa. P18163 Long-chain-fatty-acid--CoA ligase, liver 1..698 598/699 (85%) 0.0 isozyme (EC 6.2.1.3) (Long-chain acyl- 1..699 658/699 (93%) CoA synthetase 2) (LACS 2) - Rattus norvegicus (Rat), 699 aa. PFam analysis predicts that the NOV1 a protein contains the domains shown in the Table Al 0. 95 WO 2004/056961 PCT/US2003/034114 Table A10. Domain Analysis of NOVIa Identities/ Pfam Domain NOVia Match Region Similarities Expect Value for the Matched Region AMP-binding 122..588 114/484 (24%) 7.7e-105 351/484 (73%) Example A4. Human Long chain acyl-CoA synthetase 2 Gene Variants and SNPs The protocol for obtainment of gene variants and SNPs is disclosed in Example Q11. The variants of the human Long chain acyl-CoA synthetase 2 were obtained from direct cloning and/or public databases. In addition to the human version of the Long chain acyl-CoA synthetase 2 identified as being differentially expressed in the experimental study, other variants have been identified by direct sequencing of cDNAs derived from many different human tissues and from sequences in public databases. One splice variant have been identified at CuraGen CG93648-02. Interestingly, the stretch of amino acids that differ in CG93648-02 is highly similar to the same stretch in rat and mouse LACS2, making it a closer orthologue to the dysregulated rat and mouse LACS2. Therefore, this variant may also be relevant to the development of diabetes and obesity and used for screening purposes. Table A10-1 below demonstrates discovered SNP sequences. Wherein nucleotide N 1 is C or T; N 2 is A or G, and wherein residue X 1 is F or S; X 2 is K or R. TABLE A10-1. NOV1 SNP SEQUENCE ANALYSIS ISNP of CG93648-01 ISE ID NO: 146 3634 bp DNA Sequence .OR Start ATG at 14 ORF Stop: TAG at 2108 TCAACACAGGACAATGCAAGCCCATGAGCTGTTCCGGTATTTTCGAATGCCAGAGCTGGTTGACTTCC GACAGTACGTGCGTACTCTTCCGACCAACACGCTTATGGGC1TCGGAGCTTTTGCAGCACTCACCACC TTCTGGTACGCCACGAGACCCAAACCCCTGAAGCCGCCATGCGACCTCTCCATGCAGTCAGTGGAAGT GGCGGGTAGTGGTGGTGCACGAAGATCCGCACTACTTGACAGCGACGAGCCCTTGGTGTATTTCTATG ATGATGTCACAACATTATACGAAGGTTTCCAGAGGGGAATACAGGTGTCAAATAATGGCCCTTGTTTA GGCTCTCGGAAACCAGACCAACCCTATGAATGGCTTTCATATAAACAGGTTGCAGAATTGTCGGAGTG CATAGGCTCAGCACTGATCCAGAAGGGCTTCAAGACTGCCCCAGATCAGTTCATTGGCATCTTTGCTC AAAATAGACCTGAGTGGGTGATTATTGAACAAGGATGCTTTGCTTATTCGATGGTGATCGTTCCACTT TATGATACCCTTGGAAATGAAGCCATCACGTACATAGTCAACAAAGCTGAACTCTCTCTGG1T1TTGT TGACAAGCCAGAGAAGGCCAAACTCTTATTAGAGGGTGTAGAAAATAAGTTAATACCAGGCCTTAAAA TCATAGTTGTCATGGATGCCTACGGCAGTGAACTGGTGGAACGAGGCCAGAGGTGTGGGGTGGAAGTC ACCAGCATGAAGGCGATGGAGGACCTGGGAAGAGCCAACAGACGGAAGCCCAAGCCTCCAGCACCTGA AGATCTTGCAGTAATTTGTTTCACAAGTGGAACTACAGGCAACCCCAAAGGAGCAATGGTCACTCACC GAAACATAGTGAGCGATTGTTCAGCTTTTGTGAAAGCAACAGAGAATACAGTCAATCCTTGCCCAGAT GATACTTTGATATCTTTCTTGCCTCTCGCCCATATGTTTGAGAGAGTTGTAGAGTGTGTAATGCTGTG TCATGGAGCTAAAATCGGATTTTTCCAAGGAGATATCAGGCTGCTCATGGATGACCTCAAGGTGCTTC AACCCACTGTCTTCCCCGTGGTTCCAAGACTGCTGAACCGGATGTTTGACCGAATTTTCGGACAAGCA

AACACCACGCTGAAGCGATGGCTCTTGGACTN

1 TGCCTCCAAGAGGAAAGAAGCAGAGC17CGCAGCGG CATCATCAGAAACAACAGCCTGTGGGACCGGCTGATCTTCCACAAAGTACAGTCGAGCCTGGGCGGAA GAGTCCGGCTGATGGTGACAGGAGCCGCCCCGGTGTCTGCCACTGTGCTGACGTTCCTCAGAGCAGCC CTGGGCTGTCAGTTTTATGAAGGATACGGACAGACAGAGTGCACTGCCGGGTGCTGCCTAACCATGCC TGGAGACTGGACCGCAGGCCATGTTGGGGCCCCGATGCCGTGCAATTTGATAAAACTTGTTGATGTGG 96 WO 2004/056961 PCT/US2003/034114 AAGAAATGAATTACATGGCTGCCGAGGGCGAGGGCGAGGTGTGTGTGAAAGGGCCAAATGTATTTCAG GGCTACTTGAAGGACCCAGCGAAAACAGCAGAAGCTTTGGACAAAGACGGCTGGTTACACACAGGGGA CATTGGAAAATGGTTACCAAATGGCACCTTGAAAATrATCGACCGGAAAAN 2 GCACATATTTAAGCTGG CACAAGGAGAATACATAGCCCCTGAAAAGATTGAAAATATCTACATGCGAAGTGAGCCTGTTGCTCAG GTGTTTGTCCACGGAGAAAGCCTGCAGGCATTTCTCATTGCAATTGTGGTACCAGATGTTGAGACATT ATGTTCCTGGGCCCAAAAGAGAGGATTTGAAGGGTCGTTTGAGGAACTGTGCAGAAATAAGGATGTCA AAAAAGCTATCCTCGAAGATATGGTGAGACTTGGGAAGGATTCTGGTCTGAAACCATTTGAACAGGTC AAAGGCATCACATTGCACCCTGAATTATTTTCTATCGACAATGGCCTTCTGACTCCAACAATGAAGGC GAAAAGGCCAGAGCTGCGGAACTATTTCAGGTCGCAGATAGATGACCTCTATTCCACTATCAAGGTTT AGTGTGAAGAAGAAAGCTCAGAGGAAATGGCACAGTTCCACAATCTCTTCTCCTGCTGATGGCCTTCA TGTTGTTAATTTTGAATACAGCAAGTGTAGGGAAGGAAGCGTTCGTGTTTGACTTGTCCATTCGGGGT TCTTCTCATAGGAATGCTAGAGGAAACAGAACACCGCCTTACAGTCACCTCATGTTGCAGACCATGTT TATGGTAATACACACTTTCCAAAATGAGCCTTAAAAATTGTAAAGGGGATACTATAAATGTGCTAAGT TATTTGAGACTTCCTCAGTTTAAAAAGTGGGTTTTAAATCTTCTGTCTCCCTGCTTTTCTAATCAAGG GGTTAGGACTTTGCTATCTCTGAGATGTCTGCTACTTGCTGCAAATTCTGCAGCTGTCTGCTGCTCTA AAGAGTACAGTGCACTAGAGGGAAGTGTTCCCTTTAAAAATAAGAACAACTGTCCTGGCTGGAGAATC TCACAAGCGGACCAGAGATC1TFTTAAATCCCTGCTACTGTCCCTTCTCACAGGCATTCACAGAACCC TTCTGATTCGTAAGGGTTACGAAACTCATGTTCTTCTCCAGTCCCCTGTGGTTTCTGTTGGAGCATAA GGTTTCCAGTAAGCGGGAGGGCAGATCCAACTCAGAACCATGCAGATAAGGAGCCTCTGGCAAATGGG TGCTCATCAGAACGCGTGGATTCTCTTTCATGGCAGAATGCTCTTGGACTCGGTTCTCCAGGCCTGAT TCCCCGACTCCATCC1TTTCAGGGGTTATTTAAAAATCTGCCTTAGATTCTATAGTGAAGACAAGCA TTTCAAGAAAGAGTTACCTGGATCAGCCATGCTCAGCTGTGACGCCTGAATAACTGTCTACTTTATCT TCACTGAACCACTCACTCTGTGTAAAGGCCAACAGATTTTTAATGTGGTTTTCATATCAAAAGATCAT GTTGGGATTAACTTGCCTT TICCCCAAAAAATAAACTCTCAGGCAAGCATTTCTTTAAAGCTATTAA GGGAGTATATACTTGAGTACTTATTGAAATGGACAGTAATAAGCAAATGTTCTTATAATGCTACCTGA TTTCTATGAAATGTGTTTGACAAGCCAAAATTCTAGGATGTAGAAATCTGGAAAGTTCATTTCCTGGG ATTCACTTCTCCAGGGA1T TT rAAAGTTAATTTGGGAAATTAACAGCAGTTCACTTrATTGTGAGTC TTTGCCACATTTGACTGAATTGAGCTGTCATGTACATTTAAAGCAGCTGTTTTGGGGTCTGTGAGA GTACATGTATTATATACAAGCACAACAGGGCTTGCACTAAAGAATTGTCATTGTAATAACACTACTrG GTAGCCTAACTTCATATATGTATTCTTAATTGCACAAAAAGTCAATAATTTGTCACCTTGGGGTTTTG AATGTTTGCTTTAAGTGTTGGCTATTTCTATGTTTTATAAACCAAAACAAAATTTCCAAAAACAATGA AGGAAACCAAAATAAATATTTCTGCATTTC [Wherein nucleotide N 1 is C or T; N 2 is A or G.] SNP of CG93648-01 1SEQ ID NO: 147 698 aa MW at 77942.5kD Protein Sequence MQAHELFRYFRMPELVDFRQYVRTLPTNTLMGFGAFAALTTFWYATRPKPLKPPCDLSMQSVEVAGSG GARRSALLDSDEPLVYFYDDVTTLYEGFQRGIQVSNNGPCLGSRKPDQPYEWLSYKQVAELSECIGSA LIQKGFKTAPDQFIGIFAQNRPEWVIIEQGCFAYSMVIVPLYDTLGNEAITYIVNKAELSLVFVDKPE KAKLLLEGVENKLIPG LKI IVVMDAYGSELVERGQRCGVEVTSMKAMEDLG RAN RRKPKPPAPEDLAV ICFTSGTTGNPKGAMVTHRNIVSDCSAFVKATENTVNPCPDDTLISFLPLAHMFERVVECVMLCHGAK

IGFFQGDIRLLMDDLKVLQPTVFPVVPRLLNRMFDRIFGQANTTLKRWLLDX

1 ASKRKEAELRSGIIRN NSLWDRLIFHKVQSSLGGRVRLMVTGAAPVSATVLTFLRAALGCQFYEGYGQTECTAGCCLTMPGDWT AGHVGAPMPCNLI KLVDVEEMNYMAAEGEGEVCVKGPNVFQGYLKDPAKTAEALDKDGWLHTG DIG KW

LPNGTLKIIDRKX

2 HIFKLAQGEYIAPEKIENIYMRSEPVAQVFVHGESLQAFLIAIVVPDVETLCSWA QKRGFEGSFEELCRNKDVKKAILEDMVRLGKDSGLKPFEQVKGITLHPELFSIDNGLLTPTMKAKRPE LRNYFRSQIDDLYSTIKV [Wherein residue X 1 is F or S; X 2 is K or R.) Example A5. Expression Profile of the Human Long chain acyl-CoA synthetase 2 Gene The protocol for quantitative expression analysis is disclosed in Example 09. Expression of gene CG93648-01 was assessed using the primer-probe set Ag3951, described in Table Al1. Results of the RTQ-PCR runs are shown in Tables A12, A13 and A14. 97 WO 2004/056961 PCT/US2003/034114 Table Al 1. Probe Name Ag3951 riders Sequences Length Start Position iSEO ID No Forward 5'-cttcggagcttttgcagca-3' 19 109 99 Probe TET-5'-ctcaccaccttctggtacgccacgaga-3-TAMRA 27 128 100 [Reverse~ 5'-agaggtcgcatggcggct-3' [ 1 167 101 Table A12. General-screening-panelv1.6 Column A - Rel. Exp.(%) Ag3951, Run 277231320 Tissue Name A Tissue Name A ~Adipose j3.7 IRenal ca. TK-1 0 1.6 Melanoma* Hs688(A).T 6.8 Bladder 13.7 Melanoma* Hs688,(B,),.T,-",; *"" I.9 [Gastric ca. (liver met.) NCI-N87 10. Ielanoma* M14 166.4 Gastric ca. KATO Ill 48.3 IMelanoma* LOXIMVI J 0.5 Colon ca. SW-948 6.5 Melanoma* SK-MEL-5 147.6 Colon ca. SW480 17.2 ISquamous cell carcinoma SCC-4 [ 2.1 Colon ca.* (SW480 met) SW620 2.0 festis Pool 9.0 Colon ca. HT29 T 4.4 s ca.* (bone met) P0-3 1 oion a I-I6fJ. Irostate Pool 17.6 Colon ca. CaCo-2 9.2 Placenta 2.3 [Colon cancer tissue 11.5 Uterus Pool 2.3 Colon ca. SW1116 3.6 Ovarian ca. OVCAR-3 4.8 Colon ca. Colo-205 8.4 Ovarian ca. SK-OV-3 112.2 C~olon ca. SW-484. Ovarian ca. OVCAR-4 7.5 ]Colon Pool 5.8 [Ovarian ca. OVCAR-5 6. anet ol3.9 Ovarian ca. IGROV-1 5.7 Stomach Pool 6.2 [Ovarian ca. OVCAR-8 0.6 Bone Marrow Pool 3.1 Ovary 1.9 Fetal Heart 4.0 Breast ca. MCF-7 2.1 Heart Pool 12.9 Breast ca. MDA-MB-231 - I6.8 Lymph Node Pool - -7.1 Breast ca. BT 549 1 8.0 Fetal Skeletal Muscle 7.8 IBreast ca. T47D 5.4 Skeletal Muscle Pool 16.8 Breast ca. MDA-N I10.7Speen Pool 10.4 Breast Pool 4.8 Thymus Pool 9.3 Trachea 12.6 CNS cancer (glio/astro) U87-MG 17.4 Lung 0.4 ONS cancer (glo/astro) U- 8-MG '78.7 [etal Lung 8.9 ONS cancer (neuro;met) SK-N-AS 3.1 Lung ca. NCI-N417 5.9 CNS cancer (astro) SF-539 4.3 Lung ca. LX-1 1.4 CNS cancer (astro) SNB-75 14.8 [Lung ca. NCI-H146 1.7 CNS cancer (glio) SNB-19 5.3 [Lung ca. SHP-77 -- I8.5 ONS cancer (gio) SF-295 [8.6 Lung ca. A549 ....... 3.3 Brain (Amygdala) Pool 7.1 Lung ca. NCI-H526 [ 2.6 Brain (cerebellum) 7.8 Lung ca. NCI-H23 2.7 Brain (fetal) 5.9 Lung ca. NCI-H460 4.2 Bran (Hppocampus) Pool 8.4 Lung ca. HOP-62 1.3 Cerebral Cortex Pool 6.6 98 WO 2004/056961 PCT/US2003/034114 Lung ca. NCI-H522 2.9 Brain (Substantia nigra) Pool 6.5 Liver I85.3 Brain(Thalamus) Pool 10.5 Fetal Liver 49.3 Brain (whole) 10.4 Lierc. eG204 Spinal Cord Pool 15.1 Kidney Pool 7.6 Adrenal Gland 13.9 Fetal Kidney 4.2 Pituitary gland Pool 2.0 Renal ca. 786-0 8.4 Salivary Gland 12.9 n i a4- A98 65.0 Thyr~oid(female) -- _-_-------_._.4.2 Renal ca. ACHN 50.7 Pancreatic ca. CAPAN2 1.2 [Re na -1 ca. U- 31 . .. ....... ..... _ _"Ii6 h .7 1" creas Pool a Table A13. Human Metabolic Column A - Rel. Exp.(%) Ag3951, Run 324824489 isu Name A Tissue Name A 37857 psoas-AA.M.Diab.-hi100.0 139523 pancreas-HI.M.Norm-hi BMI-31 2.8 135760 psoas-HI.M.Diab.-hi BMI- 0.7 139520 pancreas-CC.M.Norm-hi BMI-29 2.6 21 .. .V ........ 34827 psoas-CC.M.Diab.-hi 6.2 142744 pancreas-HI.M.Norm-med BMI-35 0.2 1 3 7 8 6 0 p s a A.M. .Di b - e 2 8 .1 1 3 5 pm B 4 .5 137860 psoas-AA.M.Diab.-med 28.1 139545 pancreas-AA.M.Norm-med BMI-47 1.5 BMI-2 1 pac5sA.M ommdBI3 -~~ ~ ~ - - - _ .. .. ........ ..... -- _... - . 137828 psoas-CC.M.Diab.-med 30.1 137871 pancreas-CC.M.Norm-med BMI-26 0.6 13723 psoas-H.M.Diab.-med 20.3 139541 pancreas-Hi.M.Norm-low BMI-41 0.8 BMI-20 2.3 139537 pancreas-CC.M.Norm-low BMI-40 1.3 134834 psoas-AA.M.Diab.-low 16.8 139533 pancreas-CC.M . .w B - . 2 BMI-20217393 pancreas-CC.M.Norm-low BMI-401. [137850 psoas-AS. M.Norm-hi -w BMI-7 264 1137845 pancreas-AS.M.Norm-low BMI-28 0.9 135769 psoas-HI.M.Norm-hi 21.51143530 small intestine-AA.M.Diab.-hi BMI-62 1 35766 psoas-AA.M.Norm-hi 13.3 143529 small intestine-CC.M.Diab.-hi BMI-4 2.8 42746 psoas-AA.M.Norm-md 13.5 143538 small intestine-HI.M.Diab.-med BMI-23 2. 142745 psoas-HI.M.Norm-med 1.2 143531 small intestine-AA.M.Diab.-med BMI-8 4.4 BMI-35 1 3 7 8 5 5 psoas-AA.M.Norm-med 5.9 143528 small intestine-CC.M.Diab.-med BMI-2 3.6 137844 psoas-C.M.Norm-med 2.7 143537 small intestine-HI.M.Diab.-low BMI-22 2.6 IBMI-26 142742 psoas-CC.M.Norm-low 1.9 143535 small intestine-AS.M.Diab.-low BMI-20 2.2 IBMI-40 137873 psoas-AS.M.Norm-low 15.8 143534 small intestine-AA.M.Diab.-low BMI-17 1.9 99 WO 2004/056961 PCT/US2003/034114 137853 psoas-HI.M.Norm-low 4135 No J8.1 143544 small intestine-AS.M.Norm-hi BMI-34 2.2 135775 psoas-CC.M.Norm-low MI95.0 143543 small intestine-HI.M.Norm-hi BMI-31 0.4 137858 diaphragm-AA.M.Diab.-hi 633 43542 1 B63.3 143542 small intestine-CC.M.Norm-hi BM--29 1.2 BMI-6 . 135772 diaphragm-AS.M.Diab-hi 28.5 143539 small intestine-AA.M.Norm-hi BMI-25 2.0 [143539 diaphragm-H.M.NM.Dhiab.-hi 135761 diaphragm-HI.M.Diab.-hi 7.4 [143548 small intestine-AA.M.Norm-med BMI-47 1.3 B13MI-21 134828 diaphragm-CC.M.Diab.- 6.9 143547 small intestine-AA.M.Norm-med BMI-37 1.2 IN BMI-4. salntsn-AMNrmmdM-3 137835 diaphragm-CC.M.Diab.- 2. ml edi [20.9.143540 small intestine-CC.M.Norm-med BMI-26 1.1 med BMI-2 13e5764 iaphragm-HI.M.Diab.- 20.0 143550 small intestine-CC.M.Norm-low BMI-40 0.3 134835 diaphragm-AA.M.Diab.- 4.o5 B low BMI-17 low B4.517143549 small intestine-CC. M. Norm-low BMI-392. 142738 diaphragm-CC.M. Norm- 26.1 143546 small intestine-HI. M. Norm-low BMI-41 0.9 IN BMI-29 I0 139517 diaphragm-AS.M.Norm- 114.3 143525 hypothalamus-HI.M.Diab.-hi BMI-21 4.0 hi BMI-34 137848 diaphragm-HI.M.Norm-hi 24.1 143515 hypothalamus-CC.M.Diab.-hi BMI-4 0.7 BMI-31 I shptaau-CMDa.h M- . 137843 diaphragm-AA.M.Norm-_______________________________j0 hi BMI-25 hi MI-5 18,7 143513 hypothalamus-AA.M.Diab.-hi BMI-64. 137879 diaphragm-AA.M.Norm-T~ 1 3 0 . d -14.2 143507 hypothalamus-AS.M.Diab.-hi BMI-9 3.0 med BMI-47I 13 7872 diaphragm-CC.M.Norm- 7.7 143506 hypothalamus-CC.M.Diab.-med BMI-1 4.9 med BMI-2633.9 139542 diaphragm-HI.M.Norm- 15M low BMI-41 low.0M143509 hypothalamus-AA.M.Diab.-low Bl1 . 137877 diaphragm.CC.MNorm 1101 143508 hypothalamus-CC.M.Diab.-low BMI-13 2.8 low BMI-39 137874 diaphragm-AS.M.Norm- 4.1 143503 hypothalamus-AS.M.Diab.-low BMI-20 2.0 low BMI-28I 141340 subQadipose- 8.1 143522 hypothalamus-HI.M.Norm-hi BMI-31 0.2 137836 sub-ipos-HIMDb S6 subQadipose-HI.M.Diab.- 6.2 143516 hypothalamus-AS.M.Norm-hi BMI-34 0.3 135771 subQadipose- 142BI2 131sD aipMI-94.2 143511 hypothalamus-CC.M.Norm-hi BMI-29 1.7 AS.M.Diab-hi BMI-9 141329 pancreas-CC.M.Diab.-hi 4.9 143504 hypothalamus-AA.M.Norm-hi BMI-25 1.3 BMI-4_ _ ,_ _ ___________________ 137862 subOadipose- 14.0 143517 hypothalamus-AA.M.Norm-medBMI-47 2.7 CC.M.Diab.-med BMI-1 1yohlmsAAMNr-e 135762 subQadipose-HI.M.Diab.- 17 43514 hypothalamus-HI.M.Norm-med BMI-35 med BMI-23 141338 subQadipose- 14351 hypothalamus-.M.Norm- BMI- 1. 4AS.M.Diab.-low BMI-208 139547 subOadipose-HI.M.Diab.- 28.5 143512 hypothalamus-CC.M.Norm-low BMI-40 0.6 100 WO 2004/056961 PCT/US2003/034114 ..... ~ . . .......... ;-.... ._ - _.-............. . f1 135757 subQadipose- 4.0 145454 Patient-25pl (CC.Diab.low BMI.no nsuln) 1.9 CC.M.Diab.-Iow BMI-13 134832 subQadipose- 10.4 110916 Patient-18pl (HI.Diab.obese.no insulin) 1.7 AA.M.Diab.-low BMI-17 141332 subQadipose- 1.5 110913 Patient-18go (HI. Dab.obese.no nsuln) 6.9 HI.M.Norm-hi BMI-31 135767 subOadipose- 0.5 110911 Patient-17pl(CC.Diab.lowBMI.no insulin) 1.1 CC.M.Norm-hi BMI-29 0 1 135765 subQadipose- 7 110908 Patient-17go (CC.Diab.low BMI.no insulin) 11.9 AS.M.Norm-hi BMI-34 Pel n 141339 subQadipose- 1.8 100752 Patient-1 5sk (CC.Diab.obese.no insulin) 27.7 HI.M.Norm-med BMI-35 141334 subQadipose AA0M.Norm-med BMI-26 9 7828 Patient -13pl (CC.Diab.overwt.no insulin) 0.8 139544 sub~adipose- 23.7 160114 Patient 27-ut (CC.Diab.obese. insulin) 9.0 137875 subOadipose- 6.5 160113 Patient 27-pl (CC.Diab.obese.insulin) 2.6 AA.M.Norm-med BMI-37 141331 suboadipose- 0.3 160112 Patient 27-sk (CC.Diab.obese.insulin) 14.9 1388subQadipose- 4 . HC.M.Norm-low BMI-1 ...... 1 1 3 8 8 ubQ aipos e4.6 160111 Patient 27-go (CC. Diab.obese. insulin) 1 0.0 137876 subQadipose- 3.1 145461 aien-2s (CC.Diab.obese.insulin) ICC.M.Norm-low B-39 3 56 ain-6k(C iboeeisln . .. 37859... .vi.... .d........s.......A... ia---- . - - - - - - - - - - - - - - - --. ....... ... ............. 378 59 v i s.4 145441 Patient-22sk (CC.Diab.low BMI.insulin) 29.1 135770 vis.adipose-AS.M.Dab-hi 6.3 145438 Patient-22pl (CC.Diab.low BMI.insulin) 1.7 1BMI-9 135759 vis.adipose-HI.M. Diab.-hi BMI-21 145427 Patient-20p1 (CC. Diab.overwt.insulin) 4.5 143502 visadipose-CC. M .Diab.

2091 isaioe-AMDa .- 970Iain-2l(CDabukonBIisln 139510 vis.adipose-AA.M.Diab.- 0.2 145443 Patient-23pl (CC.Non-diab.overwt) 1.2 med BMI-8 137861 vis.adipose-CCM .Diab.- 2.3 145435 Patient-21 p (CC. Non-diab.overwt) 1.8 [med-1 137839 vis.adipose-HI.M.Diab.- 4.7 110921 Patient-l9pl (CC.Non-diab.low BMI) med BMI-23 139546 vis.adipose-HI.M.Diab.

low BMI-22 .8 Patient-1 9go (CC.Non-diab.low BMI) 10.5 137831 vis.adipose-CC.M.Diab.- 1.3 97481 Patient-08sk (CC.Non-diab.obese) 14.3 low BMI-13 I [97481 (CC. 139522 vis.adipose-HI.M.Norm-hi 7.2 97478 Patient-07pl (CC.Non-diab.obese) 0.8 BMI-31 139516 vis.adipose-AS.M.Norm- 0.6 160117 Human Islets-male, obese 3.0 hi BMI-34 137846 vis.adipose-CC.M.Norm- 1.5 145474 PANC1 (pancreas carcinoma) 1 3.4 hi BMI-29 137841 vis.adipose-AA.M.Norm- 1.2 154911 Capan2 (pancreas adenocarcinoma) 1.0 hi BMI-25 139543 vis.adipose-AA.M. Norm- 25 141190 SW579 (thyroid carcinoma) med BMI-47 2. 13.2 101 WO 2004/056961 PCT/US2003/034114 0139532 vis.adipose-AA.M.Norm- 0 145489 SK-N-MC neuroblastomaa) 1 1.6 139530 vis.adipose-HI.M.Norm- 0,1 145495 SK-N-SH (neuroblastoma) 1 9.3 ~med BMI-35 11~er s 139539 vis.adipose-HI.M.Norm- 491145498 low BMI-41 U87 MG (glioblastoma) 2 139535 vis.adipose-CC.M.Norm- 1.4 145484 HEp-2 (larynx carcinoma) 1 0.2 low BMI-40 .p(ayxcrio)1 137852 vis.adipose-CC.M.Norm- 30 145479 A549 (lung carcinoma) 4.2 low BMI-39 135768 vis.adipose-AS.M.Norm- 1.0 145488 A427 (lung carcinoma) 2 3.3 low BMI-28 141327 liver-CC.M.Diab.-hi BMI- 4.5 145472 FHs 738Lu (normal lung) 1 3.5 139514 liver-HI.M.Diab.-hi BM - 7.5 141187 SKW6.4 (B lymphocytes) 6.3 21 139526 liver-CC.M.Diab.-med 10.2 154644 IM-9 (immunoglobulin secreting lymphoblast) 1117 BMI-2 L 139511 liver-AA.M.Diab.-med 154645 MOLT-4 (acute lymphoblastic leukemia derived 1.2 BMI-8 1 from peripheral blood) 137840 liver-HI.M.Diab.-med 59.0 154648 U-937 (histiocystic lymphoma) 28.3 BMI-23 137827 liver-CC.M.Diab.-med 58.6 154647 Daudi (Burkitt's lymphoma) 1.7 BMI-1 137838 iver-HI.M.Diab.-low BMI- 44.

4 145494 SK-MEL-2 (melanoma) 2 4.1 22 135758 liver-CC.M.Diab.-low 50.0 141176 A375 (melanoma) 1.2 BMI-13 139519 liver-CC.M.Norm-hi BMI- 11.

0 154642 SW 1353 (humerus chondrosarcoma) 7.1 129 _ _ _ _ _ _ _ _ .S 139518 liver-AA.M.Norm-hi DM1 13951 liver-A .M.Norm-hi M .- 8.0141179 HT-1080 (fibrosarcoma) 2.5 25 134 55.5 145491 MG-63 (osteosarcoma) 1 12.7 13M.Norm-hi BM- 29.1 141186 MCF7 (breast carcinoma) 142741 liver-AA.M.Norm-med 64.2 141193 T47D (breast carcinoma) 9.7 141341 liver-HI. M.Norm-med 5.6 154641 BT-20 (breast carcinoma) 30.6 IB M I-3 5 . ................ ---------............. 141335 liver-CC.M.Norm-med 5 141175 293 (kidney transformed with adenovirus 5 1.9 BMI-26 T DNA) 139540 liver-HI.M.Norm-low BMI- 6.4 141182 HUH hepatoma 1 1.9 139534 liver-CC.M.Norm-low 16.6 141184 HUH7 hepatoma 1 1.1 BMI-39 139521 liver-AS.M.Norm-low 5.2 145478 HT1 376 (bladder carcinoma) 11.0 BMI-28 BMI-4 f1432 pncea-C.MDib.hi 4.2 145481 SCaBER (bladder carcinoma)4. 139525 pancreas-AS.M.Diab.-hi 0.8 141192 SW620 (lymph node metastatsis, colon 4.4 BMI-9 carcinoma) 2 137856 pancreas-AA.M.Diab.-hi 2.4 141180 HT29 (colon carcinoma) 1 -- 7- 4 102 WO 2004/056961 PCT/US2003/034114 BMI-6 137837 pancreas-HI.M.Diab.-hi 0.8 141188 SW480 (colon carcinoma) 1 13.8 BMI-21 _ __ _ _ _ _ _ _ _ _ _ _ _ _ 141337 pancreas-CC.M.Diab.- 0.6 154646 CAOV-3 (ovary adenocarcinoma) 2.2 med BMI-2 F___ 139527 pancreas-CC.M.Diab.- 1.3 141194 HeLa (cervix carcinoma)- 2 3.6 med BMI-1(crxcacnm)236 139515 pancreas-HI.M.Diab.- 3.6 145482 HeLa S3 (cervix carcinoma) 1 1.9 ~med BMI-23 (criFacnm)11. 1395 2 ancreas-AA.M.Dab.- 3.1 145486 DU145 (prostate carcinoma) 1.0 flow BMI-20 2.0 154643 PC-3 (prostate adenocarcinoma) 1 9513 M- reas .Ia 2.1 154649 HCT-8 (ileocecal adenocarcinoma) 6.3 low BMI-13 142743 pancreas-AA.M.Norm-hi 1 0 ...- 25 I. ... Table A14. Panel 5 Islet * TissueColumn A - Rel. Exp.(%) Ag3951, Run 304686272 Nam- --- ""ise e f ___ssue__Name _ T 97457 Patient-02go adipose 12.9 94709 Donor 2 AM - A adipose 18.0 974 6 Patient-07sk skeletal muscle 0.0 94710 Donor 2 AM - B adipose 14.1 97477 Patient-07ut uterus 1.6 94711 Donor 2 AM - C adipose 12.0 97478 Patient-07pl placenta 0.9 94712 Donor 2 AD - A adipose 74.2 99167 Bayer Patient 1 0.0 94713 Donor 2 AD - B adipose 94.0 197482.Patient-O8ut uterus f 2.1 194714 Donor 2 AD - C adipose 80.7 97483 Patient-08pl placenta 0.7 94742 Donor 3 U - A Mesenchymal Stem 1.6 1 1~ Cells 97486 Patient-09sk skeletal muscle 14. 9743 Donor 3 U - B Mesenchymal Stem 1.4 97487 Patient-09ut uterus 3. 9 4 3 0 Dn3A-Cells A 197487 Patient-09ut uterus 3.9 94732 Donor 3 AM - A adipose 23.2 197488 Patient-,09pI**placenta 16 0. 9i31 Donor 3 AM - B adipose 2. J97492 Patient-l Out uterus 13.9 [94732 Donor 3 AM - C adipose 24.31 J97493 Patient-1 OpI placenta 1.8 94733 Donor 3 AD - A adipose 100.0 97495 Patient- 11go adipose 6.7 94734 Donor 3 AD - B adipose 67.8 197496 Patient-i lsk skeletal muscle 1.17.0.19 47 .35 Donor.3 AD -- C adipose_,.- ....... 19. 197497 .Patient-1 lut uterus -3.7 177138 Liver HepG2untreated 6.2 197498 Patient-i 11p placenta 0.5 7i3556 Heart Cardiac stromal cells (primary) 0.2 9750 6 Patient-12go adpose 117.481735 Small Intestine 5.8 97501 Patient-12sk skeletal muscle 43.8 72409 Kidney Proximal Convoluted Tubule 40.3 97502 Patient-1 2ut uterus 4.9 82685 Small intestine Duodenum 11.6 97503 Patient-12pl placenta 1.6 90650 Adrenal Adrenocortical adenoma 1.7 Cells Donor 2 U - A Mesenchymal Stem 3.6 72410 Kidney HRCE 16.7 Cells Donor 2 U - B Mesenchymal Stem 2.9 72411 Kidney HRE 5.7 lCells Cell3sDonor 2 U - C Mesenchymal Stem [3.6 173139 Uterus Uterine smooth muscle cells 3.7 Cells 103 WO 2004/056961 PCT/US2003/034114 Generalscreening-panel-vl.6 Summary: Ag3951/Ag6979 Two experiments with different probe and primer sets were in good agreement, with highest expression of this gene seen in gastric cancer NCI-N87 cell line (CTs=23.5-30). High expression of this gene was detected in number of cancer cell lines derived from melanoma, pancreatic, brain, colon, lung, breast, renal, ovarian and prostate cancer. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product would be useful in the treatment of these cancers. High levels of expression of this gene was also seen in tissues with metabolic/endocrine functions including adipose, and liver. Moderate to low expression was also detected in pancreas, thyroid, adrenal gland, pituitary, smooth muscle, heart and gastrointestinal tract. This gene codes for a variant of long chain acyl-CoA synthetase 2 (LACS2). It is a microsomal enzyme involved in fatty acid esterification. Using CuraGen Corporation's GeneCalling TM method of differential gene expression, the rat orthologue of LACS2 was found to be up-regulated in liver in response to troglitazone (TZD) treatment; the mouse orthologue LACS2 was found to be down-regulated in brown adipose tissue, but not in white adipose tissue of obese mice on a high fat diet as compared to chow-fed mice. These data indicate that human LACS2 contributes to the obese phenotype induced by TZD treatment and is selectively down-regulated in brown adipose tissue to inhibit fatty acid esterification and promote beta oxidation. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product would be useful in the treatment of endocrine/metabolically related diseases, such as obesity, diabetes, hypercholesterolemia and hypertension. Human Metabolic Summary: Ag3951 The highest expression of this gene was detected in psoas muscle (CT=21). Among tissues with metabolic or endocrine function, this gene was expressed at high to moderate levels in skeletal muscle (psoas and diaphragm), pancreas, liver, small intestine and hypothalamus. This gene codes for a variant of long chain acyl-CoA synthetase 2 (LACS2). It is a microsomal enzyme involved in fatty acid esterification. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product would be useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Panel 5 Islet Summary: Ag3951 Highest expression of this gene was detected in differentiated adipose tissue (CT=25.2). This gene showed ubiquitous expression with high expression in adipose tissue. Expression of this gene was higher in differentiated adipose tissues as compared to the mesenchymal stem cells and midway differentiated adipose tissues. This data indicates LACS2 protein encoded by this gene plays a role in adipose differentiation. See panel 1.6 for further discussion on the utility of this gene. Example A6. Screening Assay Formulation Assays for screening for antibody therapeutics or small molecule drugs to treat obesity and/or diabetes by targeting human Long chain acyl-CoA synthetase 2 can be formulated utilizing the non exhaustive list of cell lines that express Long chain acyl-CoA synthetase 2 from the RTQ-PCR results shown above. 104 WO 2004/056961 PCT/US2003/034114 To assay the enzymatic activity of Long chain acyl-CoA synthetase 2 measurements of for example, radiolabeled acyl-CoA could be performed, as described in Uchida Y, Kondo N, Orii T, Hashimoto T., Purification and properties of rat liver peroxisomal very-long-chain acyl-CoA synthetase, in J Biochem (Tokyo) 1996 Mar; 119(3):565-71. . To assess the selectivity of the compounds, palmitic and lignoceric acid substrates provided either endogenously or exogenously may be used. ATP + a long-chain carboxylic acid + CoA => AMP + pyrophosphate + acyl-CoA Screening assays for long chain acyl-CoA synthethase 2 may also utilize teachings from the following references: Christmass MA et al., A semiautomated enzymatic method for determination of nonesterified fatty acid concentration in milk and plasma, Lipids 1998 Oct;33(10):1043-9; Kiziltunc A. et al., An enzymatic method for the determination of free fatty acids in serum/plasma, Clin Chem Lab Med 1998 Feb;36(2):83-6; J Biol Chem. 2001 Jul 6;276(27):24674 (2001). PMID: 11319232: "..Acyl CoA's functionally channeled to specific metabolic pathways through different ACS isoforms in unique locations." Our results indicate that a modulator of Long chain acyl-CoA synthetase 2 activity, such as an inhibitor, activator, antagonist, or agonist of Long chain acyl-CoA synthetase 2 may be useful for treatment of such disorders as obesity, diabetes, and insulin resistance, as well as for enhancement of insulin secretion. B. NOV2 - Copper-containing Amine Oxidase 3 The semicarbazide-sensitive amine oxidase (SSAO) family catalyzes the deamination of methylamine and aminoacetone to produce hydrogen peroxide and ammonia as well as toxic aldehydes, i.e. formaldehyde and methylglyoxal. A positive correlation has been found between serum SSAO levels and body mass index (BMI), body weight and hemoglobin Alc levels, plasma glucose and triglycerides (Metabolism. 48:113 (1999). PMID: 9920154.). In adipose tissue, a membrane-bound SSAO has been found that oxidizes exogenous amines and generated hydrogen peroxide (J Pharmacol Exp Ther. 297:563 (2001). PMID: 11303044). Since hydrogen peroxide is known to exert insulin-like anti-lipolytic effects, adipocytes potentially mimic insulin action by activating SSAO, increasing adipogenesis and inhibiting lipolysis. Indeed, it was shown in 3T3-L1 adipocytes that SSAO substrates induce adipose maturation (Biochem J. 356:769 (2001) .PMID: 11389684; an. Biochem J. 358:335 (2001). PMID: 11513731). We found copper containing amine oxidase 3 (AOC3), a member of the SSAO family, to be upregulated in AKR obese mice compared to lean SWR and control C57L/J mice. Differential gene expression analysis (Real Time Quantitative PCR [RTQ-PCR]) data show that AOC3 is highly expressed in adipose tissue. Therefore, we postulate that AOC3 is the predominant SSOA member in adipose and the main contributor to the generation of the hydrogen peroxide in this tissue. Inhibiting AOC3 will decrease the levels of hydrogen peroxide and the anti-lipolytic effects exerted on the tissue, and may be an effective treatment for obesity. Since there is a relationship between diabetes and SSAO activity, it may similarly be an antagonist against AOC3 and may have beneficial effects for the treatment of diabetes. 105 WO 2004/056961 PCT/US2003/034114 It was also discovered that copper containing amine oxidase 3 (AOC3) is downregulated in obese normoglycemic and obese hyperglycemic adipose tissue in animal model of diet-induced obesity (DIO). As stated above, we previously identified AOC3 to be upregulated in adipose tissue of obese AKR strain animals when compared to the adipose tissue of normal weight C57BLI6J strain or lean Cast/Ei strain animals. However, contrary to expectations, AOC3 was also found to be downregulated in multiple adipose depots of DIO animals. Diet-induced obesity is a popular model for the study of pathways involved in the evolution of weight gain due to increased caloric intake. Mice are fed a high-fat diet (- 30-45% of calories from fat) for 12-16 weeks and then tissues are analyzed for changes in metabolic pathways as compared to control animals fed a normal rodent diet. CuraGen's GeneCalling@ studies of adipose tissue from high fat-fed versus normal chow-fed mice show consistent downregulation of AOC3 in multiple adipose depots of obese normo- and hyperglycemic animals. Our interpretation of these results is that downregulation of AOC3 is a compensatory response to decrease exposure of adipose tissue to hydrogen peroxides thus attenuating their anti-lipolytic effects and decreasing adipogenesis. The discordance in AOC3 differential gene expression in diet-induced obesity versus a genetic model of obesity can be explained by the differences in the two models. In genetic obesity, the pathophysiology is static because it is hard-wired into the organism. In contrast, in diet-induced obesity, the increase in fat mass evolves over a period of 12-16 weeks, and is a result of the increase in high-fat calories. The response to the caloric overload is dynamic (as seen in CuraGen's GeneCalling@ studies), and includes compensatory responses by the organism to maintain energy homeostasis and body weight. Such a compensatory response to caloric overload appears to include a downregulation of AOC3 in adipose tissue. Our data shows that AOC3 is highly expressed in the adipose tissue. Inhibiting AOC3 will decrease the levels of hydrogen peroxide in adipose resulting in the attenuation of their anti-lipolytic and adipogenic actions. Thus, inhibition of AOC3 will be an effective treatment of obesity. Since there is a relationship between diabetes and SSAO activity, it may similarly be an antagonist against AOC3 and may have beneficial effects for the treatment of diabetes. Furthermore, our results indicate that a modulator of AOC3 activity, such as an inhibitor, activator, antagonist, or agonist of AOC3 may be useful for treatment of such disorders as obesity, diabetes, and insulin resistance, as well as for enhancement of insulin secretion. Discovery Process The following sections describe the study design(s) and the techniques used to identify the Copper-containing Amine Oxidase 3 - encoded protein and any variants, thereof, as being suitable as diagnostic markers, targets for an antibody therapeutic and targets for a small molecule drugs for Obesity and Diabetes. Example B1. Genetically Obese Mice vs Genetically Lean Mice Study A large number of mouse strains have been identified that differ in body mass and composition. The AKR and NZB strains are obese, the SWR, C57L and C57BLJ6 strains are of average weight whereas the SM/J and Cast/Ei strains are lean. Understanding the gene expression differences in the major metabolic tissues from these strains will elucidate the pathophysiologic basis 106 WO 2004/056961 PCT/US2003/034114 for obesity. These specific strains of rat were chosen for differential gene expression analysis because quantitative trait loci (QTL) for body weight and related traits had been reported in published genetic studies. Tissues included whole brain, skeletal muscle, visceral adipose, and liver. The protocol for Genetically Obese Mice vs Genetically Lean Mice is disclosed in Example Q6. A fragment of the mouse Copper-containing Amine Oxidase 3 gene was initially found to be up-regulated by 1.7 fold in the adipose tissue of genetically obese AKR mice relative to genetically lean SWR/J mice using CuraGen's GeneCalling* method of differential gene expression (disclosed in Example 07). A differentially expressed human gene fragment migrating, at approximately 272.6 nucleotides in length was definitively identified as a component of the mouse Copper-containing Amine Oxidase 3 cDNA. The method of competitive PCR was used for confirmation of the gene assessment. The electropherographic peaks corresponding to the gene fragment of the mouse Copper-containing Amine Oxidase 3 were ablated when a gene-specific primer (shown in Table B1) competes with primers in the linker-adaptors during the PCR amplification. The peaks at 272.6 nt in length were ablated in the sample from both the genetically obese AKR mice and the genetically lean SWR/J mice. Table BI. The direct sequence of the 272.6 nucleotide-long gene fragment and the gene-specific primers used for competitive PCR are indicated on the cDNA sequence of the Copper-containing Amine Oxidase 3 and are shown below in bold (fragment from 2792 to 3064 in bold. band size: 273). The gene-specific primers at the 5' and 3' ends of the fragment are underlined. Gene length is 4451 nt, only region from 2311 to 3544 is shown (SEQ ID NO:102). 2311 GACCCCCACT GTGAACTTCA CCGACTTCAT CAGCAATGAG ACCATTGCTG GAGAGGACTT 2371 GGTAGCCTGG GTGACGGCTG GCTITTTGCA CATCCCTCAT GCAGAAGATA TCCCCAACAC 2431 GGTGACTGCG GGGAACTCAG TGGGCTTCTT CCTCCGGCCG TATAACTTCT TTGACGAGGA 2491 CCCCTCCTTT CATTCTGCTG ACTCCATCTA TTTCCGGGAG GGCCAGGATG CCACGGCCTG 2551 TGAGGTTAAC CCCTTGGCTT GCCTGTCCCA GACTGCCACC TGTGCCCCCG AAATTCCTGC 2611 CTTCTCCCAT GGGGGCTTTG CTTACAGAGA CAATTGAACT GTTTCTAAGT ATCCCTCCCT 2671 CGCTCCTGCT CAGACCATGT GCTCACTTCC CCACGCCATT AAGTGTCCCC AAGATGGACA 2731 ATCTAGCTAA GAGCTGGGAA GTAGCGCAAC AGCCGGGCAG TACACAGAGC AATTCGATTG 2791 AAGATCTGGT TCCTTCTGTC CCCACATCTT TGATGTCCCC TCTCTCTTCT GCTGCCCTCC 2851 TTGTCTCTCC CTCTCTGCTT GGAGCATCCT GAGCCCATGG AAACCTGATG CACAGGGACA 2911 CTGAACTTTG TTGGTTGTGC CTGTACTGAG TTCCTGCCTT GGGAGAATAG CCTTGTTGGA 2971 GCCTGGAGTA ATGGCTATGT TTGTTTTGC TTTGAATATG GCTCCTTTTC CCCACCCCCA 3031 CCGCACCCCC TATTGGCTT TCATTTAAAA GCTTATGATA GCTTTGAGGA CTCTGCAATG 3091 AGGATAACTC TCTAGAGACC CCCAAAGTAG GGTCTCTCTG AGTCTCTCAC ATCCACAGAT 3151 TCTTCATCTA CATCCCTTTC CTACTTAAGC CTCTTTCATT TCCATTCTCT CCCTCTCCCT 3211 CCCCGCCCCC TCTCCTTTCC TCCCTCCCCC CTCCCTCCCC TCTTCCTGGA GTTCCTGCTT 3271 GCTCATACAT GCTAGGATTC CTACTCAGTC CAAAAGCGAT GTCCGTCCTA AGAGTTCTCT 3331 GAGCCCTCAT TCTCAAACTG CAGTCTCTTC TCCTGGACCC GAGTCTGTGG AAATCTCAAA 3391 GATGTAATGC AAAGCCTCAT GGGAGAGGAC CAGGC1TTC TATCTCCTAA CGTTCGTCAC 3451 ATATCAGGAA GGAGTAGGGC TTGTCCCTGC GGTAGCCCTG CTTTGCCCTC TTTACAAGAA 3511 GATGGAGGTG CTATGATTAT GACGAATGGT TATT A gene fragment of the mouse Copper-containing Amine Oxidase 3 was also found to be up regulated by 1.7 fold in the adipose tissue of genetically obese AKR mice relative to normal C57UJ mice using GeneCalling* method of differential gene expression (disclosed in Example Q7). A differentially expressed mouse gene fragment migrating, at approximately 424.6 nucleotides in length was definitively identified as a component of the mouse Copper-containing Amine Oxidase 3 cDNA. 107 WO 2004/056961 PCT/US2003/034114 The method of competitive PCR was used for confirmation of the gene assessment. The electropherographic peaks corresponding to the gene fragment of the mouse Copper-containing Amine Oxidase 3 were ablated when a gene-specific primer (shown in Table B2) competes with primers in the linker-adaptors during the PCR amplification. The peaks at 424.6 nt in length were ablated in the sample from both the genetically obese AKR mice and the normal C57L/J normal mice. Table B2. The direct sequence of the 424.6 nucleotide-long gene fragment and the gene-specific primers used for competitive PCR are indicated on the cDNA sequence of the Copper-containing Amine Oxidase 3 and are shown below in bold (fragment from 2641 to 3064 in bold. band size: 424). The gene specific primers at the 5' and 3' ends of the fragment are underlined. Gene length is 4451, only region from 2160 to 3544 is shown (SEQ ID NO:103). 2160 GCATCCAGAT ACTCAGCTTT GCTGGAAAGC CCTTGCCCCA GGAAAGTCCC ATAGAGAAAG 2220 CCTTCACCTG GGGGAGGTAT CACTTGGCTG TGACCCAGAG GAAGGAGGAG GAGCCTAGCA 2280 GCTCTAGCAT CTTCAACCAG AACGACCCGT GGACCCCCAC TGTGAACTTC ACCGACTTCA 2340 TCAGCAATGA GACCATTGCT GGAGAGGACT TGGTAGCCTG GGTGACGGCT GGCTTTTTGC 2400 ACATCCCTCA TGCAGAAGAT ATCCCCAACA CGGTGACTGC GGGGAACTCA GTGGGCTTCT 2460 TCCTCCGGCC GTATAACTTC TTTGACGAGG ACCCCTCCTT TCATTCTGCT GACTCCATCT 2520 ATTTCCGGGA GGGCCAGGAT GCCACGGCCT GTGAGGTTAA CCCCTTGGCT TGCCTGTCCC 2580 AGACTGCCAC CTGTGCCCCC GAAATTCCTG CCTTCTCCCA TGGGGGCTTT GCTTACAGAG 2640 ACAATTGAAC TGTTTCTAAG TATCCCTCCC TCGCTCCTGC TCAGACCATG TGCTCACTTC 2700 CCCACGCCAT TAAGTGTCCC CAAGATGGAC AATCTAGCTA AGAGCTGGGA AGTAGCGCAA 2760 CAGCCGGGCA GTACACAGAG CAATTCGATT GAAGATCTGG TTCCTTCTGT CCCCACATCT 2820 TTGATGTCCC CTCTCTCTTC TGCTGCCCTC CTTGTCTCTC CCTCTCTGCT TGGAGCATCC 2880 TGAGCCCATG GAAACCTGAT GCACAGGGAC ACTGAACTTT GTTGGTTGTG CCTGTACTGA 2940 GTTCCTGCCT TGGGAGAATA GCCTTGTTGG AGCCTGGAGT AATGGCTATG TTTTGTTTTG 3000 CTTTGAATAT GGCTCCTTTT CCCCACCCCC ACCGCACCCC CTATTTGGCT TTCATTTAAA 3060 AGCTTATGAT AGCTTTGAGG ACTCTGCAAT GAGGATAACT CTCTAGAGAC CCCCAAAGTA 3120 GGGTCTCTCT GAGTCTCTCA CATCCACAGA TTCTTCATCT ACATCCCTTT CCTACTTAAG 3180 CCTCTTTCAT TTCCATTCTC TCCCTCTCCC TCCCCGCCCC CTCTCCTTTC CTCCCTCCCC 3240 CCTCCCTCCC CTCTTCCTGG AGTTCCTGCT TGCTCATACA TGCTAGGATT CCTACTCAGT 3300 CCAAAAGCGA TGTCCGTCCT AAGAGTTCTC TGAGCCCTCA TTCTCAAACT GCAGTCTCTT 3360 CTCCTGGACC CGAGTCTGTG GAAATCTCAA AGATGTAATG CAAAGCCTCA TGGGAGAGGA 3420 CCAGGCTTTT CTATCTCCTA ACGTTCGTCA CATATCAGGA AGGAGTAGGG CTTGTCCCTG 3480 CGGTAGCCCT GCTTTGCCCT CTTTACAAGA AGATGGAGGT GCTATGATTA TGACGAATGG 3540 TTATT Example B2. Mouse Dietary-induced Obesity Study The predominant cause for obesity in clinical populations is excess caloric intake. This so called diet-induced obesity (DIO) is mimicked in animal models by feeding high fat diets of greater than 40% fat content. The DIO study was established to identify the gene expression changes contributing to the development and progression of diet-induced obesity. In addition, the study design sought to identify the factors that lead to the ability of certain individuals to resist the effects of a high fat diet and thereby prevent obesity. The sample groups for the study had body weights +1 S.D., + 4 S.D. and + 7 S.D. of the chow-fed controls. In addition, the biochemical profile of the + 7 S.D. mice revealed a further stratification of these animals into mice that retained a normal glycemic profile in spite of obesity and mice that demonstrated hyperglycemia. Tissues examined included hypothalamus, brainstem, liver, retroperitoneal white adipose tissue (WAT), epididymal WAT, brown adipose tissue (BAT), gastrocnemius muscle (fast twitch skeletal muscle) and soleus muscle (slow twitch skeletal muscle). The differential gene expression profiles for these tissues revealed genes 108 WO 2004/056961 PCT/US2003/034114 and pathways that can be used as therapeutic targets for obesity. The protocol for Mouse Dietary Induced Obesity study is disclosed in Example Q1. Several fragments of the mouse AOC3 gene were found to be down-regulated in multiple comparisons between normo- and hyperglycemic obese adipose depots when compared to the chow fed or sdl tissue using GeneCalling* method of differential gene expression (disclosed in Example Q7). Differentially expressed mouse gene fragments were identified as a component of the mouse AOC3 using TRAPPING T M analysis (disclosed in Example Q7, part C). These data are suggestive of AOC3 being involved in hydrogen peroxide induced anti-lipolytic effects in adipose tissue and the progression of obesity. Specifically, ten gene fragments of the mouse Copper-containing Amine Oxidase 3 gene were initially found to be downregulated by approximately 2.4 fold in the epididymal fat pads of normoglycemic obese animals when compared to the epididymal fat pads of the control non-obese animals. These ten differentially expressed mouse gene fragments, migrating at approximately 199.8, 332.1, 158.5, 424.3, 314.9, 272.6,100.2,179.3, 221.2 and 134.2 nucleotides in length, were definitively identified as components of the mouse Copper-containing Amine Oxidase 3. The method of TraPpingTM was used for confirmation of the gene assessment. A table depicting the fragment lengths, dysregulation, TraPping T M score and actual sequence data is displayed below. The numerator in the score represents the number of nucleotides matched in the gene fragment. The actual nucleotide sequence is displayed in the column labeled "Fragment TraP Data" (see Table B3). The denominator in the score represents the total number of TraP nucleotides available for this fragment with the actual nucleotide sequence presented in the column labeled "Predicted Trap Nucleotide Sequence". A score of 3/3 or 4/4 is treated with high confidence that the band belongs to that gene. Table B3. The results of the trapping data that show that the bands found to be dysregulated in Mouse Dietary-Induced Obesity study in comparison between epididymal fat pads of normoglycemic obese animals and the epididymal fat pads of control non-obese animals study are from the mouse Copper-containing Amine Oxidase 3. Length of Predicted Trap fragment in Fragment TraP Nucleotide nucleotides Fold Difference Score Data Sequence 199.8 -1.6 4/4 AGCT AG(AC)T 332.1 -1.9 4/4 TATC TA(TA)C 158.5 -2.2 4/4 TCAA TCA(AC) 424.3 -3.7 4/4 TTAA TTAA 314.9 -2.8 4/4 GAGG GAG(GT) 272.6 -2.5 4/4 TTGG T(AT)G(GT) 100.2 -2.6 4/4 GCGG GCGG 179.3 -2.1 4/4 TTAA TTAA 221.2 -2.4 4/4 GAAA GAAA 134.2 -2.2 4/4 TTCA TTC(AG) 109 WO 2004/056961 PCT/US2003/034114 Ten gene fragments of the mouse Copper-containing Amine Oxidase 3 gene were also found to be downregulated by approximately 1.8 fold in the retroperitoneal fat pads of hyperglycemic obese animals when compared to the retroperitoneal fat pads the normoglycemic non-obese animals using CuraGen's GeneCalling* method of differential gene expression. These ten differentially expressed mouse gene fragments, migrating at approximately 332.1, 181.4, 152.5, 424.4, 314.9, 272.5, 100.2, 179.4, 221.3 and 145.0 nucleotides in lenght, were definitively identified as components of the mouse Copper-containing Amine Oxidase 3. The method of TraPpingTM was used for confirmation of the gene assessment. A table depicting the fragment lengths, dysregulation, TraPpingTM score and actual sequence data is displayed below. The numerator in the score represents the number of nucleotides matched in the gene fragment. The actual nucleotide sequence is displayed in the column labeled "Fragment TraP Data" (see Table 4B). The denominator in the score represents the total number of TraP nucleotides available for this fragment with the actual nucleotide sequence presented in the column labeled "Predicted Trap Nucleotide Sequence". A score of 3/3 or 4/4 is treated with high confidence that the band belongs to that gene. Table B4. The results of the trapping data that show that the bands found to be dysregulated in Mouse Dietary-Induced Obesity study in comparison between the retroperitoneal fat pads of hyperglycemic obese animals and retroperitoneal fat pads of control normoglycemic non-obese animals are from the mouse Copper containing Amine Oxidase 3. Length of Predicted Trap fragment in Fragment TraP Nucleotide nucleotides Fold Difference Score Data Sequence 332.1 -1.8 4/4 TATC TATC 181.4 -1.5 4/4 TATC TATC 152.5 -2.1 4/4 TCAA TCAA 424.4 -1.6 4/4 TTAA TTAA 314.9 -1.6 4/4 GAGG GAGG 272.5 -1.8 4/4 TTGG T(AT)GG 100.2 -1.6 4/4 GCGG GCGG 179.4 -1.6 4/4 TTAA TTAA 221.3 -1.6 4/4 GAAA GAAA 145 -2.8 3/3 GCGT GC-T Three gene fragments of the mouse Copper-containing Amine Oxidase 3 gene were also found to be downregulated by approximately 1.8 fold in the retroperitoneal fat pads of normoglycemic obese animals when compared to the normoglycemic non-obese animals using CuraGen's GeneCalling* method of differential gene expression. These three differentially expressed mouse gene fragments, migrating at approximately 332.1, 158.5 and 100.2 nucleotides in lenght, were definitively identified as components of the mouse Copper-containing Amine Oxidase 3. The method of TraPpingTM was used for confirmation of the gene assessment. A table depicting the fragment lengths, dysregulation, TraPpingTM score and actual sequence data is displayed below. The numerator in the score represents the number of nucleotides matched in the gene fragment. The actual nucleotide sequence is displayed in the column labeled "Fragment TraP Data" (see Table B5). The denominator in the score represents the total number of TraP nucleotides available for this 110 WO 2004/056961 PCT/US2003/034114 fragment with the actual nucleotide sequence presented in the column labeled "Predicted Trap Nucleotide Sequence". A score of 3/3 or 4/4 is treated with high confidence that the band belongs to that gene. Table B5. The results of the trapping data that show that the bands found to be dysregulated in Mouse Dietary-induced Obesity study in comparison between the retroperitoneal fat pads of normoglycemic obese animals and retroperitoneal fat pads of control normoglycemic non-obese animals are from the mouse Copper containing Amine Oxidase 3. Length of Predicted Trap fragment in Fragment TraP Nucleotide nucleotides Fold Difference Score Data Sequence 332.1 -1.9 4/4 TATC TA(TA)C 158.5 -1.6 4/4 TCAA TCA(AC) 100.2 -1.8 4/4 GCGG GCGG Example B3. Identification of Human Copper-containing Amine Oxidase 3 sequence The sequence of Human Copper-containing Amine Oxidase 3 was 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, were 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 protocol for identification of human sequence(s) is disclosed in Example Q8. Table B6 shows an alignment of the protein sequences of the human (CG190178-01), rat, and mouse homologs of the Copper-containing Amine Oxidase 3. Table B7 shows sequences of human (CG190178-01), rat, and mouse homologs of the Copper-containing Amine Oxidase 3. Table B6. Protein Alignment (ClustalW) of the protein sequences of the human (CG190178-01; SEQ ID NO:24), rat (SEQ ID NO:104) and mouse (SEQ ID NO:105) versions of the Copper-containing Amine Oxidase 3. I l WO 2004/056961 PCT/US2003/034114 AOC3_rat 1 T T L I A L DL P 60 AOC3_mouse 1 IvlTQEHP S RN ~I S 60 C0190178-01 I M NTIVIILVI V VL RED EPQLPH E SPASW HPQ LF 60 AOC3_mouse 61 120 C0190178-01 61 A r EE L T F QR120 AOC3_rat 121 R A LPPL 180 AOC3_mouse 121 m E.1 C0190178-01 121 A REA L IF FR S E L 180 AOC3 mt 181 E F 240 AOC3_mouse 181 E IHEPAOLHCFYH~NLM TPGOGRTFLYLSA T 4 CG190178-01 181 Qi240 AOC3_rat 241HP LELL DKALPAL T KFY RY E LijlD FE L NVLVUNT GW30 AOC3 mouse 241 F30 CG190178-01 241 HHVr AOC3 _mt 301 L XX - . - . - ----------- 322 AOC3_mouse 301 360 C0190178-01 301 P360 AOC3 rat * * - - - - - - - - - - - - --- -. .. . - ---.- - - - - - - , . .-- - . . . . . . - -- - -- . - . * AOC3 mouse 361 420 C019017801 361 W LEL AA T 420 AOC3 Mt * * - -- --- -- - - -- -- - - - - - - ----- -- - - -,-- ----. . . .- - . - ~. . .. . . . . .. -* * AOC3_mouse 421 P i M 480 CG9193178-01 421 I D FLCL R 5 LAETL R TLY VMT F 480 AOC3 mt -** - .. **+ AOC3_mouse 481 N A K F EF A 540 CG190178-01 481 S A lIRW L GIY SE 540 AC1070 341 A-- -- ----------------------------------------- ---- - P- 60 AOC3 at ***-- ------- AOC3~mouse 601 T KI E E I K L. J60 C0190178-01 601 E A S ' E SMA R60 AOC3_mot 661 ...- 720 CG190178-01 661 R R . F ' 20 AOC3 mt * -- - --. * AOC3^mouse 721 ES YFF EG DT AS I A: 5iAF YRDN 765 CG190178-01 721 ) DDG PAEAD 763 Table B7. Sequences of rat (SEQ ID NO:104), and mouse (SEQ ID NO:105) homologs of the Copper containing Amine Oxidase 3. AOC3_rat MTQKTTLVLLALAVITIFALVCVLLAGRSGDGGRLSQPLHCPSVLPSVQPQTHSGQSQPFADLSPEELTA VMSFLIKHLG PGLVDAAQARPSDNCVFSVELQLPAKAAALAHLDRGGPPPVREALAIIFFGGQPKPNVSE LVVGPLPHPSYMRDVTVERHGGPLPYYRRPVLTREYQDIQEMIFHRELPQASGLLHHCCFYKRQGHNLLK MTTAPRGLQSGDRATWFGIYYNLSGAGFYPHPIGLELLVDHKALDPALWTIQKVFYQGRYYESLTQLEDM FEAGLVNVVLVPDNGTGGSWSLKSSVPPG RAPPLXXXPXGPX AOC3 mouse MTQKTTLVLLALAVITIFALVCVLLAGRSGDGGGLSQPLHCPSVLPSVQPRTHPSQSQPFADLSPEELTA VMSFLTKHLG PGLVDAAQARPSDNCVFSVELOLPAKAAALAHLDRGGPPPVREALAI I FFGGQPKPNVSE LVVGPLPHPSYMRDVTVERHGGPLPYYRRPVLDREYQDIEEMIFHRELPQASGLLHHCCFYKHQGQNLLT MTTAPRG LQSG DRATWFG LYYNLSGAG FYPHPIGLELLI DHKALDPALWTIQKVFYQG RYYESLTQLEDQ FEAGLVNVVLVPNNGTGGSWSLKSSVPPGPAPPLQFHPQGPRFSVQGSQVSSSLWAFSFGLGAFSGPRIF DIRFQGERVAYEISVQEAIALYGGNSPASMSTCYVDGSFGIGKYSTPLIRGVDCPYLATYVDWHFLLESQ APKTLRDAFCVFEQNQGLPLRRHHSDFYSHYFGGVVGTVLVVRSVSTLLNYDYIWDMVFHPNGAIEVKFH ATGYISSAFFFGAGEKFGNRVGAHTLGTVHTHSAHFKVDLDVAGLKNWAWAEDMAFVPTIVPWQPEYQMQ RLQVTRKLLETEEEAAFPLGGATPRYLYLASNHSNKWGHRRGYRIQILSFAGKPLPQESPIEKAFTWGRY HLAVTQRKEEEPSSSSIFNQNDPWTPTVDFTDFISNETIAGEDLVAWVTAGFLHIPHAEDIPNTVTAGNS VGFFLRPYNFFDEDPSFHSADSYFREGQDATACEVNPLACLSQTATCAPEIPAFSHGGFAYRDN 112 WO 2004/056961 PCT/US2003/034114 The laboratory cloning was performed using one or more of the methods summarized in Example Q8. The NOV2 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table B8. Table B8. NOV2 Sequence Analysis NOV2a, CG190178-02 SEQ ID NO: 21 2311 bp IDNA Sequence ORF Start: ATG at 14 ORF Stop: at 303 CACCGGATCCACCATGAACCAGAAGACAATCCTCGTGCTCCTCATTCTGGCCGTCATCACCATCTTTG CCTTGGTTTGTGTCCTGCTGGTGGGCAGGGGTGGAGATGGGGGTGAACCCAGCCAGCTTCCCCATTGC CCCTCTGTATCTCCCAGTGCCCAGCCTTGGACACACCCTGGCCAGAGCCAGCTGTTTGCAGACCTGAG CCGAGAGGAGCTGACGGCTGTGATGCGCTTTCTGACCCAGCGGCTGGGGCCAGGGCTGGTGGATGCAG CCCAGGCCCGGCCCTCGGACAACTGTGTCTTCTCAGTGGAGTTGCAGCTGCCTCCCAAGGCTGCAGCC CTGGCTCACTTGGACAGGGGGAGCCCCCCACCTGCCCGGGAGGCACTGGCCATCGTCTTCTTTGGCAG GCAACCCCAGCCCAACGTGAGTGAGCTGGTGGTGGGGCCACTGCCTCACCCCTCCTACATGCGGGACG TGACTGTGGAGCGTCATGGAGGCCCCCTGCCCTATCACCGACGCCCCGTGCTGTTCCAAGAGTACCTG GACATAGACCAGATGATCTTCAACAGAGAGCTGCCCCAGGCTTCTGGGCTTCTCCACCACTGTTGCTT CTACAAGCACCGGGGACGGAACCTGGTGACAATGACCACGGCTCCCCGTGGTCTGCAATCAGGGGACC GGGCCACCTGGTTTGGCCTCTACTACAACATCTCGGGCGCTGGGTTCTTCCTGCACCACGTGGGCTTG GAGCTGCTAGTGAACCACAAGGCCCTTGACCCTGCCCGCTGGACTATCCAGAAGGTGTTCTATCAAGG CCGCTACTACGACAGCCTGGCCCAGCTGGAGGCCCAGTTTGAGGCCGGCCTGGTGAATGTGGTGCTGA TCCCAGACAATGGCACAGGTGGGTCCTGGTCCCTGAAGTCCCCTGTGCCCCCGGGTCCAGCTCCCCCT CTACAGTTCTATCCCCAAGGCCCCCGCTTCAGTGTCCAGGGAAGTCGAGTGGCCTCCTCACTGTGGAC TTTCTCCTTTGGCCTCGGAGCATTCAGTGGCCCAAGGATCTTTGACGTTCGCTTCCAAGGAGAAAGAC TAGTTTATGAGATAAGCCTCCAAGAGGCCTTGGCCATCTATGGTGGAAATTCCCCAGCAGCAATGACG ACCCGCTATGTGGATGGAGGCTTTGGCATGGGCAAGTACACCACGCCCCTGACCCGTGGGGTGGACTG CCCCTACTTGGCCACCTACGTGGACTGGCACTTCCTTTTGGAGTCCCAGGCCCCCAAGACAATACGTG ATGCCTTTTGTGTGTTTGAACAGAACCAGGGCCTCCCCCTGCGGCGACACCACTCAGATCTCTACTCG CACTACTTTGGGGGTCTTGCGGAAACGGTGCTGGTCGTCAGATCTATGTCCACCTTGCTCAACTATGA CTATGTGTGGGATACGGTCTTCCACCCCAGTGGGGCCATAGAAATACGATTCTATGCCACGGGCTACA TCAGCTCGGCATTCCTCTTTGGTGCTACTGGGAAGTACGGGAACCAAGTGTCAGAGCACACCCTGGGC ACGGTCCACACCCACAGCGCCCACTTCAAGGTGGATCTGGATGTAGCAGGACTGGAGAACTGGGTCTG GGCCGAGGATATGGTCTTTGTCCCCATGGCTGTGCCCTGGAGCCCTGAGCACCAGCTGCAGAGGCTGC AGGTGACCCGGAAGCTGCTGGAGATGGAGGAGCAGGCCGCCTTCCTCGTGGGAAGCGCCACCCCTCGC TACCTGTACCTGGCCAGCAACCACAGCAACAAGTGGGGTCACCCCCGGGGCTACCGCATCCAGATGCT CAGCTTTGCTGGAGAGCCGCTGCCCCAAAACAGCTCCATGGCGAGAGGCTTCAGCTGGGAGAGGTACC AGCTGGCTGTGACCCAGCGGAAGGAGGAGGAGCCCAGTAGCAGCAGCGTTTTCAATCAGAATGACCCT TGGGCCCCCACTGTGGATTTCAGTGACTTCATCAACAATGAGACCATTGCTGGAAAGGATTTGGTGGC CTGGGTGACAGCTGGTTTTCTGCATATCCCACATGCAGAGGACATTCCTAACACAGTGACTGTGGGGA ACGGCGTGGGCTTCTTCCTCCGACCCTATAACTTCTTTGACGAAGACCCCTCCTTCTACTCTGCCGAC TCCATCTACTTCCGAGGGGACCAGGATGCTGGGGCCTGCGAGGTCAACCCCCTAGCTTGCCTGCCCCA GGCTGCTGCCTGTGCCCCCGACCTCCCTGCCTTCTCCCACGGGGGCTTCTCTCACAACGTCGACGGC NOV2a, CG190178-02 SEQ ID NO: 22 763 aa MW at 84621.1kD Protein Sequence MNQKTILVLLILAVITIFALVCVLLVG RG GDGGEPSQLPHCPSVSPSAQPWTHPGQSQLFADLSREEL TAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPPPAREALAIVFFGRQPQP NVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDIDQMIFNRELPQASGLLHHCCFYKHR GRNLVTMTTAPRGLQSGDRATWFGLYYNISGAGFFLHHVGLELLVNHKALDPARWTIQKVFYQGRYYD SLAQLEAQFEAGLVNVVLI PDNGTGG SWSLKSPVPPG PAPPLQ FYPQGPRFSVQGSRVASSLWTFSFG LGAFSGPRIFDVRFQGERLVYEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLA TYVDWHFLLESQAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWD TVFHPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVHTHSAHFKVDLDVAGLENWVWAEDM VFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGHPRGYRIQMLSFAG EPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVDFSDFINNETIAGKDLVAWVTA GFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYSADSIYFRGDQDAGACEVNPLACLPQAAAC APDLPAFSHGGFSHN NOV2b. CG190178-01 SEQ ID NO: 23 4026bp 113 WO 2004/056961 PCT/US2003/034114 DNA Sequence ORE Start: ATG at 1ORF Stop: TAG at 2450 GTCCTTCCCACCCTTAGTCCCAGGCATCTGACTACCGGGAACCTCAnnOAAGITinGGNAGCnnCCCA CCCCGTCCAGGAGCCAACAGAGCCCCCGTCTTGCTGGCGTGAGAATACATTGCTCTCCTTT A GTTGAA TCAGCTGTCCCTCTTCGTGGGAAAATGAACCAGAAGACAATCCTCGTGCTCCTCATTCTGGCCGTCAT CACCATCTTTGCCTTGGTTTGTGTCCTGCTGGTGGGCAGGGGTGGAGATGGGGGTGAACCCAGCCAGC TTCCCCATTGCCCCTCTGTATCTCCCAGTGCCCAGCCTTGGACACACCCTGGCCAGAGCCAGCTGTTTr GCAGACCTGAGCCGAGAGGAGCTGACGGCTGTGATGCGCTTTCTGACCCAGCGGCTGGGGCCAGGGCT GGTGGATGCAGCCCAGGCCCGGCCCTCGGACAACTGTGTCTTCTCAGTGGAGTTGCAGCTGCCTCCCA AGGCTGCAGCCCTGGCTCACTTGGACAGGGGGAGCCCCCCACCTGCCCGGGAGGCACTGGCCATCGTC TTCTTTGGCAGGCAACCCCAGCCCAACGTGAGTGAGCTGGTGGTGGGGCCACTGCCTCACCCCTCCTA CATGCGGGACGTGACTGTGGAGCGTCATGGAGGCCCCCTGCCCTATCACCGACGCCCCGTGCTGTTCC AAGAGTACCTGGACATAGACCAGATGATCTTCAACAGAGAGCTGCCCCAGGCTTCTGGGCTTCTCCAC CACTGTTGCTTCTACAAGCACCGGGGACGGAACCTGGTGACAATGACCACGGCTCCCCGTGGTCTGCA ATCAGGGGACCGGGCCACCTGGTTTGGCCTCTACTACAACATCTCGGGCGCTGGGTTCTTCCTGCACC ACGTGGGCTTGGAGCTGCTAGTGAACCACAAGGCCCTTGACCCTGCCCGCTGGACTATCCAGAAGGTG TTCTATCAAGGCCGCTACTACGACAGCCTGGCCCAGCTGGAGGCCCAGTTTGAGGCCGGCCTGGTGAA TGTGGTGCTGATCCCAGACAATGGCACAGGTGGGTCCTGGTCCCTGAAGTCCCCTGTGCCCCCGGGTC CAGCTCCCCCTCTACAGTTCTATCCCCAAGGCCCCCGCTTCAGTGTCCAGGGAAGTCGAGTGGCCTCC TCACTGTGGACTTTCTCCTTTGGCCTCGGAGCATTCAGTGGCCCAAGGATCTTTGACGTTCGCTTCCA AGGAGAAAGACTAGTTTATGAGATAAGCCTCCAAGAGGCCTTGGCCATCTATGGTGGAAATTCCCCAG CAGCAATGACGACCCGCTATGTGGATGGAGGCTTTGGCATGGGCAAGTACACCACGCCCCTGACCCGT GGGGTGGACTGCCCCTACTTGGCCACCTACGTGGACTGGCACTTCC1-1-G GAGTCCCAGGCCCCCAA GACAATACGTGATGCC1TTTGTGTGTTrGAACAGAACCAGGGCCTCCCCCTGCGGCGACACCACTCAG ATCTCTACTCGCACTACTTTGGGGGTCTTGCGGAAACGGTGCTGGTCGTCAGATCTATGTCCACCTTG CTCAACTATGACTATGTGTGGGATACGGTCTTCCACCCCAGTGGGGCCATAGAAATACGATTCTATGC CACGGGCTACATCAGCTCGGCATTCCTCTTTGGTGCTACTGGGAAGTACGGGAACCAAGTGTCAGAGC ACACCCTGGGCACGGTCCACACCCACAGCGCCCACTTCAAGGTGGATCTGGATGTAGCAGGACTGGAG AACTGGGTCTGGGCCGAGGATATGGTCTTTGTCCCCATGGCTGTGCCCTGGAGCCCTGAGCACCAGCT GCAGAGGCTGCAGGTGACCCGGAAGCTGCTGGAGATGGAGGAGCAGGCCGCCTTCCTCGTGGGAAGCG CCACCCCTCGCTACCTGTACCTGGCCAGCAACCACAGCAACAAGTGGGGTCACCCCCGGGGCTACCGC ATCCAGATGCTCAGCTTTGCTGGAGAGCCGCTGCCCCAAAACAGCTCCATGGCGAGAGGCTTCAGCTG GGAGAGGTACCAGCTGGCTGTGACCCAGCGGAAGGAGGAGGAGCCCAGTAGCAGCAGCG-II1-CAATC AGAATGACCCTTGGGCCCCCACTGTGGATTTCAGTGACTTCATCAACAATGAGACCATTGCTGGAAAG GATTTGGTGGCCTGGGTGACAGCTGGTTTTCTGCATATCCCACATGCAGAGGACATTCCTAACACAGT GACTGTGGGGAACGGCGTGGGCTTCTTCCTCCGACCCTATAACTTCTTTGACGAAGACCCCTCCTTCT ACTCTGCCGACTCCATCTACTTCCGAGGGGACCAGGATGCTGGGGCCTGCGAGGTCAACCCCCTAGCT TGCCTGCCCCAGGCTGCTGCCTGTGCCCCCGACCTCCCTGCCTTCTCCCACGGGGGCTTCTCTCACAA CTAGGCGGTCCTGGGATGGGGCATGTGGCCAAGGGCTCCAGGGCCAGGGTGTGAGGGATGGGGAGCAG CTGGGCACTGGGCCGGCAGCCTGGTTCCCTCTTTCCTGTGCCAGGACTCTCTTTCTTCCACTACCCTC CCTCGCATCCGCCTCTGAGCCAGGAGCCTCCTGACCCTGTGATGCCTGACACAGGGGACACTGAACCT TGTTGATGCCAGCTGTACTGAGTTCTCATCCACAGAGGCCAGGCATGGCCCAGCCTGGAGCCGTGGCC GAGGGCTTCCCTAGATGGTTCCCTTTGTTGCTGTCTGGCTTTCCCGAATCT1 1AGGCCACCTCCAA GGACTCTAAAAGGGGGCTATTCCCTGGAGACCCCAGAGTAGGGTTGCCAGTCCTGCAAGTCCATAGCT GAGCTGGAAAGGATGCTTCTGCTCACATTCCCTCTCATCCAGGTCCTTrCCTTCTCGTCTTCCTCTCT CTCACCTACTTCCTCCTCCTCCTCCTGTTCCTGCCTTCTCTTCTATCCTGCAATTTCTCCCGAATCCT GAGGGGATATCCCTATGTCCCAGCCCCTGGTACTCCCCCAGCCCTCAGTIyrCAGTCAAGTTCCGTCT CCTCTCCAGCCCTATGGAAGTCTCAAGGTCACGGGACCCCTAATCAGAGTGGCCAATCCCTGTGTGTC GTTCCCTTGTGTCTGTTGCTTATTGGGAGTAGGAGTTGCTCCTACCCCTGTCCTGGGGCTGGGTGTGT TTCAGGACAGCTGCTTCTGTGCATTTGTGTCTGCCTGCCTCATGCTCTCTATAGAGGAGGATGGTCAT CGTGACAGCAGCAGCTCAAGTTAGCATTTCAAGTGATTTGGGGGTGCAATGATAATGAAGAATGGCCA TTTTGTACCAGGGCTCTGTATTCTGCAACAGCCTGTTTGGGAGGCTGGAGTGGAAACAAAGGGTGGGC ATCAAAGATGAGAAGCCAAAGCCCCTACAACTCCAGCCACCCAGCCAGGAGGGGCTGTCCAATCACAT TCAGGCATGCGAATGAGCTGGGCCCTGGGTGAGGTGGGGGTCTGGCCTAGTGGGGAGGGGCCTGGCCT GGGTGGGGCAGGGCCTGGCCTGGTCCAGGCTTGGGCTCCATTCCCATCACTGCTGTCCCTCCTGAGGT CTGGATTGGGGATGGGGACAAAGAAATAGCAAGAGATGAGAAACAACAGAAACI1T111CTCTAAAGG ACTGGTTAAATCAATTCTGATACAGCCTTACAATACAATAGTATGCAGCTAAAAAATAATTGTATGTC TTTATATACTAATATGTAATAATCTTCAGGTGAAAAAGGCAAGCCACAGAAATGTGTATAGCGCACTT CCCATTTGTGTTTCAGAAAGGAGTAGAATATAAACACATAATTGCTTATGTATGCCTATTCAGAATAA ATGGGTAACACTGATTACI1TTGGGAGGGGAACCAGTAGGTTGAGGACAGGAGAGGGAAGGGTCTTAA 114 WO 2004/056961 PCT/US2003/034114 CACTTACACCCTTTTGTACATTTTGAATTTTGAACCATGTGACTGTATTACCTATTCAAAATAAACAA TAAATGGGCCCAAA NOV2b, CG190178-01 SEQ ID NO: 24 763 aa MW at 84621.1kD Protein Sequence MNQKTILVLLILAVITIFALVCVLLVG RGGDGG EPSQLPHCPSVSPSAQPWTHPGQSQLFADLSREEL TAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPPPAREALAIVFFGRQPQP NVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDIDQMIFNRELPQASGLLHHCCFYKHR GRNLVTMTTAPRGLQSGDRATWFGLYYNISGAGFFLHHVGLELLVNHKALDPARWTIQKVFYQGRYYD SLAQLEAQFEAGLVNVVLI PDNGTGGSWSLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSFG LGAFSGPRIFDVRFQGERLVYEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLA TYVDWHFLLESQAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWD TVFHPSGAIEIRFYATGYISSAFLFGATGKYGNOVSEHTLGTVHTHSAHFKVDLDVAGLENWVWAEDM VFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGHPRGYRIQMLSFAG EPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVDFSDFINNETIAGKDLVAWVTA GFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYSADSYFRGDQDAGACEVNPLACLPQAAAC APDLPAFSHGGFSHN NOV2c, CG190178-03 -SEQ ID NO: 25 2312 bp DNA Sequence ORF Start: ATG at 4 ORF Stop at 2293 ACCATGAACCAGAAGACAATCCTCGTGCTCCTCATTCTGGCCGTCATCACCATCTTTGCCTTGGTTTG TGTCCTGCTGGTGGGCAGGGGTGGAGATGGGGGTGAACCCAGCCAGCTTCCCCATTGCCCCTCTGTAT CTCCCAGTGCCCAGCCTTGGACACACCCTGGCCAGAGCCAGCTGTTTGCAGACCTGAGCCGAGAGGAG CTGACGGCTGTGATGCGCTTTCTGACCCAGCGGCTGGGGCCAGGGCTGGTGGATGCAGCCCAGGCCCG GCCCTCGGACAACTGTGTCTTCTCAGTGGAGTTGCAGCTGCCTCCCAAGGCTGCAGCCCTGGCTCACT TGGACAGGGGGAGCCCCCCACCTGCCCGGGAGGCACTGGCCATCGTCTTCTTTGGCAGGCAACCCCAG CCCAACGTGAGTGAGCTGGTGGTGGGGCCACTGCCTCACCCCTCCTACATGCGGGACGTGACTGTGGA GCGTCATGGAGGCCCCCTGCCCTATCACCGACGCCCCGTGCTGTTCCAAGAGTACCTGGACATAGACC AGATGATCTTCAACAGAGAGCTGCCCCAGGCTTCTGGGCTTCTCCACCACTGTTGCTTCTACAAGCAC CGGGGACGGAACCTGGTGACAATGACCACGGCTCCCCGTGGTCTGCAATCAGGGGACCGGGCCACCTG GTTTGGCCTCTACTACAACATCTCGGGCGCTGGGTTCTTCCTGCACCACGTGGGCTTGGAGCTGCTAG TGAACCACAAGGCCCTTGACCCTGCCCGCTGGACTATCCAGAAGGTGTTCTATCAAGGCCGCTACTAC GACAGCCTGGCCCAGCTGGAGGCCCAGTTTGAGGCCGGCCTGGTGAATGTGGTGCTGATCCCAGACAA TGGCACAGGTGGGTCCTGGTCCCTGAAGTCCCCTGTGCCCCCGGGTCCAGCTCCCCCTCTACAGTTCT ATCCCCAAGGCCCCCGCTTCAGTGTCCAGGGAAGTCGAGTGGCCTCCTCACTGTGGACTTTCTCCTTT GGCCTCGGAGCATTCAGTGGCCCAAGGATCTTTGACGTTCGCTTCCAAGGAGAAAGACTAGTTTATGA GATAAGCCTCCAAGAGGCCTTGGCCATCTATGGTGGAAATTCCCCAGCAGCAATGACGACCCGCTATG TGGATGGAGGCTTTGGCATGGGCAAGTACACCACGCCCCTGACCCGTGGGGTGGACTGCCCCTACTTG GCCACCTACGTGGACTGGCACTTCCTTTTGGAGTCCCAGGCCCCCAAGACAATACGTGATGCCTTTTG TGTGTTTGAACAGAACCAGGGCCTCCCCCTGCGGCGACACCACTCAGATCTCTACTCGCACTACTTTG GGGGTCTTGCGGAAACGGTGCTGGTCGTCAGATCTATGTCCACCTTGCTCAACTATGACTATGTGTGG GATACGGTCTTCCACCCCAGTGGGGCCATAGAAATACGATTCTATGCCACGGGCTACATCAGCTCGGC ATTCCTCTTTGGTGCTACTGGGAAGTACGGGAACCAAGTGTCAGAGCACACCCTGGGCACGGTCCACA CCCACAGCGCCCACTTCAAGGTGGATCTGGATGTAGCAGGACTGGAGAACTGGGTCTGGGCCGAGGAT ATGGTCTTTGTCCCCATGGCTGTGCCCTGGAGCCCTGAGCACCAGCTGCAGAGGCTGCAGGTGACCCG GAAGCTGCTGGAGATGGAGGAGCAGGCCGCCTTCCTCGTGGGAAGCGCCACCCCTCGCTACCTGTACC TGGCCAGCAACCACAGCAACAAGTGGGGTCACCCCCGGGGCTACCGCATCCAGATGCTCAGCTTTGCT GGAGAGCCGCTGCCCCAAAACAGCTCCATGGCGAGAGGCTTCAGCTGGGAGAGGTACCAGCTGGCTGT GACCCAGCGGAAGGAGGAGGAGCCCAGTAGCAGCAGCGTTTTCAATCAGAATGACCCTTGGGCCCCCA CTGTGGATTTCAGTGACTTCATCAACAATGAGACCATTGCTGGAAAGGATTTGGTGGCCTGGGTGACA GCTGGTTTTCTGCATATCCCACATGCAGAGGACATTCCTAACACAGTGACTGTGGGGAACGGCGTGGG CTTCTTCCTCCGACCCTATAACTTCTTTGACGAAGACCCCTCCTTCTACTCTGCCGACTCCATCTACT TCCGAGGGGACCAGGATGCTGGGGCCTGCGAGGTCAACCCCCTAGCTTGCCTGCCCCAGGCTGCTGCC TGTGCCCCCGACCTCCCTGCCTTCTCCCACGGGGGCTTCTCTCACAACCATCATCACCACCATCACTA NOV2c, CG 190178-03 lSEQ ID NO: 26 1763 aa Mat84621.lkD Protein Sequence MNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQLFADLSREEL TAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPPPAREALAIVFFGRQPQP NVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDIDQMIFNRELPQASGLLHHCCFYKHR GRNLVTMTTAPRGLQSGDRATWFGLYYNISGAGFFLHHVGLELLVNHKALDPARWTIQKVFYQGRYYD 115 WO 2004/056961 PCT/US2003/034114 SLAQLEAQFEAGLVNVVLI PDNGTGG SWSLKSPVPPG PAPPLQFYPQG PRFSVQGSRVASSLWTFSFG LGAFSGPRIFDVRFQGERLVYEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLA TYVDWHFLLESQAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWD TVFHPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVHTHSAHFKVDLDVAGLENWVWAEDM VFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGHPRGYRIQMLSFAG EPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVDFSDFINNETIAGKDLVAWVTA GFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYSADSYFRGDQDAGACEVNPLACLPQAAAC APDLPAFSHGGFSHN NOV2d, CG190178-04 SEQ ID NO: 27 12318 bp DNA Sequence [ORF Sta-- Siop: at 2293 DNA IO1RF Start: ATG t ACCATGAACCAGAAGACAATCCTCGTGCTCCTCATTCTGGCCGTCATCACCATCTTTGCCTTGGTTTG TGTCCTGCTGGTGGGCAGGGGTGGAGATGGGGGTGAACCCAGCCAGCTTCCCCATTGCCCCTCTGTAT CTCCCAGTGCCCAGCCTTGGACACACCCTGGCCAGAGCCAGCTGTTTGCAGACCTGAGCCGAGAGGAG CTGACGGCTGTGATGCGCTTTCTGACCCAGCGGCTGGGGCCAGGGCTGGTGGATGCAGCCCAGGCCCG GCCCTCGGACAACTGTGTCTTCTCAGTGGAGTTGCAGCTGCCTCCCAAGGCTGCAGCCCTGGCTCACT TGGACAGGGGGAGCCCCCCACCTGCCCGGGAGGCACTGGCCATCGTCTTCTTTGGCAGGCAACCCCAG CCCAACGTGAGTGAGCTGGTGGTGGGGCCACTGCCTCACCCCTCCTACATGCGGGACGTGACTGTGGA GCGTCATGGAGGCCCCCTGCCCTATCACCGACGCCCCGTGCTGTTCCAAGAGTACCTGGACATAGACC AGATGATCTTCAACAGAGAGCTGCCCCAGGCTTCTGGGCTTCTCCACCACTGTTGCTTCTACAAGCAC CGGGGACGGAACCTGGTGACAATGACCACGGCTCCCCGTGGTCTGCAATCAGGGGACCGGGCCACCTG GTTTGGCCTCTACTACAACATCTCGGGCGCTGGGTTCTTCCTGCACCACGTGGGCTTGGAGCTGCTAG TGAACCACAAGGCCCTTGACCCTGCCCGCTGGACTATCCAGAAGGTGTTCTATCAAGGCCGCTACTAC GACAGCCTGGCCCAGCTGGAGGCCCAGTTTGAGGCCGGCCTGGTGAATGTGGTGCTGATCCCAGACAA TGGCACAGGTGGGTCCTGGTCCCTGAAGTCCCCTGTGCCCCCGGGTCCAGCTCCCCCTCTACAGTTCT ATCCCCAAGGCCCCCGCTTCAGTGTCCAGGGAAGTCGAGTGGCCTCCTCACTGTGGACTTTCTCCTTT GGCCTCGGAGCATTCAGTGGCCCAAGGATCTTTGACGTTCGCTTCCAAGGAGAAAGACTAGTT-TATGA GATAAGCCTCCAAGAGGCCTTGGCCATCTATGGTGGAAATTCCCCAGCAGCAATGACGACCCGCTATG TGGATGGAGGCTTTGGCATGGGCAAGTACACCACGCCCCTGACCCGTGGGGTGGACTGCCCCTACTTG GCCACCTACGTGGACTGGCACTTCCTTTTGGAGTCCCAGGCCCCCAAGACAATACGTGATGCCTTTTG TGTGTTTGAACAGAACCAGGGCCTCCCCCTGCGGCGACACCACTCAGATCTCTACTCGCACTACTTTG GGGGTCTTGCGGAAACGGTGCTGGTCGTCAGATCTATGTCCACCTTGCTCAACTATGACTATGTGTGG GATACGGTCTTCCACCCCAGTGGGGCCATAGAAATACGATTCTATGCCACGGGCTACATCAGCTCGGC ATTCCTCTTrGGTGCTACTGGGAAGTACGGGAACCAAGTGTCAGAGCACACCCTGGGCACGGTCCACA CCCACAGCGCCCACTTCAAGGTGGATCTGGATGTAGCAGGACTGGAGAACTGGGTCTGGGCCGAGGAT ATGGTCTTTGTCCCCATGGCTGTGCCCTGGAGCCCTGAGCACCAGCTGCAGAGGCTGCAGGTGACCCG GAAGCTGCTGGAGATGGAGGAGCAGGCCGCCTTCCTCGTGGGAAGCGCCACCCCTCGCTACCTGTACC TGGCCAGCAACCACAGCAACAAGTGGGGTCACCCCCGGGGCTACCGCATCCAGATGCTCAGCTTTGCT GGAGAGCCGCTGCCCCAAAACAGCTCCATGGCGAGAGGCTTCAGCTGGGAGAGGTACCAGCTGGCTGT GACCCAGCGGAAGGAGGAGGAGCCCAGTAGCAGCAGCGTTTTCAATCAGAATGACCCTTGGGCCCCCA CTGTGGATTTCAGTGACTTCATCAACAATGAGACCATTGCTGGAAAGGATTTGGTGGCCTGGGTGACA GCTGGTTTTCTGCATATCCCACATGCAGAGGACATTCCTAACACAGTGACTGTGGGGAACGGCGTGGG CTTCTTCCTCCGACCCTATAACTTCTTTGACGAAGACCCCTCCTTCTACTCTGCCGACTCCATCTACT TCCGAGGGGACCAGGATGCTGGGGCCTGCGAGGTCAACCCCCTAGCTTGCCTGCCCCAGGCTGCTGCC TGTGCCCCCGACCTCCCTGCCTTCTCCCACGGGGGCTTCTCTCACAACTGGAGTCATCCTCAGTTCGA AAAGTA NOV2d, CG190178-04 SEQ ID NO: 28 763 aa MW at 84621 1kD Protein Sequence MNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQLFADLSREEL TAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPPPAREALAIVFFGRQPQP NVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDIDQMIFNRELPQASGLLHHCCFYKHR GRNLVTMTTAPRGLQSGDRATWFGLYYNISGAGFFLHHVGLELLVNHKALDPARWTIQKVFYQGRYYD SLAQLEAQFEAGLVNVVLI PDNGTGGSWSLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSFG LGAFSGPRIFDVRFQGERLVYEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLA TYVDWHFLLESQAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWD TVFHPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVHTHSAHFKVDLDVAGLENWVWAEDM VFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGHPRGYRIQMLSFAG EPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVDFSDFINNETIAGKDLVAWVTA GFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYSADSYFRGDQDAGACEVNPLACLPQAAAC 116 WO 2004/056961 PCT/US2003/034114 APDLPAFSHGGFSHN [NOV2e, 318008675 ISEQ ID NO: 29 2294 bp DNA Sequence ORF Start: at 1 ORF Stop: at 2293 ACCATGAACCAGAAGACAATCCTCGTGCTCCTCATTCTGGCCGTCATCACCATCTTTGCCTTGGTTTG TGTCCTGCTGGTGGGCAGGGGTGGAGATGGGGGTGAACCCAGCCAGCTTCCCCATTGCCCCTCTGTAT CTCCCAGTGCCCAGCCTTGGACACACCCTGGCCAGAGCCAGCTGTTTGCAGACCTGAGCCGAGAGGAG CTGACGGCTGTGATGCGCTTTCTGACCCAGCGGCTGGGGCCAGGGCTGGTGGATGCAGCCCAGGCCCG GCCCTCGGACAACTGTGTCTTCTCAGTGGAGTTGCAGCTGCCTCCCAAGGCTGCAGCCCTGGCTCACT TGGACAGGGGGAGCCCCCCACCTGCCCGGGAGGCACTGGCCATCGTCTTCTTTGGCAGGCAACCCCAG CCCAACGTGAGTGAGCTGGTGGTGGGGCCACTGCCTCACCCCTCCTACATGCGGGACGTGACTGTGGA GCGTCATGGAGGCCCCCTGCCCTATCACCGACGCCCCGTGCTGTTCCAAGAGTACCTGGACATAGACC AGATGATCTTCAACAGAGAGCTGCCCCAGGCTTCTGGGCTTCTCCACCACTGTTGCTTCTACAAGCAC CGGGGACGGAACCTGGTGACAATGACCACGGCTCCCCGTGGTCTGCAATCAGGGGACCGGGCCACCTG GTTTGGCCTCTACTACAACATCTCGGGCGCTGGGTTCTTCCTGCACCACGTGGGCTTGGAGCTGCTAG TGAACCACAAGGCCCTTGACCCTGCCCGCTGGACTATCCAGAAGGTGTTCTATCAAGGCCGCTACTAC GACAGCCTGGCCCAGCTGGAGGCCCAGTTTGAGGCCGGCCTGGTGAATGTGGTGCTGATCCCAGACAA TGGCACAGGTGGGTCCTGGTCCCTGAAGTCCCCTGTGCCCCCGGGTCCAGCTCCCCCTCTACAGTTCT ATCCCCAAGGCCCCCGCTTCAGTGTCCAGGGAAGTCGAGTGGCCTCCTCACTGTGGACTTTCTCCTTT GGCCTCGGAGCATTCAGTGGCCCAAGGATCTTTGACGTTCGCTTCCAAGGAGAAAGACTAGTTTATGA GATAAGCCTCCAAGAGGCCTTGGCCATCTATGGTGGAAATTCCCCAGCAGCAATGACGACCCGCTATG TGGATGGAGGCTTTGGCATGGGCAAGTACACCACGCCCCTGACCCGTGGGGTGGACTGCCCCTACTTG GCCACCTACGTGGACTGGCACTTCCTTTTGGAGTCCCAGGCCCCCAAGACAATACGTGATGCCTTTTG TGTGTTTGAACAGAACCAGGGCCTCCCCCTGCGGCGACACCACTCAGATCTCTACTCGCACTACTTTG GGGGTCTTGCGGAAACGGTGCTGGTCGTCAGATCTATGTCCACCTTGCTCAACTATGACTATGTGTGG GATACGGTCTTCCACCCCAGTGGGGCCATAGAAATACGATTCTATGCCACGGGCTACATCAGCTCGGC ATTCCTCTTTGGTGCTACTGGGAAGTACGGGAACCAAGTGTCAGAGCACACCCTGGGCACGGTCCACA CCCACAGCGCCCACTTCAAGGTGGATCTGGATGTAGCAGGACTGGAGAACTGGGTCTGGGCCGAGGAT ATGGTCTTTGTCCCCATGGCTGTGCCCTGGAGCCCTGAGCACCAGCTGCAGAGGCTGCAGGTGACCCG GAAGCTGCTGGAGATGGAGGAGCAGGCCGCCTTCCTCGTGGGAAGCGCCACCCCTCGCTACCTGTACC TGGCCAGCAACCACAGCAACAAGTGGGGTCACCCCCGGGGCTACCGCATCCAGATGCTCAGCTTTGCT GGAGAGCCGCTGCCCCAAAACAGCTCCATGGCGAGAGGCTTCAGCTGGGAGAGGTACCAGCTGGCTGT GACCCAGCGGAAGGAGGAGGAGCCCAGTAGCAGCAGCGTTTTCAATCAGAATGACCCTTGGGCCCCCA CTGTGGATTTCAGTGACTTCATCAACAATGAGACCATTGCTGGAAAGGATTTGGTGGCCTGGGTGACA GCTGGTTTTCTGCATATCCCACATGCAGAGGACATTCCTAACACAGTGACTGTGGGGAACGGCGTGGG CTTCTTCCTCCGACCCTATAACTTCTTTGACGAAGACCCCTCCTTCTACTCTGCCGACTCCATCTACT TCCGAGGGGACCAGGATGCTGGGGCCTGCGAGGTCAACCCCCTAGCTTGCCTGCCCCAGGCTGCTGCC TGTGCCCCCGACCTCCCTGCCTTCTCCCACGGGGGCTTCTCTCACAACTA NOV2e, 318008675 SEQ ID NO: 30 764 aa MW at 84722.2kD Protein Sequence, TMNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQLFADLSREE LTAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPPPAREALAIVFFGRQPQ PNVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDIDQMIFNRELPQASGLLHHCCFYKH RGRNLVTMTTAPRGLQSGDRATWFGLYYNISGAGFFLHHVGLELLVNHKALDPARWTIQKVFYQGRYY DSLAQLEAQFEAG LVNVVLIPDNGTGGSWSLKSPVPPG PAPPLQFYPQGPRFSVQGSRVASSLWTFSF GLGAFSGPRIFDVRFQGERLVYEISLOEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYL ATYVDWHFLLESQAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVW DTVFHPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVHTHSAHFKVDLDVAGLENWVWAED MVFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGHPRGYRIQMLSFA GEPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVDFSDFINNETIAGKDLVAWVT AGFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYSADSYFRGDQDAGACEVNPLACLPQAAA CAPDLPAFSHGGFSHN iNOIV, 318351920 ISEQ ID NO: 31 2318 bp DNA Sequence ORF Start: at 1 ORF Stop: at 2317 ACCATGAACCAGAAGACAATCCTCGTGCTCCTCATTCTGGCCGTCATCACCATCTTTGCCTIGGTTiG TGTCCTGCTGGTGGGCAGGGGTGGAGATGGGGGTGAACCCAGCCAGCTTCCCCATTGCCCCTCTGTAT CTCCCAGTGCCCAGCCTTGGACACACCCTGGCCAGAGCCAGCTGTTTGCAGACCTGAGCCGAGAGGAG CTGACGGCTGTGATGCGCTTTCTGACCCAGCGGCTGGGGCCAGGGCTGGTGGATGCAGCCCAGGCCG 117 WO 2004/056961 PCT/US2003/034114 GCCCTCGGACAACTGTGTCTTCTCAGTGGAGTTGCAGCTGCCTCCCAAGGCTGCAGCCCTGGCTCACT TGGACAGGGGGAGCCCCCCACCTGCCCGGGAGGCACTGGCCATCGTCTTCTTTGGCAGGCAACCCCAG CCCAACGTGAGTGAGCTGGTGGTGGGGCCACTGCCTCACCCCTCCTACATGCGGGACGTGACTGTGGA GCGTCATGGAGGCCCCCTGCCCTATCACCGACGCCCCGTGCTGTTCCAAGAGTACCTGGACATAGACC AGATGATCTTCAACAGAGAGCTGCCCCAGGCTTCTGGGCTTCTCCACCACTGTTGCTTCTACAAGCAC CGGGGACGGAACCTGGTGACAATGACCACGGCTCCCCGTGGTCTGCAATCAGGGGACCGGGCCACCTG GTTTGGCCTCTACTACAACATCTCGGGCGCTGGGTTCTTCCTGCACCACGTGGGCTTGGAGCTGCTAG TGAACCACAAGGCCCTTGACCCTGCCCGCTGGACTATCCAGAAGGTGTTCTATCAAGGCCGCTACTAC GACAGCCTGGCCCAGCTGGAGGCCCAGTTTGAGGCCGGCCTGGTGAATGTGGTGCTGATCCCAGACAA TGGCACAGGTGGGTCCTGGTCCCTGAAGTCCCCTGTGCCCCCGGGTCCAGCTCCCCCTCTACAGTTCT ATCCCCAAGGCCCCCGCTTCAGTGTCCAGGGAAGTCGAGTGGCCTCCTCACTGTGGACTTTCTCCTTT GGCCTCGGAGCATTCAGTGGCCCAAGGATCTTTGACGTTCGCTTCCAAGGAGAAAGACTAGTTTATGA GATAAGCCTCCAAGAGGCCTTGGCCATCTATGGTGGAAATTCCCCAGCAGCAATGACGACCCGCTATG TGGATGGAGGCTTrGGCATGGGCAAGTACACCACGCCCCTGACCCGTGGGGTGGACTGCCCCTACTTG GCCACCTACGTGGACTGGCACTTCCTTTTGGAGTCCCAGGCCCCCAAGACAATACGTGATGCCTTTTG TGTGTTTGAACAGAACCAGGGCCTCCCCCTGCGGCGACACCACTCAGATCTCTACTCGCACTACTTTG GGGGTCTTGCGGAAACGGTGCTGGTCGTCAGATCTATGTCCACCTTGCTCAACTATGACTATGTGTGG GATACGGTCTTCCACCCCAGTGGGGCCATAGAAATACGATTCTATGCCACGGGCTACATCAGCTCGGC ATTCCTCTTTGGTGCTACTGGGAAGTACGGGAACCAAGTGTCAGAGCACACCCTGGGCACGGTCCACA CCCACAGCGCCCACTTCAAGGTGGATCTGGATGTAGCAGGACTGGAGAACTGGGTCTGGGCCGAGGAT ATGGTCTTTGTCCCCATGGCTGTGCCCTGGAGCCCTGAGCACCAGCTGCAGAGGCTGCAGGTGACCCG GAAGCTGCTGGAGATGGAGGAGCAGGCCGCCTTCCTCGTGGGAAGCGCCACCCCTCGCTACCTGTACC TGGCCAGCAACCACAGCAACAAGTGGGGTCACCCCCGGGGCTACCGCATCCAGATGCTCAGCTTTGCT GGAGAGCCGCTGCCCCAAAACAGCTCCATGGCGAGAGGCTTCAGCTGGGAGAGGTACCAGCTGGCTGT GACCCAGCGGAAGGAGGAGGAGCCCAGTAGCAGCAGCGTTTTCAATCAGAATGACCCTTGGGCCCCCA CTGTGGATTTCAGTGACTTCATCAACAATGAGACCATTGCTGGAAAGGATTTGGTGGCCTGGGTGACA GCTGGTTTTCTGCATATCCCACATGCAGAGGACATTCCTAACACAGTGACTGTGGGGAACGGCGTGGG CTTCTTCCTCCGACCCTATAACTTCTTTGACGAAGACCCCTCCTTCTACTCTGCCGACTCCATCTACT TCCGAGGGGACCAGGATGCTGGGGCCTGCGAGGTCAACCCCCTAGCTTGCCTGCCCCAGGCTGCTGCC TGTGCCCCCGACCTCCCTGCCTTCTCCCACGGGGGCTTCTCTCACAACTGGAGTCATCCTCAGTTCGA AAAGTA NOV2f, 318351920 SEQ ID NO: 32 772 aa IMW at 85762.3kD Protein Sequence I I TMNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQLFADLSREE LTAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPPPAREALAIVFFGRQPQ PNVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDIDQMIFNRELPQASGLLHHCCFYKH RGRNLVTMTTAPRGLQSGDRATWFGLYYNISGAGFFLHHVGLELLVNHKALDPARWTIQKVFYQGRYY DSLAQLEAQFEAGLVNVVLIPDNGTGGSWSLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSF GLGAFSGPRIFDVRFQGERLVYEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYL ATYVDWHFLLESQAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVW DTVFHPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVHTHSAHFKVDLDVAGLENWVWAED MVFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGHPRGYRIQMLSFA GEPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVDFSDFINNETIAGKDLVAWVT AGFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYSADSIYFRGDQDAGACEVNPLACLPQAAA CAPDLPAFSHGGFSHNWSHPQFEK A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table B9. Table B9. Comparison of the NOV2 protein sequences. NOV2a -MNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQL NOV2b -MNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQL NOV2c -MNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQL NOV2d -MNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQL NOV2e TMNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQL NOV2f TMNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQL 118 WO 2004/056961 PCT/US2003/0341 14 NOV2 a FADLSREELTAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPP NOV2b FADLSREELTAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAliLDRGSPP NOV2 c FADLSREELTAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAH-LDRGSPP NOV2 d FADLSREELTAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPP NOV2 e FADLSREELTAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPP NOV2 f FADLSREELTAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAH-LDRGSPP NOV2 a PAREALAIVFFGRQPQPNVSELVVGPLPHPSYD4RDVTVERHGGPLPYHRRPVLFQEYLDI NOV2 b PAREALAIVFFGRQPQPNVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDI NOV2 c PAREALAIVFFGRQPQPNVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDI NOV2 d PAREALAIVFFGRQPQPNVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDI NOV2 e PAREALAIVFFGRQPQPNVSELVVGPLPHPSYMRDVTrVERHGGPLPYHRRPVLFQEYLDI NOV2 f PAREALAIVFFGRQPQPNVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDI NOV2 a DQMIFNRELPQASGLLHHCCFYKHRGRNLVTMTTAPRGLQSGDRATWFGLYYNISGAGFF NOV2b DQMIFNRELPQASGLLHHCCFYKHRGRNLVTMTTAPRGLQSGDRATWFGLYYNI SGAGFF NOV2 c DQMIFNRELPQASGLLHHCCFYKHRGRNLVTMTTAPRGLQSGDRATWFGLYYNISGAGFF NOV2 d DQMIFNRELPQASGLLHHCCFYKHRGRINLVTMTTAPRGLQSGDRATWFGLYYNISGAGFF NOV2 e DQMIFNRELPQASGLLHHCCFYKHRGRNLVTMTTAPRGLQSGDRATWFGLYYNI SGAGFF N0V2 f DQMIFNRELPQASGLLHHCCFYKHRGRNLVTMTTAPRGLQSGDRATWFGLYYNI SGAGFF. NOV2 a LHIIVGLELLVNI-KALDPARWTIQKVFYQGRYYDSLAQLEAQFEAGLVNVVLIPDNGTGGS NOV2b LHHVGLELLVNI-KALDPARWTIQKVFYQGRYYDSLAQLEAQFEAGLVNVVLIPDNGTGGS NOV2 c LHHVGLELLVNH-KALDPARWTIQKVFYQGRYYDSLAQLEAQFEAGLVNVVLIPDNGTGGS NOV2 d LHH-VGLELLVNH-KALDPARWTIQKVFYQGRYYDSLAQLEAQFEAGLVNVVLIPDNGTGGS N0V2 e LHHVGLELLVNHKALDPARWTIQKVFYQGRYYDSLAQLEAQFEAGLVNWVLIPDNGTGGS NOV2 f LI*IVGLELLVNHKALDPARWTIQKVFYQGRYYDSLAQLEAQFEAGLVNVVLIPDNGTGGS NOV2 a WSLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSFGLGAFSGPRIFDVRFQGERL NOV2b WSLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSFGLGAFSGPRIFDVRFQGERL NOV2 c WSLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSFGLGAFSGPRIFDVRFQGERL NOV2d WSLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSFGLGAFSGPRIFDVRFQGERL NOV2 e WSLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSFGLGAFSGPRIFDVRFQGERL NOV2 f WSLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSFGLGAFSGPRIFDVRFQGERL NOV2 a VYEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLATYVDW-FLLES NOV2 b VYEISLQEALAIYGGNS PAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLATYVDWHFLLES NOV2 c VYEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLATYVDWHFLLES NOV2 d VYEISLQEALAIYGGJSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLATYVDWHFLLES NOV2e VYEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLATYVDWHFLLES NOV2 f VYEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLATYVDWHFLLES NOV2 a QAPKTIRDAFCVFEQIJQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWDTVF NOV2b QAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWDTVF NOV2c QAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWDTVF NOV2 d QAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWDTVF NOV2 e QAPKTIRDAFCVFEQNQGLPLRRHHSDLYSYFGGLAETVLVVRSMSTLLNYDYVWDTVF NOV2 f QAPKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWDTVF N0V2 a HPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVHTHSAHFKVDLDVAGLENWV N OV2b HPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHiTLGTVHTHSAHF{VDLDVAGLENWV NOV2 c HPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVH-THSAHFKVDLDVAGLENWV NOV2 d HPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVHTHSAHFKVDLDVAGLENWV N0V2 e HPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVHTHSAHFKVDLDVAGLENWV N0V2 f HPSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVH-THSAHFKVDLDVAGLENWV N0V2 a WAEDMVFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGH NOV2b WAEDMVFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGH NOV2 c WAEDMVFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGH 119 WO 2004/056961 PCT/US2003/034114 NOV2d WAEDMVFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGH NOV2e WAEDMVFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGH NOV2 f WAEDMVFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGH NOV2a PRGYRIQMLSFAGEPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVD NOV2b PRGYRIQMLSFAGEPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVD NOV2c PRGYRIQMLSFAGEPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVD NOV2d PRGYRIQMLSFAGEPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVD NOV2e PRGYRIQMLSFAGEPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVD NOV2 f PRGYRIQMLSFAGEPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVD NOV2a FSDFINNETIAGKDLVAWVTAGFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYS NOV2b FSDFINNETIAGKDLVAWVTAGFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYS NOV2c FSDFINNETIAGKDLVAWVTAGFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYS NOV2d FSDFINNETIAGKDLVAWVTAGFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYS NOV2e FSDFINNETIAGKDLVAWVTAGFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYS NOV2 f FSDFINNETIAGKDLVAWVTAGFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYS NOV2a ADSIYFRGDQDAGACEVNPLACLPQAAACAPDLPAFSHGGFSHN--------. NOV2b ADSIYFRGDQDAGACEVNPLACLPQAAACAPDLPAFSHGGFSHN------- NOV2c ADSIYFRGDQDAGACEVNPLACLPQAAACAPDLPAFSHGGFSHN------- NOV2d ADSIYFRGDQDAGACEVNPLACLPQAAACAPDLPAFSHGGFSHN ------- NOV2e ADSIYFRGDQDAGACEVNPLACLPQAAACAPDLPAFSHGGFSHN------- NOV2 f ADS IYFRGDQDAGACEVNPLACLPQAAACAPDLPAFSHGGFSHNWSHPQFEK NOV2a (SEQ ID NO: 22) NOV2b (SEQ ID NO: 24) NOV2c (SEQ ID NO: 26) NOV2d (SEQ ID NO: 28) NOV2e (SEQ ID NO: 30) NOV2f (SEQ ID NO: 32) Further analysis of the NOV2a protein yielded the following properties shown in Table B10. Table B10. Protein Sequence Properties NOV2a SignalP analysis: Cleavage site between residues 30 and 31 PSORT 11 analysis: PSG: a new signal peptide prediction method N-region: length 4; pos.chg 1; neg.chg 0 H-region: length 23; peak value 11.30 PSG score: 6.90 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 3.56 possible cleavage site: between 19 and 20 >>> Seems to have a cleavable signal peptide (1 to 19) ALOM: Klein et al's method for TM region allocation Init position for calculation: 20 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 1.75 (at 233) ALOM score: 1.75 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 9 120 WO 2004/056961 PCT/US2003/034114 Charge difference: -2.5 C(-0.5) - N( 2.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 6.96 Hyd Moment(95): 3.18 G content: 3 D/E content: 1 S/T content: 2 Score: -5.14 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 38 GRG|GD NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 7.2% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues 121 WO2004/056961 PCT/US2003/034114 Final Results (k = 9/23): 22.2 %: vacuolar 22.2 %: endoplasmic reticulum 22.2 %: extracellular, including cell wall 22.2 %: mitochondrial 11.1 %: Golgi >> prediction for CG190178-02 is vac (k=9) 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 B1 1. Table B11. Geneseq Results for NOV2a NOV2a Identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region AAE26686 Human semicarbazide-sensitive amine 1..763 763/763 (100%) 0.0 oxidase (SSAO) - Homo sapiens, 763 aa. 1..763 763/763 (100%) [W0200266669-A1, 29-AUG-2002] AAY03219 Amino acid sequence of the vascular 1..763 763/763 (100%) 0.0 adhesion protein-1 - Homo sapiens, 763 1..763 763/763 (100%) aa. [W09853049-A1, 26-NOV-1998] AAE26690 S. japonicum GST-human SSAO construct 28..763 735/736 (99%) 0.0 protein - Chimeric - Schistosoma 263..998 736/736 (99%) japonicum, 998 aa. [W0200266669-A1, 29-AUG-2002] AAU84261 Human endometrial cancer related protein, 1..760 483/762 (63%) 0. AOC2 - Homo sapiens, 729 aa. 1..729 573/762 (74%) (W0200209573-A2, 07-FEB-2002] ABP41516 Human ovarian antigen HVVBK73, SEQ ID 305..499 83/198 (41%) 2e-44 NO:2648 - Homo sapiens, 248 aa. 16..213 128/198 (63%) (W0200200677-A1, 03-JAN-2002] 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 B12. Table B12. Public BLASTP Results for NOV2a Protein NOV2a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion Q16853 Membrane copper amine oxidase (EC 1..763 7373(0% . 1.4.3.6) (Vascular adhesion protein- 1) 1..763 763/763 (100%) (VAP-1) (HPAO) - Homo sapiens (Human), 763 aa. 122 WO 2004/056961 PCT/US2003/034114 Q9TTK6 Semicarbazide-sensitive amine oxidase 1..763 650/763 (85%) 0.0 (EC 1.4.3.6) (Copper amine oxidase) - 1..763 694/763 (90%) Bos taurus (Bovine), 763 aa. Q9R055 Semicarbazide-sensitive amine oxidase 1..762 635/762 (83%) 0.0 (EC 1.4.3.6) (Copper amine oxidase) - 1..762 695/762 (90%) Mus musculus (Mouse), 765 aa. 070423 Membrane copper amine oxidase (EC 1.762 634/762 (83%) 0.0 1.4.3.6) (Vascular adhesion protein- 1) 1..762 695/762 (91%) 046406.762 634/762 (83% 0.0 (VAP-1) - Mus musculus (Mouse), 765 aa. 046406 Copper amine oxidase, lung isozyme 14..760 620/757 (81%) 0.0 precursor (EC 1.4.3.6) (Amine oxidase 3.759 666/757 (87%) [copper-containing)) (BOLAO) - Bos taurus (Bovine), 762 aa. PFam analysis predicts that the NOV2a protein contains the domains shown in the Table B13. Table B13. Domain Analysis of NOV2a Identities/ Pfam Domain NOV2a Match Region Similarities Expect Value for the Matched Region CLamine oxidN2 65..152 1.e-29 Cu aine xidN 169..269 iio , ____ 1 81/93 (87%) Cu_amineoxidN3 21/111 (19%) 1.9e-31 1 90/111 (81%) Cu_amine oxid 308..724 167/443 (38%) 2.9e-229 393/443 (89%) Example B5. Expression Profile of the Human Copper-containing Amine Oxidase 3 Gene The protocol for quantitative expression analysis is disclosed in Example Q9. Expression of gene CG190178-01 was assessed using the primer-probe set Ag6365, described in Table 814. Results of the RTQ-PCR runs are shown in Tables BI5 and B16. Table B14. Probe Name Ag6365 Fortmersf Sequences - Lngh Strt PositlonfSE ID Forwa 5'-aagtacgggaaccaagtgtca-3d 521 1676 106 Probe- TET-5'-agcgcccactcaaggtggatct-3-TAMRA 23 1727 107 I ver*se]5'-'c*a:gtctccagtcctgctacat-3' 22 1752 108 Table B15. Generalscreeningpanelvl.6 Column A - Rel. Exp.(%) Ag6365, Run 277225263 Tissue Name A Tissue Name A Adipose 25.5 Renal ca. TK-10 2.2 Melanoma* Hs688(A).T I0.0 Badder 6.2 elanoma* Hs688(B).T 0.0 [Gastric ca. (liver met.) NCI-N87 0.2 Melanoma* M14 0.1 IGastric ca. KATO Il1 0.0 Melanoma* LOXIMVI 0.0 lColon ca. SW-948 0.0 123 WO 2004/056961 PCT/US2003/034114 Squamous cell carcinoma SCC-4 l0Colon ca.* (SW480 met) SW620 0.2 iTestis Pool 11.7 Colon ca. HT29 0.9 Prostate ca.* (bone met) PC-3 0.1 Colon ca. HCT-116 Prostate Pool 14.0 Colon ca. CaCo-2 Placenta 8.4 Colon cancer tissue 13.5 Uterus Pool 4.0 Colon ca. SW1116 0.0 6o rian ca 0.0 Colon ca. olo-205 0.0 ovarian ca. SK-OV-3 - 1A Colon ca SW-48 0.0 Ovaran ca. OVCAR-4 T 0.0 Colon Pool 34.2 Ovarian ca. OVCAR-5 0.1 Small Intestine Pool 18.0 Ovarian ca. IGROV-1 0.1 Stomach Pool 12.9 Ovarian ca. OVCAR-8 0.1 Bone Marrow Pool 17.1 1Ovary 6.8 [Feta Heart 2.2....... Breast ca. MCF-7 0.0- Heart Pool 24.3 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 40.9 Breast ca. BT 549 0.0 Fetal Skeletal Muscle j 3.8 Breast ca. T47D 0.0 Skeletal Muscle Pool 2.1 Breast ca. MDA-N 0.0 Spleen Pool 4.6 [Breast Pool ] 19.1 Thymus Pool 8.2 Trachea .0 CNS cancer (glio/astro) U87-MG 0. [Lung _ 13.6 IOCNS cancer (glio/astro) U- 18MG 0.573 6 Fetal Lung 100.0 CONS cancer (neuro;met) SK-N-AS 0.3 [Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 0.0 Lung ca. LX-1 0.2 CNS cancer (astro) SNB-75 0.1 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 0.2 Lung ca. SHP-77 0.1 ICNS cancer (glio) SF-295 Lung ca. A549 0.1 Brain (Amygdala) Pool 0.1 Lung ca. NCi-H526 0.0 Brain (cerebellum) 0.4 FLngcaNCI-H23 10.1 Brain (fetal) 0.5 Lung ca. NCI-H460 0.0 Brain (Hippocampus) Pool 11.4 [Lung ca. HOP-62 0.1 [Cerebral Cortex Pool 0.7 [Lung ca.N~-H522 1. &[rain (Substantia nigra) Pool .3 [Liver 1.4 Brain (Thalamus) Pool 0.5 Fetal Liver 2.0 Brain (whole) 0.6 Liver ca. HepG2 4.4 Spinal Cord Pool 0.6 [Kidney Pool 57.4 [Adrenal 20.7 Fetal Kidney 0.7 Pituitary gland Pool 0.2 Renal ca. 786-0 0.0 Salivary Gland 2.0 Renal ca. A498 0.0 Thyroid (female) 1.9 CHN 0.0 Pancreatic ca. CAPAN2 0.0 [Renal ca. UO-31 0.0 Pancreas Pool ...... 0.9 Table B16. Panel 5 Islet Column A - Rel. Exp.(%) Ag6365, Run 262362458 Tissue Name A Tissue Name A.. A [97457 Patien0t-2go adipose I 37.1 94709 Donor 2 AM - A adipose 40.3 124 WO 2004/056961 PCT/US2003/034114 97476 Patient-07sk skeletal muscle 18.8 94710 Donor 2 AM - B adipose 2 97477 Patient-07ut uterus 85.3 94711 Donor 2 AM - C adipose 22.4 97478 Patient-07pl placenta 18.0 94712 Donor 2 AD - A adipose 49.0 59167 Bayer Patient 1 4.3 94713 Donor 2 AD - B adipose 51.4 197482 Patient-08ut uterus 48.3 94714 Donor 2 AD -C adipose 37.1 97483 Patient-08pl placenta 1.1 9472 Donor 3 U - A Mesenchymal Stem 0.0 97486 Patient-09sk skeletal muscle 3.7 94743 Donor 3 U - B Mesenchymal Stem 0.0 -~- Cells Doo3U--. 97487 Patient-09ut uterus 61.6 94730 Donor 3 AM - A adipose 58.6 97488 Patient-09pl placenta 5.1 94731 Donor 3 AM - B adipose 33.7 97492 Patient-Out uterus 46.0 94732 Donor 3 AM - C adipose 46.3 197493 Patient-10pl placenta 8.4 94733 Donor 3 AD - A adipose 65.5 197495 Patient-i 11go adipose f3.9~4734Donor3 AD -Badipose 4.6... ..... . 97496 Patient- 11sk skeletal muscle 1 4.5 94735 Donor 3 AD - C adipose 9.3 197497 Patient-11 ut uterus 186.5 177138 Liver HepG2untreated 18.8 97498 Patient-11 pl placenta 14.8 173556 Heart Cardiac stromal cells primary ) 0.0 975OI Patient-12go adipose 72.2 81735 Small Intestine 0.1 9750 Patient-12sk skeletal muscle 17.7 72409 Kidney Proximal Convoluted Tubule 0.0 197502_Patient-1 2ut uterus 000865SalitsieDoeu . 503 Patient-12p placenta 6.7 90650 Adrenal Adrenocortical adenoma 14.8 94721 Donor 2 U - A Mesenchymal Stem 0.072410KidneyHRCE 0.3 Cells I. 721I inyHC . 94722 Donor 2 U - B Mesenchymal Stem 1 Kidney Cells j.0f7241 HRE Cells Donor 2 U - C Mesenchymal Stem 0.0 73139 Uterus Uterine smooth muscle cells 00 Gener~screning-panel-vi .6 Summary: Ag6365 The highest expression of this gene was detected in fetal lung (CT=26). Among tissues with metabolic or endocrine function, this gene was expressed in pancreas, adipose, adrenal gland, thyroid, skeletal muscle, heart, liver and the gastrointestinal tract. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product would be useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Panel 5 Islet Summary: Ag6365 The highest expression of this gene was detected in a uterus sample (CT=30). This gene was expressed at moderate levels in uterus and adipose. This gene was strongly induced during adipose differentiation. While it is not found in mesenchymal stem cells, it is expressed at moderate levels in mid-way differentiated and fully differentiated adipocytes. This observation is consistent with the hypothesis that this enzyme is involved in adipose maturation. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product would be useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Example B6. Assays Screening for Modulators of Copper-containing Amine Oxidase 3 The following chemical reaction furmula summarizes the biochemistry surrounding the human Copper-containing Amine Oxidase 3 and potential assays that may be used to screen for antibody therapeutics or small molecule drugs to treat obesity and/or diabetes: 125 WO 2004/056961 PCT/US2003/034114

RCH

2

NH

2 + H 2 0 + 02 = RCHO + NH 3 + H 2 0 2 A non-exhaustive list of cell lines that express the Copper-containing Amine Oxidase 3 can be obtained from the RTQ-PCR results presented in this application. These and other Copper-containing Amine Oxidase 3 expressing cell lines could be used for screening purposes. AOC3 catalyzes the deamination of methylamine and aminoacetone, producing toxic aldehyde like formaldehyde, methylglyoxal, hydrogen peroxide and ammonia. An assay has been described for this enzyme using radioactive benzylamine or tyroamine (J Biol Chem 273:8025 (1998) PMID: 9525902). Selective inhibitors for SSAO family members that do not recognize monoamine oxidases are 2-bromoethylamine and 2-bromopropylamine (competitive; 2-BEA, Ki 2.5 microM). (Arch Biochem Biophys. 385:154 (2001).PMID: 11361012; and Biochem Pharmacol. 61:741 (2001)). Our results indicate that a modulator of AOC3 activity, such as an inhibitor, activator, antagonist, or agonist of AOC3 may be useful for treatment of such disorders as obesity, diabetes, and insulin resistance, as well as for enhancement of insulin secretion. C. NOV3 -- MAPKAP kinase 2 Protein kinases are important drug targets. MAPKAP kinase 2 is a nuclear kinase that is rapidly translocated to the cytoplasm for substrate-interaction upon activation by p38 MAP kinase. The p38 MAP kinase-MAPKAP kinase 2 pathway mediates cellular stress responses and is activated by heat shock, bacterial lipopolysaccharide (LPS) or the pro-inflammatory cytokines IL-1 and TNF alpha. Type 2 diabetes is characterized by increased adipose and circulating levels of a number of proinflammatory cytokines including TNF-alpha [Cytokine Growth Factor Rev Oct;14(5):447 (2003);. Metabolism. May;52(5):605 (2003)]. MAPKAP kinase 2 knockout mice have been reported [Nat Cell Biol Jun;1 (2):94-7 (1999)]. Knockout mice were viable, fertile, grew to normal size and did not exhibit obvious behavioral defects. Additionally, knockout mice were resistant to LPS-induced endotoxic shock, due to a 90% reduction in the production of TNF-alpha. A direct link between increased levels of adipose tissue expression of TNF-alpha and obesity-associated insulin resistance has been documented [Eur J Clin Invest Jun;32 Suppl 3:24 (2002)]. Pharmacologic inhibition of MAPKAP kinase 2 may lead to downregulation of TNF-alpha levels in adipose and other tissues. A decrease in systemic levels of TNF-alpha may ameliorate the insulin-resistant state, which is a prelude to and a characterisitic of Type 2 diabetes. An important clinical goal in the early phases of treatment of Type 2 diabetes is to increase insulin secretion from the beta cells of the pancreas. Patients with Type 2 diabetes classically show high levels of blood glucose and deficits in insulin secretion. Glybenclamide is a sulfonylurea-class drug used to lower blood glucose in Type 2 diabetic patients by enhancing insulin secretion. However, many Type 2 diabetic patients treated with glybenclamide become resistant to the anti hyperglycemic effect of the drug and have decreased insulin secretion. Sulfonylureas such as glybenclamide have been reported to have a limited duration of effectiveness, with most patients requiring a change or additional medications after 5 years of therapy [N Engl J Med Oct 24;347(17):1342 (2002)]. Thus, new and more effective treatments for Type 2 diabetes are needed. In our study, rat MAPKAP kinase 2 gene expression was found to be upregulated in pancreatic islets treated with high glucose- or glybenclamide for 5 days. Under standard culture 126 WO 2004/056961 PCT/US2003/034114 conditions, rat pancreatic islet cells chronically treated in vitro with high glucose or glybenclamide had a significant deficit in glucose-stimulated insulin secretion (as compared to control islets). Treatment of rat pancreatic islets cells for 5 days with glybenclamide mimics the situation seen in glybenclamide resistant Type 2 diabetic patients in that insulin secretion decreases significantly. These data suggest that type 2 diabetic patients treated with glybenclamide eventually become resistant to the anti hyperglycemic effect of the drug due to an upregulation of the MAPKAP kinase 2 pathway. Furthermore, treatment of rat pancreatic islets with high glucose for 5 days mimics the situation in hyperglycemic Type 2 diabetic patients, and suggests that MAPKAP kinase 2 upregulation is a correlate of beta cell dysfunction. RTQ-PCR experiments confirm that the MAPKAP kinase 2 gene is expressed in pancreatic islet cells as well as in other metabolically relevant tissues, including adipose and skeletal muscle in humans. Therefore, pharmacologic inhibition of MAPKAP kinase 2 will enhance beta cell function and insulin secretion in Type 2 diabetes. In addition, pharmacologic inhibition of MAPKAP kinase 2 may ameliorate insulin resistance by decreasing TNF-alpha levels in adipose. A role for MAPKAP kinase 2 in Type 2 diabetes and insulin secretion has not been previously described. Furthermore, our results indicate that a modulator of MAPKAP kinase 2 activity, such as an inhibitor, activator, antagonist, or agonist of MAPKAP kinase 2 may be useful for treatment of such disorders as obesity, diabetes, and insulin resistance, as well as for enhancement of insulin secretion. Thus, MAPKAP kinase 2 nucleic acids and proteins are useful for screening for an inhibitor/antagonist of MAPKAP kinase 2 for the treatment of obesity and or diabetes. These materials are further useful in the generation of antibodies that bind immunospecifically to the substances of the invention for use in diagnostic and/or therapeutic methods. Discovery Process The following sections describe the study design(s) used to identify the MAPKAP kinase 2 protein and any variants thereof, as being suitable as diagnostic markers, targets for an antibody therapeutic and targets for a small molecule drugs for Obesity and Diabetes. Example C1. Rat Pancreatic Islet Study An important clinical goal in the early phases of Type 2 diabetes is to increase insulin secretion from the beta cells of the pancreas. Numerous agents have been identified that can modulate insulin secretion experimentally and in therapeutic situations. When applied to isolated rat pancreatic islets, the changes in gene expression can be correlated with insulin secretion. In this study, acute and chronic changes in gene expression were examined from islets treated with an agent after short (4 hour) and long-term (5 days) exposure, respectively, compared with the basal state (11 mM glucose). The agents included elevated (25 mM) glucose, glucose (11 mM) and exendin-4 (1 nM), glucose (11 mM) and glybenclamide (50 uM) and glucose (11 mM) and oleate (2 mM). The protocol for Rat Pancreatic Islet Study is disclosed in Example Q2. A fragment of the rat MAPKAP kinase 2 gene was initially found to be up-regulated by 1.9 fold in isolated rat pancreatic islets treated with 25 mM glucose versus 11 mM glucose using CuraGen's GeneCalling a method of differential gene expression (described in Example Q7). A differentially expressed rat gene fragment migrating at approximately 265 nucleotides in length was definitively 127 WO2004/056961, PCT/US2003/034114 identified as a component of the rat MAPKAP kinase 2 cDNA. The method of competitive PCR was used for confirmation of the gene assessment. The electropherographic peaks corresponding to the gene fragment of the rat MAPKAP kinase 2 were ablated when a gene-specific primer (shown in Table Cl) competes with primers in the linker-adaptors during the PCR amplification. The peaks at 265 nt in length were ablated in the sample from both the 25 mM glucose and 11 mM glucose-treated rat pancreatic islet cells. A fragment of the rat MAPKAP kinase 2 gene was also found to be up regulated by 1.7 fold in isolated rat pancreatic islets treated with glybenclamide versus 11 mM glucose. Table C1. The direct sequence of the 265 nucleotide-long gene fragment and the gene-specific primers used for competitive PCR are indicated on the cDNA sequence of MAPKAP kinase 2 (SEQ ID No:109) and are shown below in bold (fragment from 387 to 651 in bold. band size: 265) . The gene-specific primers at the 5' and 3' ends of the fragment are underlined. 1 GGAGAGGTGG AGCTGTACTG GAGGGCCTCC CAGTGCCCAC ACATCGTGCA CATCGTGGAC 61 GTCTATGAGA ACCTGTATGC CGGGAGGAAG TGCTTGCTGA TTGTCATGGA GTGTCTCGAT 121 GGTGGAGAGC TCTTTAGTCG GATCCAGGAC CGAGGAGACC AGGCATTCAC AGAAAGAGAG 181 GCATCAGAGA TCATGAAGAG CATCGGGGAG GCCATCCAGT ACCTGCACTC TATCAACATC 241 GCTCACCGGG ACGTCAAGCC CGAGAACCTC TTATACACTT CCAAAAGACC CAATGCCATC 301 CTGAAACTCA CTGATTTTGG CTTTGCCAAG GAAACCACCA GTCACAACTC TTTGACCACT 361 CCGTGTTATA CACCGTACTA TGTGGCTCCG GAAGTACTGG GCCCAGAGAA GTATGACAAG 421 TCCTGTOACA TGTGGTCCTT GGGTGTCATC ATGTATATTT TGCTGTGTGG GTATCCCCCC 481 TTCTATTCCA ACCACGGCCT TGCCATCTCT CCGGGCATGA AGACTCGCAT TCGAATGGGC 541 CAGTATGAAT TTCCTAACCC AAAATGGTCA GAAGTATCAG AAGAAGTGAA GATGCTTATT 601 CTGAATCTGC TGAAAACAGA GCCCACCCAG AGAATGACCA TCACAGAATT CATGAACCAC 661 CCGTGGATCA TGCAATCTAC GAAGGTCCCT Example C2. Identification of Human MAPKAP kinase 2 sequence. The sequence of Human MAPKAP kinase 2 was 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, were sequenced. In silicon 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 protocol for identification of human sequence(s) is disclosed in Example 08. Table C2 shows an alignment of the protein sequences of the human (CG186525-01) and rat fragment of the MAPKAP kinase 2. Table C3 shows sequence of rat fragment of the MAPKAP kinase 2. Table C2. An alignment (ClustalW) of the protein sequences of the human (CG186525-01; SEQ ID NO:34) MAPKAP kinase 2 gene and the rat fragment (SEQ ID NO:110) corresponding to MAPKAP kinase 2 that was identified by GeneCalling@. 128 WO 2004/056961 PCT/US2003/0341 14 MK2_rat fragment........................................ CGI6525-01 MK2_rat fragment 00186525-01 MK2_rat fragment AIM D CGI86525-01 MK2_rat fragment C0186523-01 MK2_rat fragment CGI86523-01 MK2_rat fragment EL C0186525-01 h~ MK2_rat fragment------ CGI86525-01 Table 03. Sequence of rat fragment of the MAPKAP kinase 2 (SEQ ID NO:1 10). >MK2_rat-fragment GEVELYWRASQ)CPHIVHIVDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGE AIQYLHSINIAHRDVKPENLLYTSKRPNAI LKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVLG PEKYDK SCDMWSLGV IMYI LLCGYPPFYSN H GLAI SPG MKTR IRMGQYEFPNP KSEVSEEVKMLI LN LLKT EPTQ RMTITEFMNHPWIMQSTKVP The laboratory cloning was performed using one or more of the methods summarized in Example Q8. The NOV3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 04. [NOV3a, CG186525-01 S.EQID NO:33258b IDNA Sequence 'ORE Start: ATG at 379 [ORF Stop: TGA at 1489 __ dATATACGAACATGAAATGC TAAAAAGTTTTAAACACTTCAATTTCTAATTCACCATGTCAC AGACTGGTGAAAAAMAAAAAAAAAGCGGCCGCTTCCCCCCGGCCGGGCCCCCGCCGCCCCGCGGTCCC CAGAGCGCCAGGCCCCCGGGGGGAGGGAGGGAGGGCGCCGGGCCGGTGGGAGCCAGCGGCGCGCGGTG GGACCCACGGAGCCCCGCGACCCGCCGAGCCTGGAGCCGGGCCGGCTCGGGGAAGCCGGCTCCAGCCC GGAGCGAACTTCGCAGCCCGTCGGGGGGCGGCGGGGAGGGGGCCCGGAGCCGGAGGAGGGGGCGGCCG CGGGCACCCCCGCCTGTGCCGCGGCGTCGCCCGGGCACCATGCTGTCGAACTCCCAGGGCCAGAGCGCG CCGGTGCCGTTCCCCGCCCCGGCGGCGCCGCCGCAGCCCCCCACCCCTGCCCTGCCGCACCCCCCGGC GCGCCGCCGCCGACGTCGCGTCCTAGCGCTCGTAG AGAACGCCATCATCGATGACTACAAGGTCACCAGCCAGGTCCTGGGGCTGGGCATCAACGGCMAAGTT TTGCAGATCTCAACAAGAGGACCCAGGAGAAATTCGCCCTCAAAATGCUGCAGGACTGCCCCAAGGC CCGCAGGGAGGTGGAGGTGCACTGGCGGGCCTCCCAGTGCCCGCAOATCGTAGGGATCGTGGATGTGT ACGAGAATCTGTACGCAGGGAGGAAGTGCCTGCTGATTGTCATGGAATG1-TTGGACGGTGGAGAACTC lTTAGCCGAATCCAGGATCGAGGAGACCAGGCATCACAGAAAGAGAAGCATCCGAAATCATGAAGAG CATCGGTGAGGCCATCCAGTATCTGCATrCAATCAACATTGCCCATCGGGATGTCAAGCCTGAGAATC TCTTATACACCTCCAAAAGGCCCAACGCCATCCTGAAACTCACTGACTTGG1-1--GCCAAGGAAACC ACCAGCGACAACTCTTTGACCACTCCTTGTTATACACCGTACTATGTGGCTCCAGAAGTGCTGGGTCC AGAGAAGTATGACAAGTCCTGTGACATGTGGTCCCTGGGTGTCATCATGTACATCCTGCTGTGTGGGT ATCCCCCCTTCTACTCCAACCACGGCCTTGCCATCTCTCCGGGCATGAAGACTCGCATCCGAATGGGC CAGTATGAATTTCCCAACCGAGAATGGTCAGMAGTATCAGAGGAAGTGAAGATGCTCAI-ICGGAATCT GCTGAAAACAGAGCCCACCCAGAGAATGACCATCACCGAGI-I-1ATGAACCACCCTT-GGATCATGCAAT CAACAAAGGTCCCTCAAACGGCACTGCACACCAGCCGGGTCCTGMAGGAGGACAAGGAGCGGTGGGAG GATGTCAAGGGGTGTCTTCATGACAAGAACAGCGACCAGGCCACTGGCTGACCAGG,-TGTGAGCAGA GGATTCTGTGTTCCTGTCCAAACTCAGTGCTGTCTTAGAATCC1-n-TATTCCCTGGGTCTCTAATG GGACCTTAAAGACCATCTGGTATCATCTTCTCA1TTTGCAGAAGAGAAACTGAGGCCCAGAGGCGGAG GGCAGTCTGCTCAAGGTCACGCAGCTGGTGACTGGTGGGGCAGACCGGACCCAGGmTCCTGACTCC 129 WO 2004/056961 PCT/US2003/0341 14 TGG CCCAAGTCTCTTCCTCCTATCCTGCGGGATCACTGGGGGGCTCTCAGGGAACAGCAGCAGTGCCA TAGCCAGGCTCTCTGCTGCCCAGCGCTGGGGTGAGGCTGCCGTTGTCAGCGTGGACCACTAACCAGCC CGTCTTCTCTCTCTGCTCCCACCCCTGCCGCCTCACCTGCCCTTGTTGTCTCTGTCTCTCACTGTCTC TTCTGCTGTCTCTCTACTGTCTTCTGGCTCTCTCTGTACCCTTCCTGGTGCTGCCGTGCCCCCAGGAG GAGATGACCAGTGCCTTGGCCACAATGCGCGTTGACTACGAGCAGATCAAGATAAAAAAGATTGAAGA TGCATCCAACCCTCTGGTGCTGAAGAGGCGGAAGAAAGCTCGGGCCCTGGAGGCTGCGGCTCTGGCCC ACTGAGCCACCGCGCCCTCCTGCCCACGGGAGGACAAGCAATAACTCTCTACAGGAATATATTTTTTA AACGAAGAGACAGAACTGTCCAGATCTGCCTCCTCTCCTCCTGAGCTGCATGGAGCGTGGAACTGCAT CAGTGACTGAATTC J___ FNOV3a, 0Gi86525-01 SEQ ID NO: 34 370 aa MWat 42202.3kD P ro tein..... S eq u en ce- ...... ........ .. ..... m;............. .... .. .... ... ............... ......... MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIKKNAIIDDYKVTSQ V LG LGING KVLQI FN KRTQEKFALKMLQDCPKAR REV ELHW RASQCPH IVRIVDVYE NLYAG RKCLLl VM ECLDG GELFSRIQDRG DQAFTEREASEI MKS IG EAiQYLHSl NIAH RDVKP ENLLYTSKRPNAI LK LTD FG FAKETTSH NSLTTPCYTPYYVAP EVLG PEKYD KSCDMWSLGVI MY[ILLCGYP PFYSN HG LAIS PGMKTRIRMG3QYEFPNPEWSEVSEEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHTSR VLKEDKERWEDVKGCLHDKNSDQATWLTRL ________ [NOV~b, CG 186525-02 ISEQ ID NO: 35 1885 bp IDNA Sequence IR Str:at1 - ORF Stop: TGA at 883 ACATGCACGTCAAGTCCGGCCTGCAGATCAAGMAGAACGGCATCATCGATGACTACAAGGTCA CCA G CCAGGTCCTGGGGCTGGGCATCAACGGCAAAG1TTFGCAGATCTTCAACAAGAGGACCCAGGAGAAAT TCGCCCTCAAAATGCTTCAGGACTGCCCCMAGGCCCGCAGGGAGGTGGAGCTGCACTGGCGGGCCTCC CAGTGCCCGCACATCGTACGGATCGTGGATGTGTACGAGAATCTGTACGGAGGGAGGAAGTGCCTGCT GATTGTCATGGAATGTTTGGACGGTGGAGAACTCTAGCCGAATCCAGGATCGAGGAGACCAGGCAT TCACAGAAAGAGAAGCATCCGAAATCATGAAGAGCATCGGTGAGGCCATCCAGTATCTGCATTCAATC AACATTGCCCATCGGGATGTCAAGCCTGAGAATCTCTTATACACCTCCAAAAGGCCCAACGCCATCCT GAAACTCACTGACTTGGCTTTGCCAAGGAAACCACCAGCCACAACTCTTTGACCACTCCTTGTTATA CACCGTACTATGTGGCTCCAGAAGTGCTGGGTCCAGAGAAGTATGACAAGTCCTGTGACATGTGGTCG CTGGGTGTCATCATGTACATCCTGCTGTGTGGGTATCCCCCCTTCTACTCCAACCACGGCCUTGCCAT CTCTCCGGGCATGAAGACTCGCATCCGAATGGGCCAGTATGAAUTTCCCAACCCAGAATGGTCAGAAG TATCAGAGGAAGTGAAGATGGTCATTCGGAATCTGCTGAAAACAGAGGCCACCCAGAGAATGAGCATC ACCGAG1TTATGAACCACCCTTGGATCATGCAATCAACAAAGGTGCCTCAAACCCCACTGCACACCTG NOV3 b CG186525-02 S QID NO: 36 194aa MW t380. D Protein Sequence-_ _ _ __ _ TMHVKSGLQI KKNAIIDDYKVTSQVLGLG ING KVLQI FNKRTQEKFALKMLQCPKAREEH A QCPHIVRIVDVYENLYAG RKCLLI VMECLDGG ELFSRIQDRG DQAFTEREASEIMKSIGEAIQYLHSI N IAHRDVKPENLLYTSKRPNAILKLTDFG FAKEUTSHNSLTTPCYTPYYVAPEVLG PEKYDKSCDMWS LGVI MYI LLCGYPP FYSNHG LAI SPG MKTRI RMGQYEFPN PEWSEVS EEVKMLI RN LLKTEPTQ RMT1 TEFMNHPWIMQSTKVPQTPLHT ___ jNOV, CG 185 3 rSEQ ID NO: 37 l1130 bp DN A .- S e 1q-uenc e FORF Start ATG at 10IRStpTG at 1120 GGATCCACCATGCTGTCCAACTCCCAGGGCCAGAGGCCGCCGGTGCCGTTCCCCGCCCCGGCCCCGCC GCCGCAGCCCCCCACCCCTGCCCTGCCGCACCCCCCGGCGCAGCCGCCGCCGCCGCCCCCGCAGCAGT TCCCGCAGTTCCACGTCAAGTCCGGCCTGCAGATCAAGAAGAACGCCATCATCGATGACTACMAGGTC ACCAGCCAGGTCCTGGGGCTGGGCATCAACGGCAAAGTTTTGCAGATCTCAACAAGAGGACCCAGGA GAAATTCGCCCTCAAMATGCTTCAGGACTGCCCCAAGGCCCGCAGGGAGGTGGAGCTGCACTGGGGGG CCTCCCAGTGCCCGCACATCGTACGGATCGTGGATGTGTACGAGAATCTGTACGCAGGGAGGAAGTGC CTGCTGATTGTCATGGAATGTGGACG GTGGAGAACTCTTTAGCCGAATCCAGGATCGAGGAGACCA GGCATTCACAGAAAGAGAAGCATCCGAAATCATGAAGAGCATCGGTGAGGCCATCCAGTATCTGCATT CAATCAACATTGCCCATCGGGATGTCAAGCCTGAGAATCTCTTATACACCTCCAAAAGGCCCAACGCC ATCCTGAAACTCGAGGACTTTGGCT11GCCAAGGAAACCACCAGCCACAACTCmTGACCACTCCUTG TTATACACCGTACTATGTGGCTCCAGAAGTGCTGGGTCCAGAGAAGTATGACAAGTCCTGTGACATGT GGTCCCTGGGTGTCATCATGTACATCCTGCTGTGTGGGTATCCCCCCTTCTACTCCMACCACGGCCUT GCCATCTCTCCGGGCATGAAGACTCGCATCGGAATGGGCCAGTATGAATFTCCCAACCCAGAATGGTC AGAAGTATCAGAGGAAGTGAAGATGCTCATTCGGAATCTGCTGAAAACAGAGCCCACCCAGAGAATGA ICCATCGAGGAG]TTrATGAACCACCCTTGGATCATGCAATCAACAAAGGTCCCTCAAACCCCACTGCAC 130 WO 2004/056961 PCT/US2003/034114 ACCAGCCGGGTCCTGAAGGAGGACAGGAGCGGTGGGAGGATGTCAAGGGGTGTCTTCATGACAAGAA CAGCGACCAGGCCACTTGGCTGACCAGGTTGTGAGCGGCCGC NOV3c, CG186525-03 SEQ ID NO: 38 370 aa MW at 42258.3kD P ot i n Sequence. ......... ............. MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQKKNAIIDDYKVTSQ VLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCPHIVRIVDVYENLYAGRKCLLI VMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAQYLHSINIAHRDVKPENLLYTSKRPNAILK LEDFGFAKETTSHNSLTTPCYTPYYVAPEVLGPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAIS PGMKTRIRMGQYEFPNPEWSEVSEEVKMLIRNLLKTEPTQRMTIEEFMNHPWIMQSTKVPOT PLHTSR VLKEDKERWEDVKGCLHDKNSDQATWLTRL [NOV3d, CG186525-04 1SQI p 91128 b DNA Sequence JORF Start: at 1 ORF Stop: TGA at 1126 CTCTGG ATCCACCATGCTGTCCAACTCCCAGGGCCAGAGCCCGCCGGTGCGTTCCCCGCCCCGGC CCCGCCGCCGCAGCCCCCCACCCCTGCCCTGCCGCACCCCCCGGCGCAGCCGCCGCCGCCGCCCCCGC AGCAGTTCCCGCAGTTCCACGTCAAGTCCGGCCTGCAGATCAAGAAGAACGCCATCATCGATGACTAC AAGGTCACCAGCCAGGTCCTGGGGCTGGGCATCAACGGCAAAGTTUGCAGATCTTCAACAAGAGGAC CCAGGAGAAATTCGCCCTCAAAATGCTTCAGGACTGCCCCAAGGCCCGCAGGGAGGTGGAGCTGCACT GGCGGGCCTCCCAGTGCCCGCACATCGTACGGATCGTGGATGTGTACGAGAATCTGTACGCAGGGAGG AAGTGCCTGCTGATTGTCATGGAATGTTTGGACGGTGGAGAACTCTTTAGCCGAATCCAGGATCGAGG AGACCAGGCATTCACAGAAAGAGAAGCATCCGAAATCATGAAGAGCATCGGTGAGGCCATCCAGTATC TGCATTCAATCAACATTGCCCATCGGGATGTCAAGCCTGAGAATCTCTTATACACCTCCAAAAGGCCC AACGCCATCCTGAAACTCACTGACTTTGGCTTTGCCAAGGAAACCACCAGCCACAACTCTTTGACCAC TCCTTGTTATACACCGTACTATGTGGCTCCAGAAGTGCTGGGTCCAGAGAAGTATGACAAGTCCTGTG ACATGTGGTCCCTGGGTGTCATCATGTACATCCTGCTGTGTGGGTATCCCCCCTTCTACTCCAACCAC GGCCTTGCCATCTCTCCGGGCATGAAGACTCGCATCCGAATGGGCCAGTATGAATTTCCCAACCCAGA ATGGTCAGAAGTATCAGAGGAAGTGAAGATGCTCATTCGGAATCTGCTGAAAACAGAGCCCACCCAGA GAATGACCATCACCGAGTTTATGAACCACCCTTGGATCATGCAATCAACAAAGGTCCCTCAAACCCCA CTGCACACCAGCCGGGTCCTGAAGGAGGACAAGGAGCGGTGGGAGGATGTCAAGGGGTGTCTTCATGA CAAGAACAGCGACCAGGCCACTTGGCTGACCAGGTTGTGA NOV3d, CG186525-04 SEQ ID NO: 40 375 aa MW at 42631.8kD oteeqence ALGSTMLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLIKKNAIIDDY KVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCPHIVRIVDVYENLYAGR KCLLIVMECLDGGELFSRIQDRGDQAFTEREASEMKSIGEAQYLHSINIAHRDVKPENLLYTSKRP NAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVLGPEKYDKSCDMWSLGVIMYILLCGYPPFYSNH GLAISPGMKTRIRMGQYEFPNPEWSEVSEEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTP LHTSRVLKEDKERWEDVKGCLHDKNSDQATWLTRL_ _ }NOV3e, CG186525-05 5E~__NO:_41 1133 bp DNA Sequence ORF Start: ATG at 21 ORF Stop: TGA at 1131 ANGGGCCCCTGGGATCCACCATGCTGTCCAACTCCCAGGGCCAGAGCCCGCCGGTGCCGTTCCCCGCC CCGGCCCCGCCGCCGCAGCCCCCCACCCCTGCCCTGCCGCACCCCCCGGCGCAGCCGCCGCCGCCGCC CCCGCAGCAGTTCCCGCAGTTCCACGTCAAGTCCGGCCTGCAGATCAAGAAGAACGCCATCATCGATG ACTACAAGGTCACCAGCCAGGTCCTGGGGCTGGGCATCAACGGCAAAGTTTTGCAGATCTTCAACAAG AGGACCCAGGAGAAATTCGCCCTCAAAATGCTTCAGGACTGCCCCAAGGCCCGCAGGGAGGTGGAGCT GCACTGGCGGGCCTCCCAGTGCCCGCACATCGTACGGATCGTGGATGTGTACGAGAATCTGTACGCAG GGAGGAAGTGCCTGCTGATTGTCATGGAATGTTTGGACGGTGGAGAACTCTTTAGCCGAATCCAGGAT CGAGGAGACCAGGCATTCACAGAAAGAGAAGCATCCGAAATCATGAAGAGCATCGGTGAGGCCATCCA GTATCTGCATTCAATCAACATTGCCCATCGGGATGTCAAGCCTGAGAATCTCTTATACACCTCCAAAA GGCCCAACGCCATCCTGAAACTCGAGGACTTTGGCTTTGCCAAGGAAACCACCAGCCACAACTCTTTG ACCACTCCTTGTTATACACCGTACTATGTGGCTCCAGAAGTGCTGGGTCCAGAGAAGTATGACAAGTC CTGTGACATGTGGTCCCTGGGTGTCATCATGTACATCCTGCTGTGTGGGTATCCCCCCTTCTACTCCA ACCACGGCCTTGCCATCTCTCCGGGCATGAAGACTCGCATCCGAATGGGCCAGTATGAATTTCCCAAC CCAGAATGGTCAGAAGTATCAGAGGAAGTGAAGATGCTCATTCGGAATCTGCTGAAAACAGAGCCCAC CCAGAGAATGACCATCGAGGAGTTTATGAACCACCCTTGGATCATGCAATCAACAAAGGTCCCTCAAA CCCCACTGCACACCAGCCGGGTCCTGAAGGAGGACAAGGAGCGGTGGGAGGATGTCAAGGGGTGTCTT CATGACAAGAACAGCGACCAGGCCAC11GGCTGACCAGGTTGTGA 131 WO 2004/056961 PCT/US2003/034114 NOV3e, CG186525-05 SEQ ID NO: 42 370 aa MW at 42258.3kD Protein Sequence I MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQKKNAlDDYKVTSQ VLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCPHIVRIVDVYENLYAGRKCLLI VMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAQYLHSINIAHRDVKPENLLYTSKRPNAILK LEDFG FAKETTSHNSLTT PCYTPYYVAPEVLG PEKYDKSCDMWSLGVIMYI LLCGYPPFYSNHGLAIS PGMKTRIRMGQYEFPNPEWSEVSEEVKMLIRNLLKTEPTQRMTIEEFMNHPWIMQSTKVPQTPLHTSR VLKEDKERWEDVKGCLHDKNSDQATWLTRL NOV3f, CG186525-06 SEQ ID NO: 43 11026 bp DNA Sequence JORF Start: ATG at 11 IORF Stop: at 1025 GGGATCCACCATGCTGTCCAACTCCCAGGGCCAGAGCCCGCCGGTGCCGTTCCCCGCCCCGGCCCCGC CGCCGCAGCCCCCCACCCCTGCCCTGCCGCACGCCCCGGCGCAGCCGCCGCCGCCGCCCCCGCAGCAG TTCCCGCAGTTCCACGTCAAGTCCGGCCTGCAGATCAAGAAGAACGCCATCATCGATGACTACAAGGT CACCAGCCAGGTCCTGGGGCTGGGCATCAACGGCAAAGTTTTGCAGATCTTCAACAAGAGGACCCAGG AGAAATTCGCCCTCAAAATGCTTCAGGACTGCCCCAAGGCCCGCAGGGAGGTGGAGCTGCACTGGGGG GCCTCCCAGTGCCCGCACATCGTACGGATCGTGGATGTGTACGAGAATCTGTACGCAGGGAGGAAGTG CCTGCTGATTGTCATGGAATGTTTGGACGGTGGAGAACTCTTTAGCCGAATCCAGGATCGAGGAGACC AGGCATTCACAGAAAGAGAAGCATCCGAAATCATGAAGAGCATCGGTGAGGCCATCCAGTATCTGCAT TCAATCAACATTGCCCATCGGGATGTCAAGCCTGAGAATCTCTTATACACCTCCAAAAGGCCCAACGC CATCCTGAAACTCACTGACTTTGGCTTTGCCAAGGAAACCACCAGCCACAACTCTTTGACCACTCCTT GTTATACACCGTACTATGTGGCTCCAGAAGTGCTGGGTCCAGAGAAGTATGACAAGTCCTGTGACATG TGGTCCCTGGGTGTCATCATGTACATCCTGCTGTGTGGGTATCCCCCCTTCTACTCCAACCACGGCCT TGCCATCTCTCCGGGCATGAAGACTCGCATCCGAATGGGCCAGTATGAATTTCCCAACCCAGAATGGT CAGAAGTATCAGAGGAAGTGAAGATGCTCATTCGGAATCTGCTGAAAACAGAGCCCACCCAGAGAATG ACCATCACCGAGTTTATGAACCACCCTTGGATCATGCAATCAACAAAGGTCCCTCAAACCCCACTGCA CACCTG NOV3f, CG186525-06 SEQID NO: 44 338 aa MW at 38363.0kD Protein Sequence ___ I N :4__ MLSNSQGOSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQKKNAIIDDYKVTSQ VLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCPHIVRIVDVYENLYAGRKCLLI VMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAQYLHSINIAHRDVKPENLLYTSKRPNAILK LTDFGFAKETTSHNSLTTPCYT PYYVAPEVLGPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAIS PGMKTRIRMGQYEFPNPEWSEVSEEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHT NOV3g, 317973998 ISEQ ID NO: 45 1885 bp DNA Sequence ORFStart:at 1ORF Stop: TGA at 883 ACCATGCACGTCAAGTCCGGCCTGCAGATCAAGAAGAACGCCATCATCGATGACTACAAGGTCACCAG CCAGGTCCTGGGGCTGGGCATCAACGGCAAAGTTTTGCAGATCTTCAACAAGAGGACCCAGGAGAAAT TCGCCCTCAAAATGCTTCAGGACTGCCCCAAGGCCCGCAGGGAGGTGGAGCTGCACTGGCGGGCCTCC CAGTGCCCGCACATCGTACGGATCGTGGATGTGTACGAGAATCTGTACGCAGGGAGGAAGTGCCTGCT GATTGTCATGGAATGTTTGGACGGTGGAGAACTCTTTAGCCGAATCCAGGATCGAGGAGACCAGGCAT TCACAGAAAGAGAAGCATCCGAAATCATGAAGAGCATCGGTGAGGCCATCCAGTATCTGCATTCAATC AACATTGCCCATCGGGATGTCAAGCCTGAGAATCTCTTATACACCTCCAAAAGGCCCAACGCCATCCT GAAACTCACTGACTTTGGCTTTGCCAAGGAAACCACCAGCCACAACTCTTTGACCACTCCTTGTTATA CACCGTACTATGTGGCTCCAGAAGTGCTGGGTCCAGAGAAGTATGACAAGTCCTGTGACATGTGGTCC CTGGGTGTCATCATGTACATCCTGCTGTGTGGGTATCCCCCCTTCTACTCCAACCACGGCCTTGCCAT CTCTCCGGGCATGAAGACTCGCATCCGAATGGGCCAGTATGAATTTCCCAACCCAGAATGGTCAGAAG TATCAGAGGAAGTGAAGATGCTCATTCGGAATCTGCTGAAAACAGAGCCCACCCAGAGAATGACCATC ACCGAGTTTATGAACCACCCTTGGATCATGCAATCAACAAAGGTCCCTCAAACCCCACTGCACACCTG A NOV3g, 31 7973998 1SQI NO: 4 194aa 1MW at 33805.9kD Protein Sequence TMHVKSGLQI KKNAIIDDYKVTSQVLGLG INGKVLQI FNKRTQEKFALKMLQDCPKARREVELHWRAS QCPHIVRIVDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEMKSIGEAQYLHSI NIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVLGPEKYDKSCDMWS LGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVSEEVKMLRNLLKTEPTQRMTI TEFMNHPWIMQSTKVPQTPLHT 132 WO 2004/056961 PCT/US2003/034114 A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table C5. Table C5. Comparison of the NOV3 protein sequences. [NOV3a ----- MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIK NOV3b -------------------------------------------------TMHVKSGLQIK NOV3c -----MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIK NOV3d ALGSTMLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIK NOV3e ----- MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIK NOV3f ----- MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIK NOV3g -------------------------------------------------TMHVKSGLQIK NOV3a KNAIIDDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCP NOV3b KNAIIDDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCP NOV3c KNAIIDDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCP NOV3d KNAIIDDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCP NOV3e KNAIIDDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCP NOV3 f KNAII DDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCP NOV3g KNAIIDDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCP NOV3a HIVRIVDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQ NOV3b HIVRIVDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQ NOV3c HIVRIVDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQ NOV3d HIVRIVDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQ NOV3e HIVRIVDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQ NOV3 f HIVRIVDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQ NOV3g HIVRIVDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQ NOV3a YLHSINIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVL NOV3b YLHSINIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVL NOV3c YLHSINIAHRDVKPENLLYTSKRPNAILKLEDFGFAKETTSHNSLTTPCYTPYYVAPEVL NOV3d YLHSINIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVL NOV3e YLHSINIAHRDVKPENLLYTSKRPNAILKLEDFGFAKETTSHNSLTTPCYTPYYVAPEVL NOV3 f YLHSINIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVL NOV3g YLHSINIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVL NOV3a GPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVS NOV3b GPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVS NOV3c GPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVS NOV3d GPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVS NOV3e GPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVS NOV3 f GPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVS NOV3g GPEKYDKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVS NOV3a EEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKGC NOV3b EEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHT---------------- NOV3c EEVKMLIRNLLKTEPTQRMTIEEFMNHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKGC NOV3d EEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKGC NOV3e EEVKMLIRNLLKTEPTQRMTIEEFMNHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKGC NOV3 f EEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHT ----------------- NOV3g EEVKMLIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHT---------------- NOV3a LHDKNSDQATWLTRL NOV3b

----

NOV3c LHDKNSDQATWLTRL NOV3d LHDKNSDQATWLTRL NOV3e LHDKNSDQATWLTRL NOV3f ------ --- NOV3g ------ --- 133 WO 2004/056961 PCT/US2003/034114 NOV3a (SEQ ID NO: 34) NOV3b (SEQ ID NO: 36) NOV3c (SEQ ID NO: 38) NOV3d (SEQ ID NO: 40) NOV3e (SEQ ID NO: 42) NOV3f (SEQ ID NO: 44) NOV3g (SEQ ID NO: 46) Further analysis of the NOV3a protein yielded the following properties shown in Table C6. Table C6. Protein Sequence Properties NOV3a SignalP analysis: INo Known Signal Sequence Predicted [PSORT I analysis: PSG: a new signal peptide prediction method N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 48; peak value 4.58 PSG score: 0.18 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -13.01 possible cleavage site: between 35 and 36 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 0.85 (at 243) ALOM score: 0.85 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 6 Charge difference: -0.5 C( 0.5) - N( 1.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 4.55 Hyd Moment(95): 3.49 G content: 2 D/E content: 1 S/T content: 5 Score: -4.96 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: PKARREV (5) at 99 bipartite: none content of basic residues: 11.6% NLS Score: -0.04 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none 134 WO 2004/056961 PCT/US2003/034114 SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 69.6 %: nuclear 13.0 %: peroxisomal 13.0 %: cytoplasmic 4.3 %: mitochondrial >> prediction for CG186525-01 is nuc (k=23) 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 C7. Table C7. Geneseq Results for NOV3a NOV3a Identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for the Expect Identifier Date] Match Matched Region Value Residues ABU61622 Human cancer-expressed protein 1..370 370/370 (100%) 0.0 MAPKAP kinase 2 - Homo sapiens, 370 1..370 370/370 (100%) aa. [US2003045491-Al, 06-MAR-2003] 135 WO 2004/056961 PCT/US2003/034114 ABP54949 Human MAPKAP kinase 2 - Homo 1..370 370/370 (100%) 0.0 sapiens, 370 aa. [W0200268444-A1, 06- 1.370 370/370 (100%) SEP-2002] AAE29899 Human full length MAPKAP-2 kinase, 1..353 353/353 (100%) 0.0 fldnaMAPKAP-2 - Homo sapiens, 400 aa. 1.353 353/353 (100%) [W0200290524-A2, 14-NOV-2002] AAE29898 Human truncated MAPKAP-2 kinase, 5.353 349/349 (100%) 0.0 tdnaMAPKAP-2 - Homo sapiens, 396 aa. 1..349 349/349 (100%) [W0200290524-A2, 14-NOV-2002] ABR41296 Human DITHP intracellular signalling 53.370 317/318 (99%) 0.0 protein - Homo sapiens, 324 aa. 7..324 318/318 (99%) [W0200297031 -A2, 05-DEC-2002] 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 C8. Table C8. Public BLASTP Results for NOV3a ProteinNOV3a Identities/ Accession Protein/Organism/Length ResiduesT Similarities for Expect Number Match the Matched Value Residues Portion JC2204 MAPK-activated protein kinase (EC 2.7.1.- 1.370 370/370 (100%) 0.0 2 - human, 370 aa. 1..370 370/370 (100%) Q81YD6 Hypothetical protein - Homo sapiens 1..353 353/353 (100%) 0.0 (Human), 470 aa (fragment). 71..423 353/353 (100%) P49137 MAP kinase-activated protein kinase 2 (EC 1..353 353/353 (100%) 0.0 2.7.1.-) (MAPK-activated protein kinase 2) 1.353 353/353 (100%) (MAPKAP kinase 2) (MAPKAPK-2) Homo sapiens (Human), 400 aa.- S39793 I MAPK-activated protein kinase 2 (EC 5..353 346/349 (99%) 0.0 2.7.1.-) - human, 396 aa (fragment). 1..349 346/349 (99%) Q8OZF4 Mitogen-activated protein kinase-activated 1.353 326/353 (92%) 0.0 protein kinase-2 (EC 2.7.1.-) - Rattus 1..339 332/353 (93%) norvegicus (Rat), 386 aa. PFam analysis predicts that the NOV3a protein contains the domains shown in the Table C9. Table C9. Domain Analysis of NOV3a Identities/ Pfam Domain NOV3a Match Region Similarities Expect Value for the Matched Region pkinase 64..325 97/306 (32%) 7.3e-76 1_ I 200/306 (65%) Example C3. Expression Profile of the Human MAPKAP kinase 2 Gene The protocol for quantitative expression analysis is disclosed in Example Q9. 136 WO 2004/056961 PCT/US2003/034114 Expression of gene CG186525-01 was assessed using the primer-probe set Ag7320, described in Table C10. Results of the RTQ-PCR runs are shown in Tables Cl1, C12 and C13. Table 010. Probe Name Ag320 Prers Sequences Length Start Position]SEQ ID No (Forward]5'-agtgctgtttcttagaatccttttatc-3' 28 1522 111 Probe _TET-5'-cctgggtctctaatgggaccttaaagacc-3'-TAMRA 29 1550 112 Rers e 5'- gcaaaatgagaagatgataccagat-3' 25 1579 113 Table C11. General-screenng-panev1.7 Column A - Rel. Exp.(%) Ag7320, Run 318348880 Tissue Name A Tissue Name A (Adipose F 22.5 Gastric ca. (liver met.) NCI-N87 1.2 HUVEC 8.3 Stomach 0.8 IMelanorna* Hs688(A).T 10.0( Colon ca. SW-948 7.2 lMelanoma* Hs688(B).T 100.0 Colon ca. SW480 1.6 (M ela n om -a (met) SK-MEL--5 . (.....7-89Coon ca. (SW480 met) SW620 {14.1 Testis F2.1 Colon ca. HT29 28.7 Prostate ca. (bone met) PC-3 0.3 Colon ca. HCT-i 16 35.1 Prostate ol 20.6 Colon cancer tissue 1.2 caarianca..OVCr -A (Prostate pool { 1.4 lColon ca. SW1116 5.7 j~ter pool 0.8 lColon ca. Colo-205 8.1 erusca. OVCAR-3 I7.3 (Colon ca. SW-48 Ovarian ca. (ascites) SK-OV-3 2.3 (Colon . 6 (Ovarian ca. OVCAR-4 29.7 (Small Intestine 1.4 Ovarian ca. OVCAR-5 ( 25.5 (Fetal Heart 17.7 Ovarian ca. IGROV-1 42.0 (Heart 1.6 Ovarian ca. OVCAR-8 7.4 (Lymph Node Poo 2.2 Lynph Node pool 2 50.3 I(O vary.. ........ . ....... - , - ----... __ _- .... .O (L...mp.. . . ... (Breast ca. MCF-7 24.3 Fetal Skeletal Muscle 4.2 Breast ca. MDA-MB-231 96.6 Skeletal Muscle pool 3.4 BT 549 10.5 Skeletal Muscle .1 breast ca. T47D -21.8 5leen 9.9 (113452 mammary gland 0.0 (Thymus 7.9 Trachea 41.2 CNS cancer (glio/astro) SF-268 12.2 Luing ~ 6-N--- --. 4 cancer(gli oT (Fetal Lung T 58.6 CNS cancer (neuro;met) SK-N-AS ( 1.6 Lng ca. NC-417 1.0 NS cancer (astro) SF-539 (Lung ca. LX-1 4.4 (ONS cancer (astro) SNB-75 127. (L , 6a. . 0(... ga. NCl-H 146 27.2.. ........ CNScancer (glio) SNB-1916.0 (Lung ca. SHP-77 T17.4 CNS cancer (glio) SF-295 11.3 (Lung ca. NCI-H23 j 15.1 (Brain (Amygdala) 2 Lng cl I-460 15.8 Brain (Cerebellum) 12.4 Lung ca. HOP-62 21.6 Brain (Fetal) 0.4 ungc a-N-H5'22 _ 13. 7Brain (Hippocampus) 2.5 Lung ca. DMS-114 1.7 (Cerebral Cortex pool Liver f 2.0 (Brain (Substantia nigra) 1.0 (Fetal Liver 21.0 Brain (Thalamus) 1 .6 137 WO 2004/056961 PCT/US2003/034114 Kidney pool 18.4 Brain (Whole) 16. Fetal Kidney 1 .4 ]Spinal Cord 1.6 Renal ca. 786-0 26.8 IAdrenal Gland 132.1 Renal ca. ACHN 40.1 Salivary Gland 98 Renal ca. UO-31 f22.2 Thyroid 21.8 Renal ca. TK-10 37.9 Pancreatic ca. PANC-1 6.7 }Bladder ____ __ 38IPancreas poo I____ 3.1 Table C12. Human Metabolic Column A - Rel. Exp.(%) Ag7320, Run 322941549 Tissue Name A Tissue Name A 137857 psoas-AA.M.Diab.-hi-1 63.3 139523 pancreas-HI.M.Norm-hi-1 5.5 135760 psoas-HMD-hi-1 3.0 139520 pancreas-CC.M.Norm-hi-1 1. 1134827 psoas-CMD-hi-1 14.7 142744 pancreas-HI.M.Norm-med-1 0.8 137860 psoas-AA.M.Diab.- 15.51 39545 pancreas-AA.M.Norm-med-2 8.3 137834 psoas-CC.M.Diab.- 31.61139531 pancreas-AA.M.Norm-med-1 3.6 137828 psoas-CC.M.Diab.- 37.1137871 ancreas-CC.M.Norm-med-1 med-i 37__ 1 137871 ___pancreas___1.5 135763 psoas-HMD-med-1 17.3, 139541 pancreas-Hi.M.Norm-low-1 9.4 142740 psoas-AS.M.Diab-low- 11.1 139537 pancreas-CC.M.Norm-low-2 9.6 134834 psoas-AAMD-low-1 11.7139533 pancreas-CC.M.Norm-low-1 1.2 137850 psoas-AS.M.Norm.-hi- 45.1 137845 pancreas-AS.M.Norm-low-1 1.9 15 _________-1 1631353 135769 psoas-HMND-hi-1 16.3 143530 small intestine-AA.M.Diab-hi-1 3.1 135766 psoas-AAMND-hi-1 9.5 1143529 small intestine-CC.M.Diab-hi-1 142746 psoas-AA. M. Norm- 143538 small intestine-HI.M.Diab-med-1 5.3 med-1 3.1 1143531 small intestine-AA.M.Diab-med-1 126 med-2 137855 psoas-AA.M.Norm- 8.7 1143528 small intestine-CC.M.Diab-med-2 6.5 med-i____ _1__________________ 137844 psoas-CC.M.Norm- 4.9 143537 small intestine-HI.M.Diab-low-1 7.7 142742 psoas-CC.M.Norm- 5.6 143535 small intestine-AS.M.Diab-low-1 3.8 137873 psoas-AS. M. Norm- 6.1 143534 small intestine-AA.M.Diab-low-1 3. low-i ________________ low-1 ~ Nom. 114.71143544 small intestine-AS.M.omh- . 1377 psoas-CMND-low-i 4544"3 small intestine-HI. M. Norm-hi-i 19 137858 diaphragm- 40.1 143542 small intestine-CC.M. Norm-hi-1 2.9 AA.M.Diab.-hi-1 135772 diaphragm-AMD-hi-1 118.2 143539 small intestine-AA.M.Norm-hi-1 6.6 135761 diaphragm-HMD-hi-I j20.71*143548 small intestine-AA. M.Norm-med-23. 828 diaphragm-CMD-hi- 19.9 1143547 small intestine-AA.M.Norm-med- 2.9 138 WO 2004/056961 PCT/US2003/034114 137835 diaphragm- 30.4 143540 small intestine-CC.M.Norm-med-1 1.5 CC.M.Diab.-med-2 I _____________________ 135764 diaphragm-HMD-med- 24.1 143550 small intestine-CC.M.Norm-low-2 0.1 134835 diaphragm-AAMD-low- 2.9 143549 small intestine-CC.M.Norm-low-1 [11.3 142738 diaphragm- 11.1 143546 small intestine-HI.M.Norm-low-1 1.0 CC.M.Norm-hi-i __ __ 139517 diaphragm- 10.8 143525 hypothalamus-HI.M.Diab-hi-1 5.2 AS.M.Norm-hi-1 10. 143525 hy 5.. 137848 diaphragm-HI.M.Norm- 16.5 143515 hypothalamus-CC.M.Diab-hi-i 1.3 137843 diaphragm- 12.3 143513 hypothalamus-AA.M.Diab-hi-1 2.1 AA.M.Norm-hi-1 _____________________ 137879 diaphragm _______m_____ 19.6 143507 hypothalamus-AS.M.Diab-hi-1 1.9 137872 diaphragm- 17.4 143506 hypothalamus-CC.M.Diab-med-1 1.7 CC.M.Norm-med-1hpohlmsCM.ibmdij7 135773 diaphragm-HMND- 24.7 143505 hypothalamus-H M.Diab-med-1 11.7 med-i yohlmsH.MDa-e- 1. 139542 diaphragm-HI.M.Norm- 6. hypothalamus-AA.M.Diab-low-1 1.7 Si a 3.0 143508 hypothalamus-CC.M.Diab-low-1 1.4 3.M. N ram- 4.7 143503 hypothalamus-AS.M.Diab-low-1 1.3 AS.M.Norm-low-1 __ 1yohlau-S..ib-o 141340 subadipose- 4.5 143522 hypothalamus-HI.M.Norm-hi-1 0.5 137836 subQadipose- 0.2 143516 hypothalamus-AS.M.Norm-hi-1 0.8 I.M.Diabhi___ yp a m . 135771 subQadipose-AMD-hi- 1.8 143511 hypothalamus-CC.M.Norm-h-1 1.3 141329 subQadipose- 0.3 143504 hypothalamus-AA.M.Norm-hi-1 JAA. M. Diab-med-1 F 130 hIohlmsA..omh- . C3 DisubQadose- 0.6 143517 hypothalamus-AA.M.Norm-med-2 135762 subQadpose-HMD- 1.4 143514 hypothalamus-HI.M.Norm-med-1 1 m1433 sub~adipose-HD 1141338 subQadipose- 1.1 [143521 hypothalamus-AS.M.Norm-low-138 AS.M.Diab-low-1 139547 subOadipose- 2.8 143512 hypothalamus-CC.M.Norm-low-2 HI.M.Diab-low-1 1_1 135757 subQadipose-CMD- 1.1 145454 Patient-25pl (CC.Diab.no insulin) 18.3 low-1 i34832 subQadipose-AAMD- 171110916 7.7 low-1 I n 141332 subQadipose- 0.8 1 HI.M.Norm-hi-1 I 13 hptha Bu-SMNr4o1 135767 sub1adipose-CMND- Patient-17pl (8.7 hi- 5 subQadipose-AMND- I0.6 110908 Patient-17go 5 I.M Nom-i 1141339 subQadipose: 1 1100752 Patient-i 1Ssk 1. 139 WO 2004/056961 PCT/US2003/034114 HI.M.Norm-med-1 141334 subOadipose- 1.4197828 Patient-13pl 7.1 CC.M.Norm-med-1 139544 subQadipose- 1.3 160114 Patient 27-ut (CC. Diab.obese. insulin) 5.9 IAA.M.Norm-med-2 I __ ___ _9_________ 137875 subOadipose- 0.2 160113 Patient 27-p (CC.Diab.obese.insulin) 16.3 AA.M.Norm-med-1 .b . 1 331 subQadipose- 10.0 160112 Patient 27-sk (CC.Diab.obese.insulin) 7.9 AS.M.Norm-Iow-1 _____________________ ~137878 subQadipose- 10101 ain 7g C.Da~bs.isln . HI .M.Norm-low-1 1.101 ain 7g C.iboeeisln . 137876 subOadipose- 0.8 145461 Patient-26sk (CC.Diab.obese.insulin) 4.5 137859 vis.adipose- 0.2 145441 Patient-22sk (CC.Diab.insulin) 9.7 AA.M.Diab.-hi-1 135770 vis.adipose-AMD-hi-1 2.7 145438 Patient-22p (CC. Diab. insulin) 10.7 135759 vis.adipose-HMD-hi-1 10.0 145427 Patient-20p (CC. Diab.overwt. insulin) 23.3 143502 vis.adipose- 6.1 97503 Patient-12pl 1.6 CC.M. Diab-med-2II 139510 vis.adipose- 0.7 145443 Patient-23pl (CC.Non-diab.overwt) 8.3 AA.M.Diab-med-1 I1 1 C MDi b. ed-1 0.3 145435 Patient-21pi (CC.Non-diab.overwt) 11.0 137839 vis.adipose- 1.6 110921 Patient-19pl 6.1 IHI.M.Diab.-med-1 ........ at.... 6 139546 vis.adipose-Hl.M.Diab- -191 66o low-1 2 .2 110918 Patient-1g 6.6 137831 vis.adipose- 3.0 97481 Patient-08sk 3.4 ICC.M.Diab.-low-1________________________ 139522 vis.adipose- 0.8 97478 Patient-07pi 3.8 HI.M.Norm-hi-1 _____ ______________________ 139516 vis.adipose- 3.7 160117 Human Islets-male, obese 27.2 AS.M.Norm-hi-1_______________________ 37846 vis.adipose- 1.1 145474 PANCI (pancreas carcinoma) 1 35.8 137841 vis.adipose- 0.01154911 Capan2 (pancreas adenocarcinoma) 41.5 AA.M.Norm-hi-1 139543 vis.adipose 139543 visado- 5.8 141190 SW579 (thyroid carcinoma) 12.7 AA. M.aNorm-med-2 3932 visadipose 10.3 145489 SK-N-MC (neuroblastoma) 1 8.8 IAA.M.Norm-med-1______________________ .M.30 v.adipose- 0.6 145495 SK-N-SH (neuroblastoma) 1 30.8 139539 vis.adipose- 0.3 145498 U87 MG (glioblastoma) 2 100.0 IHI.M.Norm-low-1_______________________ CCM Norlose- 3.7 145484 HEp-2 (larynx carcinoma) 1 43.2 C5M Normo ose- 0.4 145479 A549 (lung carcinoma) 32.8 113576 M .dioe-AM - 11 135768 vis.adipose-AMND- 1.4 145488 A427 (lung carcinoma) 2 11.1 liver-C M1a-h- 1~ 1141327 . C0145472FHs 738Lu (normal ung)1 140 WO 2004/056961 PCT/US2003/034114 139514 liver-HI.M.Diab-hi-1 10.2 141187 SKW6.4 (B lymphocytes) 29.9 139526 liver-CC.M.Diab-med-2 1i5.6l 154644 IM-9 (immunoglobulin secreting lymphoblast) 39.5 139511 liver-AA.M.Diab-med-1 19.1 154645 MOLT-4 (acute lymphoblastic leukemia derived from peripheral blood) [I7840 liver-HI.M.Diab.-med-1 5.0 1154648 U-937 (histiocystic lymphoma) 81.8 137827 liver-CC.M.Diab.-med- 2.5 154647 Daudi (Burkitt's lymphoma) 6.2 Fifa 8iveriiiiI-iow 9 1454 4 SK-MEL-2 (melanoma) 2 56.3 135758 liver-CMD-low-1 17.2 141176 A375 (melanoma) 22.8 139519 liver-CC.M.Norm-hi-1 110.7 154642 SW 1353 (humerus chondrosarcoma) 39.0 139518 liver-AA.M.Norm-hi-1 13.1 141179 HT-1080 (fibrosarcoma) 25.9 ll 37849 liver-AS.M.Norm.-hi-1 26 1145491 MG-63 (osteosarcoma) I g8.9 1i37847 liver-HI.M.Norm -hi-1 2.0 1141186 MCF7 (breast carcinoma) 40.1 142741 liver-AA.M.Norm-med- 9.5 141193 T47D (breast carcinoma) 85.9 141341 liver-H.M.Norm-med-1 2.8 54641 -20 rest carcinoma 141335 liver-CC.M.Norm-med- 4.8 141175 293 (kidney transformed wth adenovrus5 DNA) 3.8 1 2 135560 IeI I.NIow 1 1 U8H2 NUihepatoma 1 24.3 139534 liver-CC.M.Norm-low-1 21.0 141184 HUH7 hepatoma 1 24.5 139521 liver-AS.M.Norm-low-i 110.9145478 HT1 376 (bladder carcinoma) -13. 141328 pancreas-CC.M.Diab- 5.3 145481 SCaBER (bladder carcinoma) 48.6 139525 pancreas-AS.M.Diab- 1 1141192 SW620 (lymph node metastatsis, colon 9.7 hi-i carcinoma) 2 137856 pancreas-AA.M.Diab.- 8.8 141180 HT29 (colon carcinoma) 1 38.2 137837 pancreas-HI.M.Diab.- 1.4 141188 SW480 (colon carcinoma) 1 28.1 hi-i 141337 pancreas-CC.M.Diab- 2.9 154646 CAOV-3 (ovary adenocarcinoma) 20.7 139527 pancreas-CC.M.Diab- 4.7 141194 HeLa (cervix carcinoma)- 2 25.2 Imed-i 194 139515 pancreas-HI.M.Diab- 10.2 145482 HeLa S3 (cervix carcinoma) 1 27.2 med-1 1 139512 pancreas-AA.M.Diab- 9.7 145486 DU145 (prostate carcinoma) 35.1 142739 pancreas-AS.M.Diab- 2.8 154643 PC-3 (prostate adenocarcinoma) 75.8 139513 pancreas-CC.M.Diab- 6.1 154649 HCT-8 (ileocecal adenocarcinoma) 34.2 142743 pancreas-AA.M.Norm- 1

.

7 Table C13. Panel 5 Islet Column A - Rel. Exp.(%) Ag7320, Run 317448630 Tissue Name A Tissue Name A 97457 Patient-02go adipose 6.6 94709 Donor 2 AM -A adipose 8.5 197476 Patient-07sk skeletal muscle 0.0 94710 Donor 2 AM - B adipose 6.4 974Patient-7ut uterus 8.2 94711 Donor 2AM- C adipose 1.7 141 WO 2004/056961 PCT/US2003/034114 97 Patient-07p placenta 8.7 94712 Donor 2 AD - A adipose 40.6 199167 BayerPatient 1 00.0o94713 Donor 2 AD - B adipose 36.9 197482 Patient-08ut uterus 0.0 194714 Donor 2 AD - C adipose 23.7 97483 Patient-08pl placenta 4.3 9C4742 Donor 3 U - A Mesenchymal Stem 141 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ells 97486 Patient-09sk skeletal muscle 23.8 C4 Donor 3 U - B Mesenchymal Stem 4.2 Cells 97487 Patient-09ut uterus 1.9 94730 Donor 3 AM - A adipose 126.4 97488 Patient-09pl placenta 5.1 94731 Donor 3 AM - B adipose 128.5 97492 Patient-I Out uterus 5.8 94732 Donor 3 AM - C adipose 23.3 97493 Patient-1 Opl placenta 15.7 94733 Donor 3 AD -A adipose 44.4 97495 Patient-11 go adipose 7.7 94734 Donor3AD-Badipose 36.3 97496 Patient- 11sk skeletal muscle 5.9 94735 Donor 3 AD - C adipose 1 8

.

9 97497 Patient-i1 ut uterus 9.4 17 713 8 ;Liver HepG2untreated 144.4 97498 Patient-i 1 pl placenta 4.9 73556 Heart Cardiac stromal cells (primary) 111.7 97500 Patient-1 2go adipose 11.5 81735 Small Intestine 126.6 97501 Patient-1 2sk skeletal muscle 60.7 72409 Kidney Proximal Convoluted Tubule 26.6 97502 Patient-12ut uterus 7.5 82685 Small intestine Duodenum 21.9 placenta 14.5 90650 Adrenal Adrenocortical adenoma 19.3 94721 Donor 2 U -A Mesenchymal Stem 23.2 72410 Kidney HRCE 48.6 'Cells 94722 Donor 2 U - B Mesenchymal Stem 15.9 72411 Kidney HRE 26.6 Cells [94723 Donor 2 U - C Mesenchymal Stem 170.7 73139 Uterus Uterine smooth muscle cells 8.2 Genra~sceeing..paneLvi.7 Summary: A72The highest expression of this gene was detected in a sample derived from melanoma skin (Hs688(B).T)(CT=27). This gene's expression was increased in 4 out of 4 breast cancer cell lines, as compared to a normal mammary tissue sample. This gene's expression was decreased in 9 out of 9 lung cancer cell lines, as compared to both adult and fetal normal lung tissue. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of lung cancer and breast cancer. Among tissues with metabolic or endocrine function, this gene is expressed at moderate to low levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Human Metabolic Summary: Ag7320 The highest expression of this gene was detected in the glioblastoma cell line U87 MG (CT=26). Among tissues with metabolic or endocrine function, this gene was expressed at moderate levels in skeletal muscle, liver pancreas, small intestine. Low expression was detected in adipose and hypothalamus. Panel 5 Islet Summary: Ag7320 The highest expression of this gene was detected in human pancreatic islet cells (Bayer Patient 1). This confirms our original finding that the MAPKAP kinase 2 gene is expressed in human pancreatic islet cells. The other tissues on this panel showed no significant expression. Example C4. Assays Screening for Modulators of MAPKAP Kinase 2 142 WO 2004/056961 PCT/US2003/034114 The following summarizes the biochemistry surrounding the human MAPKAP kinase 2 and potential assays that may be used to screen for antibody therapeutics or small molecule drugs to treat obesity and/or diabetes. Stress-activated p38 MAP kinase activates MAPKAP kinase 2 by phosphorylation. Following phosphorylation of MAPKAP kinase 2, nuclear p38 MAP kinase is exported to the cytoplasm in a complex with MAPKAP kinase 2. Activated MAPKAP kinase 2 has been shown to phosphorylate nuclear targets CREB/ATF1, serum response factor, and E2A protein E47 and cytoplasmic targets HSP25/27, LSP-1, Eipoxygenase, glycogen synthase, and tyrosine hydroxylase. The crystal structure of unphosphorylated MAPKAP kinase 2 including the kinase domain and the C-terminal regulatory domain has been determined at 2.8 A resolution [J Biol Chem Oct 4;277(40):37401 (2002)]. The above properties may be used to design potential screening assays for MAPKAP kinase 2. The MAPKAP kinase 2 gene is known to be expressed in the mouse beta-cell line MIN6 [J Biol Chem Aug 15;272(33):20936 (1997)]. In the same study, wortmannin and LY 294002, two structurally unrelated inhibitors of phosphatidylinositide (PI) 3-kinase, were shown to inhibit glucose (but not arsenite) stimulation of MAPKAP kinase 2 activity in isolated human islets of Langerhans and MIN6 cells. Additional assays for MAPKAP kinase 2 activity using a cell lysate have been described [Methods Mol Biol;124:121 (2001)]. Other cell lines that express MAPKAP kinase 2 can be obtained from the RTQ-PCR results shown in Table 2. These and other MAPKAP kinase 2 expressing cell lines could be used for screening purposes. Our results indicate that a modulator of MAPKAP kinase 2 activity, such as an inhibitor, activator, antagonist, or agonist of MAPKAP kinase 2 may be useful for treatment of such disorders as obesity, diabetes, and insulin resistance, as well as for enhancement of insulin secretion. D. NOV4-10 -- AMP-activated Protein Kinase AMP-activated Protein kinase (AMPK) is a heterotrimeric protein composed of a catalytic alpha subunit, a regulatory beta and a gamma subunit. There are two alpha, two beta and three gamma subunits known, each with different tissue distribution. AMPK serves as a metabolic sensor of cellular AMP levels. Activation of AMPK has been shown to positively influence metabolic processes in many tissues, for instance, it decreases adipose lipogenesis/lipolysis, increases liver fatty acid oxidation, and regulates the insulin secretion in pancreatic islets (Nature 415, 339-43 PMID: 11797013; Diabetes Technol. Ther. Autumn 2, 441 (2002); J Clin. Invest.108:1167 (2001)). However, the most pronounced consequences of AMPK activation have been observed in skeletal muscle. It has been demonstrated that activation of AMPK in skeletal muscle causes both an increase in fatty acid oxidation by inactivation of acetyl-CoA carboxylase as well as increase in glucose uptake by a mechanism independent of insulin. Muscle contractions lead to activation of AMPK. Recent data shows AMPK as a principal mediator of leptin signaling in skeletal muscle. AICAR, an agonist of AMPK, improves hyperglycemia in diabetic animal mainly by increasing utilization of glucose in skeletal muscle. In particular the invention relates to the use of AMP-activated Protein Kinase (AMPK) protein as a diagnostic and/or target for small molecule drugs and antibody therapeutics. AMPK is a 143 WO 2004/056961 PCT/US2003/034114 heterotrimeric protein composed of a catalytic alpha subunit, a regulatory beta and a gamma subunit. There are two alpha, two beta and three gamma subunits known. The inventors have discovered that each subunit has its own unique different tissue distribution. The alpha 2 catalytic subunit encoded by CG186855-01 is highly expressed in skeletal muscle, a tissue where the most pronounced consequences of AMPK activation are observed. Furthermore, the inventors have discovered the upregulation of the beta 2 subunit encoded by CG186873-01 in glycolytic diabetic muscle taken from diabetic animals after treatment with AICAR, an agonist of AMPK. Further investigation by the inventors revealed that the beta 2 and a gamma 3 are subunits enriched in skeletal muscle and preferentially associated with alpha 2 encoded by CG1 86913-01. In a particular embodiment of the invention, AMPK alpha 2, beta 2, and gamma 3 are each targets for screening. In another embodiment of the invention, the heterotrimeric protein composed of alpha 2, beta 2 and gamma 3 subunits is the target for screening. As such the current invention embodies the use of recombinantly expressed and/or endogenously expressed protein in various screens to identify AMPK agonist therapeutic antibodies and/or therapeutic small molecules beneficial in the treatment of diabetes. Not to be limited by a particular mechanism of action, the inventors nevertheless have discovered that activation of AMPK has beneficial effects for treating diabetes by acting in many metabolic tissues, including adipose, liver and skeletal muscle. Specifically, in skeletal muscle AMPK activation leads to increase in glucose uptake and fatty acid oxidation that modulates hyperglycemia and insulin sensitivity in diabetes. The finding that treatment with anti-diabetic drugs causes up regulation of the beta 2 subunit in skeletal muscle, indicating the positive role of AMP-activated kinase in peripheral metabolism. Therefore an agonist of AMP-activated kinase is useful for the treatment of diabetes. Example D1. Rat Insulin Sensitivity Study ZDF rats or their lean littermates were treated with a variety of agents that are known to alter insulin sensitivity. Metformin, vanadate, and AICAR enhance tissue response to insulin, while the free fatty acids generated by Liposyn (intravenous lipid infusion) treatment reduces the response. A variety of tissues were harvested, including gastrocnemius and soleus muscles, liver, retroperitoneal and epididymal WAT, and IBAT. The protocol of Rat Insulin Sensitivity Study is disclosed in Example Q3. A fragment of the rat AMP-activated Protein Kinase Beta 2 gene (shown in Table D1) was found to be up-regulated 2.2 fold in comparisons of gastrocnemius (glycolytic) vs. soleus (oxidative) diabetic skeletal muscle after AICAR treatment using GeneCalling TM method of differential gene expression (described in Example 07). AICAR is a known anti-diabetic drug that improves glucose uptake and utilization in skeletal muscle. A differentially expressed rat gene fragment migrating at approximately 70 nucleotides in length was definitively identified as a component of the rat AMP activated Protein Kinase Beta 2 cDNA. The method of competitive PCR was used for confirmation of the gene assessment. The electropherographic peaks corresponding to the gene fragment of the rat AMP-activated Protein Kinase Beta 2 were ablated when a gene-specific primer (shown in Table D1) competes with primers in the linker-adaptors during the PCR amplification. The peaks at 70 nt in 144 WO 2004/056961 PCT/US2003/034114 length were ablated in the samples from both the gastrocnemius and soleus rat diabetic skeletal muscle. Table D1. The direct sequence of the 64 nucleotide-long gene fragment and the gene-specific primers used for competitive PCR are indicated on the cDNA sequence of rat AMP-activated Protein Kinase Beta 2 and are shown below in bold (fragment from 1354 to 1417 in bold. band size: 64). The gene-specific primers at the 5' and 3' ends of the fragment are underlined. Gene length is 1760, only region from 873 to 1760 is shown (SEQ ID NO:114) 873 TTGCCTTTGA ACTGAGCTGG CCTCCTCTGA GCCTGGCAGG CTGTTTGTTT TGAGGCTGAT 933 GTGTGTGTCA GAGCCTCTGG TAGGAGCTCT GCTTTGCCTT TGATTGCAGA CGAGAGCTTT 993 ATGAGTTCAT GGAGTTTATT TTAAGAAACA CAAAACCATA TATATGCATA TGAGAGGAAG 1053 GTTACCAGAA GCCTCCTGGC CCAGCTGTCC ACACTCTCTC TGCCTGTGGG TAGTTGCCAG 1113 GGCCTGACTG GGAAGCTGTG GCTGCAGGAA TGGGTGTACC GGAAGCTTCT TTTTCTAAAG 1173 TGAGAGAATA GCAAACTCTT AGGATCCTTG TTGGGCAGAG GTCCTGGACC ACTGGTGTCC 1233 AAGGGTCAGA GTGTGCCAGG CCACTGCCCT ACTTAGAGCT GCCTCGTGCG GGTGGCTTTC 1293 CTTGCATGGG TTGATTCTGT ATCCCACACT GTGTGACACA ATCCACCGTG GTTTATATGG 1353 CACTAGTTGC TCCACAAGAA CCCTCCTCAT TTTATGTACC CTGTGGAATG ACTTCCCTCA 1413 GATCTCATAC ATGACCCAGT AATGCAAAAC TCACTGGGCG AGGAACCCTT TTGAAGAGTT 1473 TGTGGGATGA GCCTCACCTT AGAGCCTGAG GTGCCAGGGT CTCCTTTTTA GCTCAGTGAA 1533 GGCCTAACCC TGTGTGTTGC AGTTTACTTT AACATCTAGA GAAAAGAAAT GCACACCGTT 1593 GTGTCTCGGT TGGTCCTGTG TATTGGCTGT GTGGGCCTGT CTCCGGTTTT CTTTATCAGA 1653 GCACTCAGCT TGTAGGCAGG CTTGCACTTA GGGAAACCTT CCATATCTTT CATCCCTGAA 1713 AGTTTTTTTA TGTGCCTACA TTTTTCTTTA ATTAAAAAAA AAAAAAAA Example D2: Human AMP-activated Protein kinase Sequence Identification The sequence of Human AMP-activated Protein kinase was 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, were 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 protocol for identification of human sequence(s) is disclosed in Example Q8. An alignment (ClustalW) of the protein sequences of the human (CG186855-01) and rat homolog of AMPKA2 (alpha 2) is shown in Table D2. Table D3 shows amino acid sequence of rat homolog of AMPKA2 (alpha 2). Table D2. An alignment (ClustalW) of the protein sequences of the human (CG186855-01; SEQ ID NO:54 and rat homolo of AMPKA2 (alpha 2) (SEQ iD NO:115). 145 WO 2004/056961 PCT/US2003/034114 PRKAA2-rat 1 Iv1AELEL 60 CG186855-01 1 IvAE K v K 60 PRKAA2-mt 61 120 C0186855-01 61 120 PRKAA2-rat 121 QMiAKADLMSGFLIISC SPN 180 C0186855-01 121 QQNIE Iv IfGLNMDGFRhCGSPN 180 PRKAA2-mt 181 240 C0186855-01 181 240 PRKAA2-mt 241 ElATLHQ lfhEEWFKQDL fh 300 CG186855-01 241 V AhMQWDP LRAThIKDIH!E LP FEDPS YANVIDEANiV EE 300 PRKAA2-mt 301 E NTSEMNR IMAE S MDIM 360 CG186855-01 301 TS MN Y DP QAAH D D I 360 PRKAA2-rat 361 420 C0186855-01 361 420 PRKAA2-mt 421 R A MQD 480 C0186855-01 421 480 PRKAA2-mt 481 540 C0186855-01 481 540 PRKAA2-mt 541 552 C0186855-01 541 552 Table D3. amino acid sequence of rat homolog of AMPKA2 (alpha 2). Rat AMPKA2 (alpha 2) (SEQ ID NO: 115) MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHOLTGHKVAVKILNRQKIRSLDVVGKIKREQNLKL FRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEVEARRLFQQILSAVDYCHRHMVVHRDL KPENVLLDAQMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDWSCGVILYALLCG TLPFDDEHVPTLFKKIRGGVFYIPEYLNRSIATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPED PSYDANVIDDEAVKEVCEKFECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPTGS FMDDMAMHIPPGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKPYDIMAEVY RAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQRSGSSTPQRSC SAAGLHRPRSSVDSSTAENHSLSGSLTGSLTGSTLSSASPRLGSHTMDFFEMCASLITALAR NOV4 - AMPK alpha 1 The laboratory cloning was performed using one or more of the methods summarized in Example 08. The NOV4 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table D4. Table D4. NOV4 Sequence Analysis NOV4a, CG91 149-01 SEQ ID NO: 47 1863 bp DNA Sequence ORF Start: ATG at 24 ORF Stop: TAA at 1674 GCAGACTCAGTTCCTGGAGAAAGATGGCGACAGCCGAGAAGCAGAAACACGACGGGCGGGTGAAGATC GGCCACTACATTCTGGGTGACACGCTGGGGGTCGGCACCTTCGGCAAAGTGAAGGTTGGCAAACATGA ATTGACTGGGCATAAAGTAGCTGTGAAGATACTCAATCGACAGAAGATTCGGAGCCTTGATGTGGTAG GAAAAATCCGCAGAGAAATTCAGAACCTCAAGCT1TTCAGGCATCCTCATATAATTAAACTGTACCAG GTCATCAGTACACCATCTGATATTTTCATGGTGATGGAATATGTCTCAGGAGGAGAGCTATTTGATTA TATCTGTAAGAATGGAAGGCTGGATGAAAAAGAAAGTCGGCGTCTGTTCCAACAGATCCTTTCTGGTG TGGATTATTGTCACAGGCATATGGTGGTCCATAGAGATTTGAAACCTGAAAATGTCCTGCTTGATGCA CACATGAATGCAAAGATAGCTGATITIGGTCTTTCAAACATGATGTCAGATGGTGAA I I I I I AAGAAC AAGTTGTGGCTCACCCAACTATGCTGCACCAGAAGTAATTTCAGGAAGATTGTATGCAGGCCCAGAGG 146 WO2004/056961 PCT/US2003/034114 TAGATATATGGAGCAGTGGGGTTATTCTCTATGCTTTATTATGTGGAACCCTTCCATTTGATGATGAC CATGTGCCAACTCTTTTTAAGAAGATATGTGATGGGATCTTCTATACCCCTCAATATTTAAATCCTTC TGTGATTAGCCTTTTGAAACATATGCTGCAGGTGGATCCCATGAAGAGGGCCTCAATCAAAGATATCA GGGAACATGAATGGTTTAAACAGGACCTTCCAAAATATCTCTTTCCTGAGGATCCATCATATAGTTCA ACCATGATTGATGATGAAGCCTTAAAAGAAGTATGTGAAAAGTTTGAGTGCTCAGAAGAGGAAGTTCT CAGCTGTCTTTACAACAGAAATCACCAGGATCCTTTGGCAGTTGCCTACCATCTCATAATAGATAACA GGAGAATAATGAATGAAGCCAAAGATCTATTTGGCGACAAGCCCACCTGATTCTTTTCTTGATGAT CATCACCTGACTCGGCCCCATCCTGAAAGAGTACCATTCTTGGTTGCTGAAACACCAAGGGCACGCCA TACCCTTGATGAATTAAATCCACAGAAATCCAAACACCAAGGTGTAAGGAAAGCAAAATGGCATTTAG GAATTAGAAGTCAAAGTCGACCAAATGATATTATGGCAGAAGTATGTAGAGCAATCAAACAATTGGAT TATGAATGGAAGGTTGTAAACCCATATTATTTGCGTGTACGAAGGAAGAATCCTGTGACAAGCACTTA CTCCAAAATGAGTCTACAGTTATACCAAGTGGATAGTAGAACTTATCTACTGGATTTCCGTAGTATTG ATGATGAAATTACAGAAGCCAAATCAGGGACTGCTACTCCACAGAGATCGGGATCAGTTAGCAACTAT CGATCTTGCCAAAGGAGTGATTCAGATGCTGAGGCTCAAGGAAAATCCTCAGAAGTTTCTCTTACCTC ATCTGTGACCTCACTTGACTCTTCTCCTGTTGACCTAACTCCAAGACCTGGAAGTCACACAATAGAAT 1TITTGAGATGTGTGCAAATCTAATTAAAATTCTTGCACAATAAACAGAAAACTTTGCTTATTTCTTT TGCAGCAATAAGCATGCATAATAAGTCACAGCCAAATGCTTCCATTTGTAATCAAGTTATACATAATT ATAACCGAGGGCTGGCGTTTTGGAATCGAATTTCGACAGGGATTGGAACATGATTTATAGTTAAAAGC CTAATATCGAGAAATGAATTAAGATCA NOV4a, CG91149-01 SEQ ID NO: 48 1550 aa MW at 62793.OkD Protein Sequence MATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNRQKIRSLDVVGKIRREIQ NLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNGRLDEKESRRLFQQILSGVDYCHRHM VVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGV ILYALLCGTLPFDDDHVPTLFKKICDGIFYTPQYLNPSVISLLKHMLQVDPMKRASIKDIREHEWFKQ DLPKYLFPEDPSYSSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIDNRRIMNEAK DFYLATSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQSRP NDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDFRSIDDEITEAK SGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVDLTPRPGSHTIEFFEMCANL IKILAQ fNOV4b, CG91149-02 SEQ ID NO: 49 11863 bp DNA Sequence O t at24 F Stop: TAA at 1674 GCAGACTCAGTTCCTGGAGAAAGATGGCGACAGCCGAGAAGCAGAAACACGACGGGCGGGTGAAGATC GGCCACTACATrCTGGGTGACACGCTGGGGGTCGGCACCTTCGGCAAAGTGAAGGTTGGCAAACATGA ATTGACTGGGCATAAAGTAGCTGTGAAGATACTCAATCGACAGAAGATTCGGAGCCTTGATGTGGTAG GAAAAATCCGCAGAGAAATTCAGAACCTCAAGCTTTTCAGGCATCCTCATATAATTAAACTGTACCAG GTCATCAGTACACCATCTGATATTTTCATGGTGATGGAATATGTCTCAGGAGGAGAGCTATTTGATTA TATCTGTAAGAATGGAAGGCTGGATGAAAAAGAAAGTCGGCGTCTGTTCCAACAGATCCTTTCTGGTG TGGATTATTGTCACAGGCATATGGTGGTCCATAGAGATTTGAAACCTGAAAATGTCCTGCTTGATGCA CACATGAATGCAAAGATAGCTGATTTTGGTCTTTCAAACATGATGTCAGATGGTGAA1T1 1AAGAAC AAGTTGTGGCTCACCCAACTATGCTGCACCAGAAGTAATTTCAGGAAGATTGTATGCAGGCCCAGAGG TAGATATATGGAGCAGTGGGGTTATTCTCTATGCTTTATTATGTGGAACCCTTCCATTTGATGATGAC CATGTGCCAACTCTTT-rAAGAAGATATGTGATGGGATCTTCTATACCCCTCAATATTTAAATCCTTC TGTGATTAGCCTTGAAACATATGCTGCAGGTGGATCCCATGAAGAGGGCCTCAATCAAAGATATCA GGGAACATGAATGGTTTAAACAGGACCTTCCAAAATATCTCTTTCCTGAGGATCCATCATATAGTTCA ACCATGATTGATGATGAAGCCTTAAAAGAAGTATGTGAAAAGTTTGAGTGCTCAGAAGAGGAAGTTCT CAGCTGTCTTTACAACAGAAATCACCAGGATCCTTTGGCAGTTGCCTACCATCTCATAATAGATAACA GGAGAATAATGAATGAAGCCAAAGATTTCTATTTGGCGACAAGCCCACCTGATTCTTTTCTTGATGAT CATCACCTGACTCGGCCCCATCCTGAAAGAGTACCATTCTTGGTTGCTGAAACACCAAGGGCACGCCA TACCCTTGATGAATTAAATCCACAGAAATCCAAACACCAAGGTGTAAGGAAAGCAAAATGGCATTTAG GAATTAGAAGTCAAAGTCGACCAAATGATATTATGGCAGAAGTATGTAGAGCAATCAAACAATTGGAT TATGAATGGAAGGTTGTAAACCCATATTATTTGCGTGTACGAAGGAAGAATCCTGTGACAAGCACTTA CTCCAAAATGAGTCTACAGTTATACCAAGTGGATAGTAGAACTTATCTACTGGATTTCCGTAGTATTG ATGATGAAATTACAGAAGCCAAATCAGGGACTGCTACTCCACAGAGATCGGGATCAGTTAGCAACTAT CGATCTTGCCAAAGGAGTGATTCAGATGCTGAGGCTCAAGGAAAATCCTCAGAAGTTTCTCTTACCTC ATCTGTGACCTCACTTGACTCTTCTCCTGTTGACCTAACTCCAAGACCTGGAAGTCACACAATAGAAT 111TTGAGATGTGTGCAAATCTAATTAAAATTCTTGCACAATAAACAGAAAACTTTGCTTATTTCTTT TGCAGCAATAAGCATGCATAATAAGTCACAGCCAAATGCTTCCATTTGTAATCAAGTTATACATAATT 147 WO 2004/056961 PCT/US2003/034114 ATAACCGAGGGCTGGCGTTTTGGAATCGAATTTCGACAGGGATTGGAACATGATTTATAGTTAAAAGC CTAATATCGAGAAATGAATTAAGATCA NOV4b, CG91149-02 [SEQ ID NO: 50 550 aa MW at 62793.OkD Protein Sequence MATAEKQKHDGRVKlGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNRQKIRSLDVVGKIRREIQ NLKLFRHPHIIKLYQVISTPSDI FMVMEYVSGGELFDYICKNGRLDEKESRRLFQQILSGVDYCHRHM VVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGV ILYALLCGTLPFDDDHVPTLFKKICDGIFYTPQYLNPSVISLLKHMLQVDPMKRASIKDIREHEWFKQ DLPKYLFPEDPSYSSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAK DFYLATSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQSRP NDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDFRSIDDEITEAK SGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVDLTPRPGSHTIEFFEMCANL IKILAQ NOV4c, CG91 149-03 -1.S.EQ .. 0 ID NO: 51 f 908 bp........-........-.............. DNA Sequence OI-lrlAr O-io ~tii [ORF Start:nAe at 24 RF Stp: TAA at 1719 GCAGACTCAGTTCCTGGAGAAAGATGGCGACAGCCGAGAAGCAGAAACACGACGGGCGGGTGAAGATC GGCCACTACATTCTGGGTGACACGCTGGGGGTCGGCACCTTCGGCAAAGTGAAGGTTGGCAAACATGA ATTGACTGGGCATAAAGTAGCTGTGAAGATACTCAATCGACAGAAGATTCGGAGCCTTGATGTGGTAG GAAAAATCCGCAGAGAAATTCAGAACCTCAAGCTTTTCAGGCATCCTCATATAATTAAACTGTACCAG GTCATCAGTACACCATCTGATATTTTCATGGTGATGGAATATGTCTCAGGAGGAGAGCTATTTGATTA TATCTGTAAGAATGGAAGGAAATCTGATGTACCTGGAGTAGTAAAAACAGGCTCCACGAAGGAGCTGG ATGAAAAAGAAAGTCGGCGTCTGTTCCAACAGATCCTTTCTGGTGTGGATTATTGTCACAGGCATATG GTGGTCCATAGAGATTTGAAACCTGAAAATGTCCTGCTTGATGCACACATGAATGCAAAGATAGCTGA TTTTGGTCTTTCAAACATGATGTCAGATGGTGAA111T1AAGAACAAGTTGTGGCTCACCCAACTATG CTGCACCAGAAGTAATTTCAGGAAGATTGTATGCAGGCCCAGAGGTAGATATATGGAGCAGTGGGGTT ATTCTCTATGCTTTATTATGTGGAACCCTTCCATTTGATGATGACCATGTGCCAACTCTl1TTAAGAA GATATGTGATGGGATCTTCTATACCCCTCAATATTTAAATCCTTCTGTGATTAGCCTTTTGAAACATA TGCTGCAGGTGGATCCCATGAAGAGGGCCTCAATCAAAGATATCAGGGAACATGAATGGTTTAAACAG GACCTTCCAAAATATCTCTTTCCTGAGGATCCATCATATAGTTCAACCATGATTGATGATGAAGCCTT AAAAGAAGTATGTGAAAAGTTTGAGTGCTCAGAAGAGGAAGTTCTCAGCTGTCTTTACAACAGAAATC ACCAGGATCCTTTGGCAGTTGCCTACCATCTCATAATAGATAACAGGAGAATAATGAATGAAGCCAAA GATTTCTATTTGGCGACAAGCCCACCTGATTCTTTTCTTGATGATCATCACCTGACTCGGCCCCATCC TGAAAGAGTACCATTCTTGGTTGCTGAAACACCAAGGGCACGCCATACCCTTGATGAATTAAATCCAC AGAAATCCAAACACCAAGGTGTAAGGAAAGCAAAATGGCATTTAGGAATTAGAAGTCAAAGTCGACCA AATGATATTATGGCAGAAGTATGTAGAGCAATCAAACAATTGGATTATGAATGGAAGGTTGTAAACCC ATATTATTTGCGTGTACGAAGGAAGAATCCTGTGACAAGCACTTACTCCAAAATGAGTCTACAGTTAT ACCAAGTGGATAGTAGAACTTATCTACTGGATTTCCGTAGTATTGATGATGAAATTACAGAAGCCAAA TCAGGGACTGCTACTCCACAGAGATCGGGATCAGTTAGCAACTATCGATCTTGCCAAAGGAGTGATTC AGATGCTGAGGCTCAAGGAAAATCCTCAGAAGTTTCTCTTACCTCATCTGTGACCTCACTTGACTCTT CTCCTGTTGACCTAACTCCAAGACCTGGAAGTCACACAATAGAATT1TGAGATGTGTGCAAATCTA ATTAAAATTCTTGCACAATAAACAGAAAACTTTGCTTATTTCTTGCAGCAATAAGCATGCATAATA AGTCACAGCCAAATGCTTCCATTTGTAATCAAGTTATACATAATTATAACCGAGGGCTGGCGTTTTGG AATCGAATTTCGACAGGGATTGGAACATGATTTATAGTTAAAAGCCTAATATCGAGAAATGAATTAAG ATCA NOV4c, CG91149-03 SEQ ID NO: 52 565 aa MW at 64306.7kD Protein Sequence MATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILN RQKIRSLDVVGKIRREIQ NLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNGRKSDVPGVVKTGSTKELDEKESRRL FQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISG RLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLFKKICDGIFYTPQYLNPSVISLLKHMLQVDPMK RASIKDIREHEWFKQDLPKYLFPEDPSYSSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVA YHLIIDNRRIMNEAKDFYLATSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGV RKAKWHLGIRSQSRPNDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTY LLDFRSIDDEITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVDLTPR PGSHTIEFFEMCANLIKILAQ A ClustaiW comparison of the above protein sequences yields the following sequence alignment shown in Table D5. 148 WO 2004/056961 PCT/US2003/034114 Table D5. Comparison of the NOV4 protein sequences. NOV4a MATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNRQKIRSLDVV NOV4b MATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNRQKIRSLDVV NOV4c MATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNRQKIRSLDVV NOV4a GKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNGR------- NOV4b GKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNGR

-------

NOV4c GKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNGRKSDVPGVV NOV4a ------- LDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNM NOV4b -------- LDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNM NOV4c KTGSTKELDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNM NOV4a MSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLF NOV4b MSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLF NOV4c MSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLF NOV4a KKICDGIFYTPQYLNPSVISLLKHMLQVDPMKRASIKDIREHEWFKQDLPKYLFPEDPSY NOV4b KKICDGIFYTPQYLNPSVISLLKHMLQVDPMKRASIKDIREHEWFKQDLPKYLFPEDPSY NOV4c KKICDGIFYTPQYLNPSVISLLKHMLQVDPMKRASIKDIREHEWFKQDLPKYLFPEDPSY NOV4a SSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLA NOV4b SSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLA NOV4c SSTMIDDEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLA NOV4a TSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQ NOV4b TSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQ NOV4c TSPPDSFLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQ NOV4a SRPNDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDF NOV4b SRPNDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDF NOV4c SRPNDIMAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDF NOV4a RSIDDEITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVD NOV4b RSIDDEITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVD NOV4c RSIDDEITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVD NOV4a LTPRPGSHTIEFFEMCANLIKILAQ NOV4b LTPRPGSHTIEFFEMCANLIKILAQ NOV4c LTPRPGSHTIEFFEMCANLIKILAQ NOV4a (SEQ ID NO: 48) NOV4b (SEQ ID NO: 50) NOV4c (SEQ ID NO: 52) Further analysis of the NOV4a protein yielded the following properties shown in Table D6. Table D6. Protein Sequence Properties NOV4a SignalP analysis: No Known Signal Sequence Predicted PSORT 11 analysis: PSG: a new signal peptide prediction method N-region: length 10; pos.chg 2; neg.chg 2 H-region: length 1; peak value -8.94 PSG score: -13.34 GvH: von Heijne's method for signal seq. recognition 149 WO 2004/056961 PCT/US2003/034114 GvH score (threshold: -2.1): -7.87 possible cleavage site: between 30 and 31 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 0.58 (at 199) ALOM score: 0.58 (number of TMSs: 0) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 1.32 Hyd Moment(95): 1.79 G content: 0 D/E content: 2 S/T content: 1 Score: -7.91 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 13.1% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: KKXX-Iike motif in the C-terminus: KILA SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none 150 WO 2004/056961 PCT/US2003/034114 checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 55.5 COIL: Lupas's, algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 65.2 %: nuclear 17.4 %: mitochondrial 13.0 %: cytoplasmic 4.3 %: peroxisomal >> prediction for CG91149-01 is nuc (k=23) 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 D7. Table D7. Geneseq Results for NOV4a NOV4a Identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region AAR64312 Rat liver adenosine monophosphate 4..550 416/553 (75%) 0.0 protein kinase - Rattus rattus, 552 aa. 2..552 475/553 (85%) [W09428116-Al, 08-DEC-1994] I I AAW29894 Mammalian AMPK-alpha1 subunit active 4..349 343/346 (99%) 0.0 peptide 1 - Mammalia, 345 aa. 2..345 344/346 (99%) [W09725341-Al, 17-JUL-1997) 603 Drosophila melanogaster polypeptide SEQ 13..550 338/590 (57%) e-178 ID NO 5601 - Drosophila melanogaster, 23..582 407/590 (68%) 582 aa. [W0200171042-A2, 27-SEP-2001] AAW29899 Mammalian AMPK-alphal subunit active 16..272 256/257 (99%) e-150 peptide 6 - Mammalia, 257 aa. 1..257 257/257 (99%) [W09725341-Al, 17-JUL-1997] ABR40709 Zea mays oil trait related protein sequence 18..437 227/427 (53%) e-124 SEQ ID NO:238 - Zea mays, 579 aa. 90..501 305/427 (71%) [W02003002751 -A2, 09-JAN-2003] I 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 D8. Table D8. Public BLASTP Results for NOV4a Protein NOV4a Identities/ Accesion Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion Q13131 5'-AMP-activated protein kinase, catalytic 1..550 550/550 (100%) 0.0 151 WO 2004/056961 PCT/US2003/034114 alpha-1 chain (EC 2.7.1.-) (AMPK alpha- 1..550 550/550 (100%) 1 chain) - Homo sapiens (Human), 550 aa. AAH37303 Protein kinase, AMP-activated, alpha 1 1..550 549/550 (99%) 0.0 catalytic subunit - Homo sapiens 1..550 550/550 (99%) (Human), 550 aa. Q86VS1 PRKAA1 protein - Homo sapiens 1..550 548/565 (96%) 0.0 (Human), 574 aa. 10..574 550/565 (96%) P54645 5'-AMP-activated protein kinase, catalytic 4..550 541/547 (98%) 0.0 alpha-1 chain (EC 2.7.1.-) (AMPK alpha- 2..548 545/547 (98%) 1 chain) - Rattus norvegicus (Rat), 548 aa. Q8UVW8 SNF1-like protein AMPK - Xenopus 4..550 491/550 (89%) 0.0 laevis (African clawed frog), 560 aa. 12..560_I 523/550 (94%) PFam analysis predicts that the NOV4a protein contains the domains shown in the Table D9. Table D9. Domain Analysis of NOV4a Identities/ Pfan Domain NOV4a Match Region Similarities Expect Value for the Matched Region pkinase 18..270 117/299 (39%) 8.6e-96 203/299 (68%) 8.6e-96 NOV5 - AMPK alpha 2 The laboratory cloning was performed using one or more of the methods summarized in Example Q8. The NOV5 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table D1 0. Table D1O. NOV5 Sequence Analysis N'OV5a, CG186855-01 SEQ ID NO: 53 2361 bp DNA Sequence !ORF Start: ATG at 65 ORF Stop: TGA at 1721 GGTAGCGGCGGCGGCGGCGGCTAGCGGAGCGGCAGGCGGTGGAGCGAGGCCGCGCGCGCCGAAGATGG CTGAGAAGCAGAAGCACGACGGGCGGGTGAAGATCGGACACTACGTGCTGGGCGACACGCTGGGCGTC GGCACCTTCGGCAAAGTGAAGATTGGAGAACATCAATTAACAGGCCATAAAGTGGCAGTTAAAATCTT AAATAGACAGAAGATTCGCAGTTTAGATGTTGTTGGAAAAATAAAACGAGAAATTCAAAATCTAAAAC TCTTTCGTCATCCTCATATTATCAAACTATACCAGGTGATCAGCACTCCAACAGA I I I I I I I ATGGTA ATGGAATATGTGTCTGGAGGTGAATTATTTGACTACATCTGTAAGCATGGACGGGTTGAAGAGATGGA AGCCAGGCGGCTCTTTCAGCAGATTCTGTCTGCTGTGGATTACTGTCATAGGCATATGGTTGTTCATC GAGACCTGAAACCAGAGAATGTCCTGTTGGATGCACACATGAATGCCAAGATAGCCGATTTCGGATTA TCTAATATGATGTCAGATGGTGAATTTCTGAGAACTAGTTGCGGATCTCCAAATTATACAGCACCTGA AGTCATCTCAGGCAGATTGTATGCAGGTCCTGAAGTTGATATCTGGAGCTGTGGTGTTATCTTGTATG CTCTTCTTTGTGGCACCCTCCCATTTGATGATGAGCATGTACCTACGTTATTTAAGAAGATCCGAGGG GGTGTCTTTTATATCCCAGAATATCTCAATCGTTCTGTCGCCACTCTCCTGATGCATATGCTGCAGGT TGACCCACTGAAACGAGCAACTATCAAAGACATAAGAGAGCATGAATGGTTTAAACAAGGTTTGCCCA GTTACTTATTTCCTGAAGACCCTTCCTATGATGCTAACGTCATTGATGATGAGGCTGTGAAAGAAGTG TGTGAAAAATTTGAATGTACAGAATCAGAAGTAATGAACAGTTTATATAGTGGTGACCCTCAAGACCA GCTTGCAGTGGCTTATCATCTTATCATTGACAATCGGAGAATAATGAACCAAGCCAGTGAGTTCTACC TCGCCTCTAGTCCTCCATCTGGTTCTTTTATGGATGATAGTGCCATGCATATTCCCCCAGGCCTGAAA CCTCATCCAGAAAGGATGCCACCTCTTATAGCAGACAGCCCCAAAGCAAGATGTCCATTGGATGCACT GAATACGACTAAGCCCAAATCTTTAGCTGTGAAAAAAGCCAAGTGGCGTCAAGGAATCCGAAGTCAGA 152 WO 2004/056961 PCT/US2003/034114 GCAAACCGTATGACATTATGGCTGAAGTTTACCGAGCTATGAAGCAGCTGGATTTTGAATGGAAGGTA GTGAATGCATACCATCTTCGTGTAAGAAGAAAAAATCCAGTGACTGGCAATTACGTGAAAATGAGCTT ACAACTTTACCTGGTTGATAACAGGAGCTATCTTTTGGACTTTAAAAGCATTGATGATGAAGTAGTGG AGCAGAGATCTGGTTCCTCAACACCTCAGCGTTCCTGTTCTGCTGCTGGCTTACACAGACCAAGATCA AGTTTTGATTCCACAACTGCAGAGAGCCATTCACTTTCTGGCTCTCTCACTGGCTCTTTGACCGGAAG CACATTGTCTTCAGTTTCACCTCGCCTGGGCAGTCACACCATGGAT111 GAAATGTGTGCCAGTC TGATTACTACTTTAGCCCGTTGATCTGTCTCTAGTTTCTTTCTGTTATTGCACTATGAAAATCAGTTA TATTCTTTAAATTTTTATCTTACTTTTGGATAATATCCACTGCAATACTAATTGAGAAACATGAATTA TTTOCAGGGGCACACAATGCTATTGAAATTACTGAAAACAAAATATCTGACATCTTATTTACTTGTAG AAATCTGTAATTCTATTGTGCCTATGATAAATTCACATAGGCAATATCTTTAATAGGTTAATATCAAT GAAGATTTTTAATTACAATAATGAGTTCACTACAGACGATTAACACACCACACTGGCGAACCATCTCA ATGTAAGGGTGGTTTGGCAACACCTCCTTGCTTTGCTGTTTGGTGTAGTAAATCTAGTTTACTTCCTA AAYTrCAGTAGGCTTTATGCTGTGTTTATCGCCCAATTTATTTTAACAAAAGAAGATTAAAAAGTAAA GAACCACGAGTAAGATATTATTTAAATGTTGAAATCTTAAAACCTGCCTCCAAGATTTCAGAAGCCAA GTTT1TCTAACAGTATTTGTACAAATACTGCCTAGTGTATTCAACAGAAGACTGTGGTCATGTAACAG GTAACCACAATTTTCAGGTTTCTTAAAAACAGCTGTAACTAACTCAGGA NOV5a, CG 186855-01 JSEQ ID NO: 54 ~52a 1MW at 62324.9kD Protein Sequence MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGKIKREIQNL KLFRHPHI IKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLFQQLSAVDYCHRHMVV HRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYTAPEVISGRLYAGPEVDIWSCGVIL YALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRSVATLLMHMLQVDPLKRATIKDIREHEWFKQGL PSYLFPEDPSYDANVIDDEAVKEVCEKFECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEF YLASSPPSGSFMDDSAMHI PPGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWRQG IRS OSKPYDIMAEVYRAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEV VEQRSGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFFEMCA SLITTLAR NOV5bG 186855-02 SEQ ID NO: 55 1678 bp DNA Sequence ORF Start ATG at 14 ORF Stop: at 1670 5ACCGGATCCACCATGGCTGAGAAGCAGAAGCACGACGGGCGGGTGAAGATCGGACACTACGTGCTGG GCGACACGCTGGGCGTCGGCACCTTCGGCAAAGTGAAGATTGGAGAACATCAATTAACAGGCCATAAA GTGGCAGTTAAAATCTTAAATAGACAGAAGATTCGCAGTTTAGATGTTGTTGGAAAAATAAAACGAGA AATTCAAAATCTAAAACTCTTTCGTCATCCTCATATTATCAAACTATACCAGGTGATCAGCACTCCAA CAGATTTTTTTATGGTAATGGAATATGTGTCTGGAGGTGAATTATTTGACTACATCTGTAAGCATGGA CGGGTTGAAGAGATGGAAGCCAGGCGGCTCTTTCAGCAGATTCTGTCTGCTGTGGATTACTGTCATAG GCATATGGTTGTTCATCGAGACCTGAAACCAGAGAATGTCCTGTTGGATGCACACATGAATGCCAAGA TAGCCGATTTCGGATTATCTAATATGATGTCAGATGGTGAATTTCTGAGAACTAGTTGCGGATCTCCA AATTATGCAGCACCTGAAGTCATCTCAGGCAGATTGTATGCAGGTCCTGAAGTTGATATCTGGAGCTG TGGTGTTATCTTGTATGCTCTTCTTTGTGGCACCCTCCCATTTGATGATGAGCATGTACCTACGTTAT TTAAGAAGATCCGAGGGGGTGTCTTTTATATCCCAGAATATCTCAATCGTTCTGTCGCCACTCTCCTG ATGCATATGCTGCAGGTTGACCCACTGAAACGAGCAACTATCAAAGACATAAGAGAGCATGAATGGTT TAAACAAGATTTGCCCAGTTACTTATTTCCTGAAGACCCTTCCTATGATGCTAACGTCATTGATGATG AGGCTGTGAAAGAAGTGTGTGAAAAATTTGAATGTACAGAATCAGAAGTAATGAACAGTTTATATAGT GGTGACCCTCAAGACCAGCTTGCAGTGGCTTATCATCTTATCATTGACAATCGGAGAATAATGAACCA AGCCAGTGAGTTCTACCTCGCCTCTAGTCCTCCATCTGGTTCTTTTATGGATGATAGTGCCATGCATA TTCCCCCAGGCCTGAAACCTCATCCAGAAAGGATGCCACCTCTTATAGCAGACAGCCCCAAAGCAAGA TGTCCATTGGATGCACTGAATACGACTAAGCCCAAATCTTTAGCTGTGAAAAAAGCCAAGTGGCATCT TGGAATCCGAAGTCAGAGCAAACCGTATGACATTATGGCTGAAGTTTACCGAGCTATGAAGCAGCTGG ATTTTGAATGGAAGGTAGTGAATGCATACCATCTTCGTGTAAGAAGAAAAAATCCAGTGACTGGCAAT TACGTGAAAATGAGCTTACAACTTTACCTGGTTGATAACAGGAGCTATCTTTTGGACTTTAAAAGCAT TGATGATGAAGTAGTGGAGCAGAGATCTGGTTCCTCAACACCTCAGCGTTCCTGTTCTGCTGCTGGCT TACACAGACCAAGATCAAGTTTTGATTCCACAACTGCAGAGAGCCATTCACTTTCTGGCTCTCTCACT

GGCTCTTTGACCGGAAGCACATTGTCTTCAGTTTCACCTCGCCTGGGCAGTCACACCATGGATTT

1 T TGAAATGTGTGCCAGTCTGATTACTACTTTAGCCCGTGTCGACGGC N .... 5....: .6855- .s. S Q . Ns 56s.552 aa Mw at 231 -. 9kD Protein Sequence MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGKIKREIQNL KLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLFQQLSAVDYCHRHMVV 153 WO 2004/056961 PCT/US2003/034114 HRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSCGVIL YALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRSVATLLMHMLQVDPLKRATIKDIREHEWFKQDL PSYLFPEDPSYDANVIDDEAVKEVCEKFECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEF YLASSPPSGSFMDDSAMHIPPGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRS QSKPYDIMAEVYRAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEV VEQRSGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFFEMCA SLITTLAR NOV5c, CG186855-03 SEQ ID NO:57 3 bp DNA Sequence ORF Start: ATG at 1 ORF Stop: end of sequence IATG__ NOV5c, CG186855-03 tSEQ ID NO: 5891 aalMW at 149.2kD Protein SequenceI A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table DI1. Table D11. Comparison of the NOV5 protein sequences. NV5a MAEKQKHDG RVKGHYVLGDTLGVGTFG KVKG EHQLTG HKVAVKILNRQKI RSLDVVGK NOV5b MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGK NOV5c --------------------------------- NOV5a IKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHG RVEEMEARRLF NOV5b IKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLF NOV5c ----- ------------------------ NOV5a QQILSAVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYT NOV5b QQILSAVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYA NOV5c --------------------------------- NOV5a APEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRS NOV5b APEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRS NOV5c --------------------------------- NOV5a VATLLMHMLQVDPLKRATIKDIREHEWFKQGLPSYLFPEDPSYDANVIDDEAVKEVCEKF NOV5b VATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPEDPSYDANVIDDEAVKEVCEKF NOV5c --------------------------------- NOV5a ECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPSGSFMDDSAMHIP NOV5b ECTESEVMNSLYSGDPQDQLAVAYHLIlDNRRIMNQASEFYLASSPPSGSFMDDSAMHIP NOV5c --------------------------------- NOV5a PGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWRQGIRSQSKPYDMAEVY NOV5b PGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKPYDIMAEVY NOV5c --------------------------------- NOV5a RAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQR NOV5b RAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQR NOV5c --------------------------------- NOV5a SGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFF NOV5b SGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFF NOV5c --------------------------------- NOV5a EMCASLITTLAR NOV5b EMCASLITTLAR NOV5c -M--- 154 WO 2004/056961 PCT/US2003/034114 NOV5a (SEQ ID NO: 54) NOV5b (SEQ ID NO: 56) NOV5c (SEQ ID NO: 58) Further analysis of the NOV5a protein yielded the following properties shown in Table D12. .... .... . ...... . . . ... ..........----- -- " . -......... Table D12. Protein Sequence Properties NOV5a SignalP analysis: No Known Signal Sequence Predicted PSORT I analysis: PSG: a new signal peptide prediction method N-region: length 10; pos.chg 3; neg.chg 2 H-region: length 1; peak value -0.20 PSG score: -4.60 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -7.77 possible cleavage site: between 28 and 29 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 0 PERIPHERAL Likelihood = 5.14 (at 76) ALOM score: -1.17 (number of TMSs: 0) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 8.09 Hyd Moment(95): 6.70 G content: 0 D/E content: 2 S/T content: 0 Score: -6.70 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 12.3% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: 155 WO 2004/056961 PCT/US2003/034114 type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 70.6 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 47.8 %: cytoplasmic 26.1 %: nuclear 21.7 %: mitochondrial 4.3 %: endoplasmic reticulum > prediction for CG186855-01 is cyt (k=23) 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 D13. Table D13. Geneseq Results for NOV5a NOV5a identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region AAR64312 Rat liver adenosine monophosphate 1 ..552 537/552 (97%) 0.0 protein kinase - Rattus rattus, 552 aa. 1,.552 542/552 (97%) [WO9428116-Al, 08-DEC-1994] ABB59603 Drosophila melanogaster polypeptide SEQ 11..552 352/589 (59%) 0.0 ID NO 5601 - Drosophila melanogaster, 23..582 414/589 (69%) 582 aa. [W0200171042-A2, 27-SEP-2001] AAW29894 Mammalian AMPK-alphal subunit active 1..347 298/347 (85%) e-177 peptide 1 - Mammalia, 345 aa. 1..345 324/347 (92%) [W09725341-Al, 17-JUL-1997] 2 i9 M a M27a 31/5 (9% e13 Mammalian AMPK-alphal subunit active 156 WO 2004/056961 PCT/US2003/034114 peptide 6 - Mammalia, 257 aa. 1.257 246/257 (94%) [W09725341-A1, 17-JUL-1997] ABR40815 Cucumis sativus oil trait related protein 11..472 233/499 (46%) e-123 sequence SEQ ID NO:407 - Cucumis 3..483 318/499 (63%) sativus, 504 aa. [W02003002751-A2, 09 JAN-2003] 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 D14. Table D14. Public BLASTP Results for NOV5a Protein NOV5a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Acen PMatch the Matched Value Number Residues Portion 138503 AMP-activated protein kinase - human, 1..552 552/552 (100%) 0.0 552 aa. 1..552 552/552 (100%) P54646 5'-AMP-activated protein kinase, catalytic 1..552 548/552 (99%) 0.0 alpha-2 chain (EC 2.7.1.-) (AMPK alpha- 1..552 54/2(9% 2 chain) - Homo sapiens (Human), 552 aa. 009137 5'-AMP-activated protein kinase, catalytic 1..552 538/552 (97%) 0.0 alpha-2 chain (EC 2.7.1.-) (AMPK alpha- 1..552 543/552 (97%) 2 chain) - Rattus norvegicus (Rat), 552 aa. AAO17789 AMP-activated protein kinase alpha 2 - 1..552 538/552 (97%) 0.0 Sus scrofa (Pig), 552 aa. 1.552 542/552 (97%) Q8BRK8 Inferred: 5'-AMP-activated protein kinase 23..552 513/530 (96%) 0.0 catalytic alpha-2 subunit - Mus musculus 1..530 518/530 (96%) (Mouse), 530 aa (fragment). PFam analysis predicts that the NOV5a protein contains the domains shown in the Table D15. Table D15. Domain Analysis of NOV5a Identities/ Pfam Domain NOV5a Match Region Similarities Expect Value for the Matched Region pkinase 16..268 112/299 (37%) 4.2e-92 202/299 (68%) NOV6 - AMPK beta 1 The laboratory cloning was performed using one or more of the methods summarized in Example Q8. The NOV6 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table D1 6. Table D16. NOV6 Sequence Analysis jV~a, CG 127397-01 ISEQ ID NO: 59 12438 bp IDNA Sequence :I A . T. Ga . t 27.6 ....o... FS to:s G a i i. -8 -........ ....... GCEAGAGGAAGCG GGA AAGTGTCGGTTTATCTTCGCGCCCCTTGCGTTCTTGCCGCGGCTTGC 157 WO 2004/056961 PCT/US2003/034114 CTGGGCAGGTAAAGCGCGATTGCGAGAGCTCGGCAACCCTGCCGACTCAGCCGGAACCGGCTCCCGGC CCGAGGGGCGTGGTGTCCTGGTGCTCCGACTCCTTCCGCAGGCTCCTTGGGACCCGCGGTTCCGGGAG TCCCTTGCTCAGGGTCCCTTTCCTGCAGTGAGGCGCCGTCCGCCTTCCCTGTGTCCCCGCAGACCCCC ATCATGGGCAATACCAGCAGTGAGCGCGCCGCGCTGGAGCGGCATGGTGGCCATAAGACGCCCCGGAG GGACAGCTCGGGGGGCACCAAGGACGGGGACAGGCCCAAGATCCTGATGGACAGCCCCGAAGACGCCG ACCTCTTCCACTCCGAGGAAATCAAGGCACCAGAGAAGGAGGAATTCCTGGCCTGGCAGCATGATCTG GAAGTGAATGATAAAGCTCCCGCCCAGGCTCGGCCAACGGTGTTTCGATGGACGGGGGGCGGAAAGGA AGTTTACTTATCTGGGTCCTTCAACAACTGGAGTAAACTTCCCCTCACCAGAAGCCACAATAACTTTG TAGCCATCCTGGATCTGCCGGAAGGAGAGCATCAGTACAAGTTCTTTGTGGATGGTCAGTGGACGCAC GACCCTTCCGAGCCCATAGTAACCAGCCAGCTTGGCACAGTTAACAACATCATTCAAGTGAAGAAAAC TGACTTTGAAGTATTTGATGCTTTAATGGTGGATTCCCAAAAGTGCTCCGATGTGTCTGAGCTGTCCA GTTCTCCCCCAGGACCCTACCATCAGGAGCCCTACGTCTGCAAACCCGAAGAGCGCTTTCGGGCACCC CCTATTCTCCCCCCACATCTCCTCCAGGTCATCCTGAACAAGGACACGGGGATTTCCTGTGATCCAGC TTTGCTTCCTGAGCCCAATCACGTCATGCTGAACCACCTATACGCGCTGTCTATCAAGGATGGAGTGA TGGTGCTCAGCGCAACCCACCGGTACAAGAAGAAGTACGTCACCACCTTGTTATACAAGCCCATATGA AGAGCTGGGGGCGGATGGTGGCCCAGGAGACAGCACACCACCAGGCTCCACACGTGCATGCTTmCCCC AAGAGGGAATGGACTGTACATTGCTCATTTCACACTCTTCAGAAGACATTTCATACCTGCCCTGGTCC TGCTTGAAGGTTiGTCCAGGCAGAGCAGCTCCTGCAGCGCCTCGGTCTGTGACAGTCCTCCTAGCACC CCCATGGCTTTGAGCCTCGGGGACTCATCAAGTCCAAGAAAAGAGGGAGGGGTGGCAGAGGATCTGCA GCCCTGGCCCCGCGGTGCATGAGGCTGGGTGCAGTTCTAAACCTACATTCTCGATTTTTCTTAAGCCA AAAATGAATGCTAACTCCTTTGCCAGTAAAATTCTGGGAAACAGGGACTGAGGCCACACATCATTTCC AGTCATCTGTGTGTTTTTAAGGCCAGCCACTTGTCCCTGTTGAGGCCTGGCTATGGAACTAAATACAG TGTTGGTCTTGCCTGTCCTTCAAAATCAACAACAGATTGTCTCTCGGCTCCAGGGAGGTGTCATTTCT ATAGAAATTAGAAGCTTTCTGATTTCTAGATGAGGTTTTACAATTGTTTCTTACAGTCATGTGCACTA AGTACTCTTT1TGTAAGCAGAGGTGGCTGGCTCTGCAGCCTTAAGGCCAWTTTTTAAGTCACCACGTC TAGAAGTCACATGAACTCTGCTCAGCAATAATCTGUCTCAGAACAGACTT1CAACCTGCTGCCGGA TTTCTCCATTCAGCTGGATGATCCTCAGGACTGACCAGTTAGCTGGCAGGTTGTCCAGCTTTTTATTC CAGTCATAATAGGTGACAGTGTTAACCGTGAAAACTTGAGAGGCACTCTGCCCTCTTCCCTATAAAAT CACACAGCGTGATFACAAGGTCCCGTGGCACCTTGCTCAGGACCTCTGCCCCTAGU7AGCAAGACT GCAGCAGTTGCTGTTGCTATTTGAMGGAATGTAGAACTTGACAGCAGCCTCTGAGTCTGGGTCA GGAAGATGTCCTGGACCAAAGCAGACTTCTGTATACGCAGCTCAG1TTCCCGGGAGTCGCCACAGA TGTACCCACTAGCCCAGG1TTGCTGTGAGTCAGCGGAAGCTCCCGTATGCCC1TrGCTCCTGGTGGGA GAGGGAGGAGTGAGCTCCCTGGGTTCCAGTATTTACTTGGTATACCTGAGTTTGGGGGTACCCThLL TGTGACTTTTCAAAACAGTGAATTACTGTCACCTTGATGGACAAGTTTCAATAAAACTTTGTAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAMAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA __ NOV6a, CG 127397-01 SEd I NO: 60 270 aa MW at 30382.OkD Protein Sequence _ MGNTSSERAALERHGGHKTPRRDSSGGTKDGDRPKILMDSPEDADLFHSEEIKAPEKEEFLAWQHDLE VNDKAPAQARPTVFRWTGGGKEVYLSGSFNNWSKLPLTRSHNNFVAILDLPEGEHQYKFFVDGQWTHD PSEPIVTSQLGTVNNIIQVKKTDFEVFDALMVDSQKCSDVSELSSSPPGPYHQEPYVCKPEERFRAPP ILPPHLLQVILNKDTGISCDPALLPEPNHVMLNHLYALSIKDGVMVLSATHRYKKKYVTTLLYKPI Further analysis of the NOV6a protein yielded the following properties shown in Table D17. Table D17. Protein Sequence Properties NOV6a SignalP analysis: No Known Signal Sequence Predicted PSORT lI analysis: PSG: a new signal peptide prediction method N-region: length 8; pos.chg 1; neg.chg 1 H-region: length 3; peak value -8.11 PSG score: -12.51 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -15.87 possible cleavage site: between 48 and 49 158 WO 2004/056961 PCT/US2003/034114 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 4.98 (at 234) ALOM score: 4.98 (number of TMSs: 0) MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 12.66 Hyd Moment(95): 9.34 G content: 1 D/E content: 2 S/T content: 3 Score: -4.42 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 11.1% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: KKXX-like motif in the C-terminus: LYKP SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: MGNTSSE Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination 159 WO 2004/056961 PCT/US2003/034114 Prediction: nuclear Reliability: 70.6 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 78.3 %: nuclear 21.7 %: mitochondrial >> prediction for CG127397-01 is nuc (k=23) 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 D18. Table Di8. Geneseq Results for NOV6a NOV6a Identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region AAW29816 Mammalian AMPK beta subunit protein - 1..270 259/270 (95%) e-155 Mammalia, 270 aa. [W09725341-Al, 17- 1..270 265/270 (97%) JUL-19971 ABR63657 Human AMP-activated protein kinase beta 1..270 192/273 (70%) e-109 2 subunit - Homo sapiens, 272 aa. 1..272 223/273 (81%) (WO2003054228-A2, 03-JUL-2003) ABB59106 Drosophila melanogaster polypeptide SEQ 77..270 122/194 (62%) 7e-68 ID NO 4110 - Drosophila melanogaster, 154..341 146/194 (74%) 341 aa. [W0200171042-A2, 27-SEP-2001] Arabidopsis thaliana protein fragment SEQ 76..270 74/198 (37%) 3e-29 ID NO: 12405 - Arabidopsis thaliana, 244 55..242 104/198 (52%) aa. [EP1033405-A2, 06-SEP-2000] AAG 13054 Arabidopsis thaliana protein fragment SEQ 76..270 74/198 (37%) 3e-29 ID NO: 12404 - Arabidopsis thaliana, 259 70..257 104/198 (52%) aa. [EP1033405-A2, 06-SEP-2000] -- In a BLAST search of public sequence databases, the NO.'/a protein was found to have homology to the proteins shown in the BLASTP data in Table D19. Table Di9. Public BLASTP Results for NOV6a NOV6a Identities/ Protein Residues/ Similarities for Expect Accession Protein/Orgamsm/Length Match the Matched Value Number Residues Portion Q9Y478 5'-AMP-activated protein kinase, beta-1 2..270 269/269 (100%) e-160 subunit (AMPK beta-1 chain) (AMPKb) - 1..269 269/269 (100%) Homo sapiens (Human), 269 aa. J T09514 5'-AMP-activated protein kinase (EC 2.7.1.- 1..270 268/270 (99%) e-160 beta-1 chain - human, 270 aa. J1..270 268/270 (99%) 160 WO 2004/056961 PCT/US2003/034114 BAC40237 2 days neonate thymus thymic cells cDNA, 1..270 261/270 (96%) e-155 RIKEN full-length enriched library, 1..270 264/270 (97%) clone:E430008F22 product:5'-AMP activated protein kinase beta subunit - Mus musculus (Mouse); 270 aa. P80386 5'-AMP-activated protein kinase, beta-1 2..270 259/269 (96%) e-155 subunit (AMPK beta-1 chain) (AMPKb) (40 1..269 265/269 (98%) kDa subunit) - Rattus norvegicus (Rat), 269 aa. Q9R078 5'-AMP-activated protein kinase, beta-1 2..270 260/269 (96%) e-1 55 subunit (AMPK beta-1 chain) (AMPKb) - 1..269 263/269 (97%) Mus musculus (Mouse), 269 aa. PFam analysis predicts that the NOV6a protein contains the domains shown in the Table D20. Table D20. Domain Analysis of NOV6a Identities/ Pfam Domain NOV6a Match Region Similarities Expect Value for the Matched Region isoamylaseN 72..151 23/121 (19%) 0.95 58/121 (48%) AMPKBI 180..270 57/133 (43%) 6e-48 85/133 (64%) NOV7 - AMPK beta 2 The laboratory cloning was performed using one or more of the methods summarized in Example Q8. The NOV7 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table D21. Table D21. NOV7 Sequence Analysis INOV7a, CG 186873-01 SED NO: 61 181 9 b p DNA Sequence ORF Start: ATG at 1 IORF Stop: TGA at 817 ATGGGAAACACCACCAGCGACCGGGTGTCCGGGGAGCGCCACGGCGCCAAGGCTGCACGCTCCGAGGG CGCAGGCGGCCATGCCCCGGGGAAGGAGCACAAGATCATGGTGGGGAGTACGGACGACCCCAGCGTGT TCAGCCTCCCTGACTCCAAGCTCCCTGGGGACAAAGAGTTTGTATCATGGCAGCAGGATTTGGAGGAC TCCGTAAAGCCCACACAGCAGGCCCGGCCCACTGTTATCCGCTGGTCTGAAGGAGGCAAGGAGGTCTT CATCTCTGGGTCTTTCAACAATTGGAGCACCAAGATTCCACTGATTAAGAGCCATAATGACTTTGTTG CCATCCTGGACCTCCCTGAGGGAGAGCACCAATACAAGTTCTTTGTGGATGGACAGTGGGTTCATGAT CCATCAGAGCCTGTGGTTACCAGTCAGCTTGGCACAATTAACAATTTGATCCATGTCAAGAAATCTGA TTTTGAGGTGTTCGATGCTTTAAAGTTAGATTCTATGGAAAGTTCTGAGACATCTTGTAGAGACCTTT CCAGCTCACCCCCAGGGCCTTATGGTCAAGAAATGTATGCGTTTCGATCTGAGGAAAGATTCAAATCC CCACCCATCCTTCCTCCTCATCTACTTCAAGTTATTCTTAACAAAGACACTAATATTTCTTGTGACCC AGCCTTACTCCCTGAGCCCAACCATGTTATGCTGAACCATCTCTATGCATTGTCCATTAAGGACAGTG TGATGGTCCTTAGCGCAACCCATCGCTACAAGAAGAAGTATGTTACTACTCTGCTATACAAGCCCATT TGA NOV7a, CG186873-01 SEQ ID NO: 62 272 aa MvW at 30301 .9kD Protein Sequence I MGNTTSDRVSGERHGAKAARSEGAGGHAPGKEHKIMVGSTDDPSVFSLPDSKLPGDKEFVSWQQDLED SVKPTQQARPTVIRWSEGGKEVFISGSFNNWSTKIPLIKSHNDFVAILDLPEGEHQYKFFVDGQWVHD PSEPVVTSQLGTINNLIHVKKSDFEVFDALKLDSMESSETSCRDLSSSPPGPYGQEMYAFRSEERFKS 161 WO 2004/056961 PCT/US2003/034114 PPiLPPHLLQVLNeKDT-NISCDPALLPEPNHVMLNHLYALSIKDSVMVLSATHRYKKKYVTTLLYKPI Further analysis of the NOV7a protein yielded the following properties shown in Table D22. Table D22. Protein Sequence Properties NOV7a SignalP analysis: No Known Signal Sequence Predicted PSORT 1I analysis: PSG: a new signal peptide prediction method N-region: length 8; pos.chg 1; neg.chg 1 H-region: length 3; peak value -8.74 PSG score: -13.14 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -6.95 possible cleavage site: between 47 and 48 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood= 5.20 (at 236) ALOM score: 5.20 (number of TMSs: 0) MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 13.26 Hyd Moment(95): 10.04 G content: 2 D/E content: 2 S/T content: 4 Score: -4.43 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 10.7% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: KKXX-like motif in the C-terminus: LYKP SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none 162 WO 2004/056961 PCT/US2003/034114 NMYR: N-myristoylation pattern: MGNTTSD Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 70.6 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 65.2 %: nuclear 30.4 %: mitochondrial 4.3 %: cytoplasmic >> prediction for CG186873-01 is nuc (k=23) 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 D23. Table D23. Geneseq Results for NOV7a NOV7a Identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Rgo ABR63657 Human AMP-activated protein kinase beta 1..272 272/272 (100%) e-160 2 subunit - Homo sapiens, 272 aa. 1..272 272/272 (100%) AAW29816 Mammalian AMPIK beta subunit protein - I1..272 190/273 (69%) e-1 07 Mammalia, 270 aa. [W09725341 -Al, 17- 1..270 220/273 (79%) JUL-i 997] ABB59106 Drosophila melanogaster polypeptide 67..272 121/206 (58%) 5e-64 SEQ I D NO 4110 - Drosophila 147..341 150/206 (72%) melanogaster, 341 aa. [W02001S71042 A2, 27-SEP-2001]________ AAG13055 Arabidopsisthaliana protein fragment 61..272 77/216 (35%) 9e-32 SEQ ID NO: 12405- Arabidopsis thaliana, 39..242 111/216 (50%) 244aa.[EP1033405-A2, 06-SEP-2000] 163 WO 2004/056961 PCT/US2003/034114 AAG13054 Arabidopsis thaliana protein fragment 61..272 77/216 (35%) 9e-32 SEQ ID NO: 12404 - Arabidopsis thaliana, 54..257 111/216 (50%) 259 aa. [EP1033405-A2, 06-SEP-2000] 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 D24. Table D24. Public BLASTP Results for NOV7a Protein NOV7a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion 043741 5'-AMP-activated protein kinase, beta-2 1..272 272/272 (100%) e-160 subunit (AMPK beta-2 chain) - Homo 1..272 272/272 (100%) sapiens (Human), 272 aa. Q9QZH4 5'-AMP-activated protein kinase, beta-2 1..272 264/272 (97%) e-155 subunit (AMPK beta-2 chain) - Rattus 1..271 26/7(9% norvegicus (Rat), 271 aa. AAH53787 Hypothetical protein - Xenopus laevis 1..272 230/275 (83%) e-130 (African clawed frog), 271 aa. 1..271 246/275 (88%) T09514 5'-AMP-activated protein kinase (EC 1..272 193/273 (70%) e-109 2.7. 1.-) beta- I chain - human, 270 aa. 1. .270 223/273 (80%) Q9Y478 5'-AMP-activated protein kinase, beta-1 2..272 191/272 (70%) e-108 subunit (AMPK beta-1 chain) (AMPKb) - 1..269 222/272 (81%) Homo sapiens (Human), 269 aa. PFam analysis predicts that the NOV7a protein contains the domains shown in the Table D25. Table D25. Domain Analysis of NOV7a Identities/ Pfam Domain NOV7a Match Region Similarities Expect Value for the Matched Region AMPKBI ] 182..272 59/133 (44%) 1 e-48 82/133 (62%) NOV8 - AMPK gamma 1 The laboratory cloning was performed using one or more of the methods summarized in Example Q8. The NOV8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table D26. Table D26. NOV8 Sequence Analysis NOV8a, CG186882-01 SEQ ID NO: 63 1578 bp DNA Sequence art: ATG at 68 op: TGA at 1088 GCGCCCTTAAAGATGGTGAGGGGGCTCATGCTCTGAGTAGAAGGTGGTGACCTCCAGGAGCGGTGGGA TGATGAGGGCCCGGGCGCCTCTTGCAATGGAGACGGTCATTTCTTCAGATAGCTCCCCAGCTGTGGAA AATGAGCATCCTCAAGAGACCCCAGAATCCAACAATAGCGTGTATACTTCCTTCATGAAGTCTCATCG CTGCTATGACCTGATTCCCACAAGCTCCAAATTGGTTGTATTTGATACGTCCCTGCAGGTGAAGAAAG C1 1TFIT GCTTTGGTGACTAACGGTGTACGAGCTGCCCCTTTATGGGATAGTAAGAAGCAAAGTTTT GTGGGCATGCTGACCATCACTGATTTCATCAATATCCTGCACCGCTACTATAAATCAGCCTTGGTACA 164 WO 2004/056961 PCT/US2003/034114 GATCTATGAGCTAGAAGAACACAAGATAGAAACTIGGAGAGAGGTGTATCTCCAGGACCCTTTAAAC CGCTTGTCTGCATTTCTCCTAATGCCAGCTTGTGATGCTGTCTCTTCATTAATTCGGAACAAGATC CACAGGCTGCCAGTTATTGACCCAGAATCAGGCAATACTTTGTACATCCTCACCCACAAGCGCATTCT GAAGTTCCTCAAATTGTTTATCACTGAGTTCCCCAAGCCAGAGTTCATGTCCAAGTCTCTGGAAGAGC TACAGATTGGCACCTATGCCAATATTGCTATGGTTCGCACTACCACCCCCGTCTATGTGGCTCTGGGG ATTTlTGTACAGCATCGAGTCTCAGCCCTGCCAGTGGTGGATGAGAAGGGGCGTGTGGTGGACATCTA CTCCAAGTTTGATGTTATCAATCTGGCAGCAGAAAAGACCTACAACAACCTAGATGTATCTGTGACTA AAGCCTTGCAACATCGATCACATTACTTTGAGGGTGTTCTCAAGTGCTACCTGCATGAGACTCTGGAG ACCATCATCAACAGGCTAGTGGAAGCAGAGGTTCACCGACTTGTAGTGGTGGATGAAAATGATGTGGT CAAGGGAATTGTATCACTGTCTGACATCCTGCAGGCCCTGGTGCTCACAGGTGGAGAGAAGAAGCCCT GAGCTGGGGGAAGGG GTCATGCAGCACCAGGGGATATGCCCAACTCACTGCCTGCTGGAAGCTTGTG GGAATCAGATGAAACTTGAGGGAATTGTGACTCTGTTCCCTGTTCAGGGTCCCCTGCCCTTCTATCTG GGGTGAGAGG GAGAGATGA[ATAGCTACC1TACCCTCACACATACAC TTGAAAAAACTTTCAGCCTAGCCAGTTCTAGCCCCTGTCCTCTTAGATATATCCCCCTTTCTGGGTGA ACTATAGGCTCTGTGCCTCTCAGACAAACTGATCTCTAAGAGATCCCCAGACCTCACTTGCCTCTG CCTCCATCTTGGCCCTGATTCAACCCTAAGATAATAGCAAACAAAATTCTTCATAAAGATA1 MiA TTCACCTGTTCCGTGCTATATGGAGGAGGCCAAGTCCATTAGTGACAmCCCCATAATGTGAGT GGGGAGGATTGTGG NOV8a, C186882-01 SEIDN:6 J340 aa Mat38577.2k Protein Sequence IRARAPLAMETVISSDSSPAVENEHPQETPESNNSVYTSFMKSHRCYDLIPTSSKLVVFDTSLQVKK AFFALVTNGVRAAPLWDSKKQSFVGMLTITDFINILHRYYKSALVQIYELEEHKIETWREVYLQDSFK PLVCISPNASLFDAVSSLIRNKIHRLPVIDPESGNTLYILTHKRILKFLKLFITEFPKPEFMSKSLEE LQIGTYANIAMVRTTTPVYVALGIFVQHRVSALPVVDEKGRVVDIYSKFDVINLAAEKTYNNLDVSVT KALQHRSHYFEGVLKCYLHETLETIINRLVEAEVHRLVVVDENDVVKGIVSLSDILQALVLTGGEKKP NOV8b, SNP 13382600 of CG186882-01 SEQ ID NO: 65 1578 bp IDNA Sequence OFIF Start: ATG at 68 JORF Stop: TGA at 1088 dGCCCTAAAGATGGTGAGGGGGCTCATGCTCTGAGTAGAAGGTGGTGACCTCCAGGAGCGGTGGGA TGATGAGGGCCCGGGCGCCTCTTGCAATGGAGACGGTCATTTCTTCAGATAGCTCCCCAGCTGTGGAA AATGAGCATCCTCAAGAGACCCCAGAATCCAACAATAGCGTGTATACTTCCTTCATGAAGTCTCATCG CTGCTATGACCTGATTCCCACAAGCTCCAAATTGGTTGTATTTGATACGTCCCTGCAGGTGAAGAAAG CTTTTT rGCTTTGGTGACTAACGGTGTACGAGCTGCCCCTTTATGGGATAGTAAGAAGCAAAGTTTT GTGGGCATGCTGACCATCAGTGATTTCATCAATATCCTGCACCGCTACTATAAATCAGCCTTGGTACA GATCTATGAGCTAGAAGAACACAAGATAGAAACTTGGAGAGAGGTGTATCTCCAGGACTCCTTTAAAC CGCTTGTCTGCATTTCTCCTAATGCCAGCTTGTTTGATGCTGTCTCTTCATTAATTCGGAACAAGATC CACAGGCTGCCAGTTATTGACCCAGAATCAGGCAATACTTTGTACATCCTCACCCACAAGCGCATTCT GAAGTTCCTCAAATTGTTTATCACTGAGTTCCCCAAGCCAGAGTTCATGTCCAAGTCTCTGGAAGAGC TACAGATTGGCACCTATGCCAATATTGCTATGGTTCGCACTACCACCCCCGTCTATGTGGCTCTGGGG AlTTTGTACAGCATCGAGTCTCAGCCCTGCCAGTGGTGGATGAGAAGGGGCGTGTGGTGGACATCTA CTCCAAGTTTGATGTTATCAATCTGGCAGCAGAAAAGACCTACAACAACCTAGATGTATCTGTGACTA AAGCCTTGCAACATCGATCACATTACTTTGAGGGTGTTCTCAAGTGCTACCTGCATGAGACTCTGGAG ACCATCATCAACAGGCTAGTGGAAGCAGAGGTTCACCGACTTGTAGTGGTGGATGAAAATGATGTGGT CAAGGGAATTGTATCACTGTCTGACATCCTGCAGGCCCTGGTGCTCACAGGTGGAGAGAAGAAGCCCT GAGCTGGGGGAAGGGGTCATGCAGCACCAGGGGATATGCCCAACTCACTGCCTGCTGGMGCTCTGTG G ATAAGACTAGATGGCCGTCTGTTCAGGGTCCCCTGCCCTTCTATCTG GGACAGAGTTGGAGAGGAGAATAGCTACCCTTACCCTCACACATACAC ITTGAAAAC1rCACCTACCATVCAGCCCTTCTCAGATATATCCCCCmTCTGGGTGA A TTGCCGGCCCGCACGTTTAGAGATCCCCAGACCTCACTTGCCTCTG CTCCATCTTGGCCCTGATTCAACCCTA AGATAATAGCACAACAAAATTCTTCATAAAGATATTTTA TTCACCTGTTCCGTGCTATATGGAGGAGGCCAAGTCCATTTAGTGACAITTCTICCCTAATGTGAGT GGGGAGGATTGTGG NOV8b, SNP 13382600 of CG186882-01 SEQ ID NO: 66 340 aa MW at 38563.2kD Protein Sequence MMRARAPLAMETVISSDSSPAVENEHPQETPESNNSVYTSFMKSHRCYDLIPTSSKLVVFDTSLQVKK AFFALVTNGVRAAPLWDSKKQSFVGMLTISDFINILHRYYKSALVQYELEEHKIETWREVYLQDSFK PLVCISPNASLFDAVSSLIRNKIHRLPVIDPESGNTLYILTHKRILKFLKLFITEFPKPEFMSKSLEE LQIGTYANIAMVRTTTPVYVALGIFVQHRVSALPVVDEKGRVVDIYSKFDVINLAAEKTYNNLDVSVT KALQHRSHYFEGVLKCYLHETLETilNRLVEAEVHRLVVVDENDVVKGIVSLSDILQALVLTGGEKKP 165 WO 2004/056961 PCT/US2003/034114 A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table D27. Table D27. Comparison of the NOV8 protein sequences. NOV63a MMRARAPLAMETVISSDSSPAVENEHPQETPESNNSVYTSFMKSHRCYDLIPTSSKLVVF NOV63b MMRARAPLAMETVISSDSSPAVENEHPQETPESNNSVYTSFMKSHRCYDLIPTSSKLVVF NOV63a DTSLQVKKAFFALVTNGVRAAPLWDSKKQSFVGMLTITDFINILHRYYKSALVIYELEE NOV63b DTSLQVKKAFFALVTNGVRAAPLWDSKKQSFVGMLTISDFINILHRYYKSALVQIYELEE NOV63a HKIETWREVYLQDSFKPLVCISPNASLFDAVSSLIRNKHRLPVIDPESGNTLYILTHKR NOV63b HKIETWREVYLQDSFKPLVCISPNASLFDAVSSLIRNKIHRLPVIDPESGNTLYLTHKR NOV63a ILKFLKLFITEFPKPEFMSKSLEELQIGTYANIAMVRTTTPVYVALGIFVQHRVSALPVV NOV63b ILKFLKLFITEFPKPEFMSKSLEELQGTYANIAMVRTTTPVYVALGIFVQHRVSALPVV NOV63a DEKGRVVDIYSKFDVINLAAEKTYNNLDVSVTKALQHRSHYFEGVLKCYLHETLETILNR NOV63b DEKGRVVDIYSKFDVINLAAEKTYNNLDVSVTKALQHRSHYFEGVLKCYLHETLETIINR NOV63a LVEAEVHRLV VDENDVVKGIVSLSDILQALVLTGGEKKP NOV63b LVEAEVHRLVVVDENDVVKGIVSLSDILQALVLTGGEKKP NOV8a (SEQ ID NO: 64) NOV8b (SEQ ID NO: 66) Further analysis of the NOV8a protein yielded the following properties shown in Table D28. Table D28. Protein Sequence Properties NOV8a SignalP analysis: Cleavage site between residues 4 and 5 PSORT 11 analysis: PSG: a new signal peptide prediction method N-region: length 11; pos.chg 2; neg.chg 1 H-region: length 5; peak value 0.05 PSG score: -4.35 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -7.25 possible cleavage site: between 20 and 21 >>> Seems to have no N-terminal signal peptide ALOM: Klein -et al's method for TM region allocation init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 0 PERIPHERAL Likelihood = 0.74 (at 224) ALOM score: -1.59 (number of TMSs: 0) MITDISC: discrimination of mitochondrial targeting seq R content: 2 Hyd Moment(75): 5.23 Hyd Moment(95): 2.75 G content: 0 D/E content: 2 S/T content: 3 Score: -4.83 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 15 ARAJPL 166 WO 2004/056961 PCT/US2003/034114 NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 11.2% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: MRAR KKXX-like motif in the C-terminus: GEKK SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 52.2 %: mitochondrial 21.7 %: cytoplasmic 13.0 %: nuclear 4.3 %: vacuolar 167 WO 2004/056961 PCT/US2003/034114 4.3 %: endoplasmic reticulum 4.3 %: peroxisomal >>prediction for CG 186882-01 is mit (k=23) 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 D29. Table D29. Geneseq Results for NOV8a NOV8a Identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect identifier Date] Match the Matched Value Residues Region ABU04259 Human expressed protein tag (EPT) #925 4..340 336/337 (99%) 0.0 - Homo sapiens, 344 aa. [W0200278524- 8..344 337/337 (99%) 1 A2, 10-OCT-2002] AAB54009 Human pancreatic cancer antigen protein 4..340 336/337 (99%) 0.0 sequence SEQ ID NO:461 - Homo 8..344 337/337 (99%) sapiens, 344 aa. [W0200055320-A1, 21 SEP-2000] ABU04262 Human expressed protein tag (EPT) #928 10..340 331/331 (100%) 0.0 - Homo sapiens, 331 aa. [W0200278524- 1..331 331/331 (100%) A2, 1 0-OCT-2002] ABU04261 Human expressed protein tag (EPT) #927 10..340 331/331 (100%) 0.0 -Homo sapiens, 331 aa. [W0200278524- 1 -331 331/331 (100%) A2, 10O-OCT-2002] ABU04258 Human expressed protein tag (EPT) #924 10.340 331/331 (100%) 0.0 - Homo sapiens, 331 aa. [W0200278524- 1..331 331/331 (100%) A2, 10-OCT-2002] In a BLAST search of public sequence databases, the NOV8a protein was found to have homology to the proteins shown in the BLASTP data in Table D30. Table D30. Public BLASTP Results for NOV8a Protein NOV8a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion P54619 5'-AMP-activated protein kinase, gamma- 10..340 331/331 (100%) 0.0 1 subunit (AMPK gamma-1 chain) 1..331 331/331 (100%) (AMPKg) - Homo sapiens (Human), 331 aa. Q8N7V9 Hypothetical protein FLJ40287 - Homo 10.340 331/340 (97%) 0.0 sapiens (Human), 340 aa. 1.340 331/340 (97%) P58108 5'-AMP-activated protein kinase, gamma- 10..338 324/329 (98%) 0.0 1 subunit (AMPK gamma-1 chain) 1..329 325/329 (98%) (AMPKg) - Bos taurus (Bovine), 330 aa. P80385 5'-AMP-activated protein kinase, gamma- 14..340 316/327 (96%) e-180 1 subunit (AMPK gamma-1 chain) 4..330 324/327 (98%) (AMPKg) - Rattus norvegicus (Rat), 330 aa. 168 WO 2004/056961 PCT/US2003/034114 054950 5'-AMP-activated protein kinase, gamma- 14..340 312/327 (95%) e-177 1 subunit (AMPK gamma-1 chain) 4..330 319/327 (97%) (AMPKg) - Mus musculus (Mouse), 330 aa. PFam analysis predicts that the NOV8a protein contains the domains shown in the Table D31. Table D31. Domain Analysis of NOV8a Identities/ Pfam Domain NOV8a Match Region Similarities Expect Value for the Matched Region CBS 51..105 11/55(20%) 0.0059 38/55 (69%) CBS 132..186 17/55 (31%) 3.2e-09 44/55 (80%) CBS 207..260 15/54(28%) 5.4e-08 39/54 (72%) CBS 279..332 20/54(37%) 2.1e-09 40/54 (74%) NOV9 - AMPK gamma 2 The laboratory cloning was performed using one or more of the methods summarized in Example Q8. The NOV9 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table D32. Table D32. NOV9 Sequence Analysis NOV9a, CG186895-01 SEQ ID NO: 67 2223 bp DNA Sequen ce ORF Start: ATG at 160 fORF Stop: TGA at 1144 AGGCCCCTCCTCCCGGCGGCGCGGCAGAGCCAGGCCCCAGCGCTCGGCCGGCCGCAAGCCCGCCGGCC GGGGACGAGCGTCGCAGCTCATGCTGATCGCTGTCCTCCTCCTCCCCCTCAGGCGGCGCTGGCGGCGG CCCTGGGACCCGCGGAAGCCGGCATGCTGGAGAAGCTGGAGTTCGAGGACGAAGCAGTAGAAGACTCA GAAAGTGGTGTTTACATGCGATTCATGAGGTCACACAAGTGTT ATGACATCGTTCCAACCAGTTCAAA GCTTGTTGTCTTTGATACTACATTACAAGTTAAAAAGGCCTTCTTTGCTTTGGTAGCCAACGGTGTCC GAGCAGCGCCACTGTGGGAGAGTAAAAAACAAAGTTTGTAGGAATGCTAACAATTACAGATTTCATA AATATACTACATAGATACTATAAATCACCTATGGTACAGATTTATGAATTAGAGGAACATAAAATTGA AACATGGAGGGAGCTTTATTTACAAGAAACATTTAAGCCTTTAGTGAATATATCTCCAGATGCAAGCC TCTTCGATGCTGTATACTCCTTGATCAAAAATAAAATCCACAGATTGCCCGTTATTGACCCTATCAGT GGGAATGCACTTTATATACTTACCCACAAAAGAATCCTCAAGTTCCTCCAGC -1-11ATGTCTGATAT GCCAAAGCCTGCCTTCATGAAGCAGAACCTGGATGAGCTTGGAATAGGAACGTACCACAACATTGCCT TCATACATCCAGACACTCCCATCATCAAAGCCTTGAACATATTTGTGGAAAGACGAATATCAGCTCTG CCTGTTGTGGATGAGTCAGGAAAAGTTGTAGATATTTATTCCAAATTTGATGTAATTAATCT-TGCTGC TGAGAAAACATACAATAACCTAGATATCACGGTGACCCAGGCCCTTCAGCACCGTTCACAGTATTTTG AAGGTGTTGTGAAGTGCAATAAGCTGGAAATACTGGAGACCATCGTGGACAGAATAGTAAGAGCTGAG GTCCATCGGCTGGTGGTGGTAAATGAAGCAGATAGTATTGTGGGTATTATTTCCCTGTCGGACATTCT GCAAGCCCTGATCCTCACGCCAGCAGGTGCCAAACAAAAGGAGACAGAAACGGAGTGACCGCCGTGAA TGTAGACGCCCTAGGAGGAGAACTTGAACAAAGTCTCTGGGTCACGTTTTGCCTCATGAACACTGGCT GCAAGTGGTTAAGAATGTATATCAGGGTTTAACGATAGGTATTTCTTCCAGTGATGTTGAAATTAAGC TTAAAAAAGAAAGATTATGTGCTTGAAGATTCAGGCTTGCATTAAAAGACTGTTTTCAGACCTTTG TCTGAAGGATTTTAAATGCTGTATGTCATTAAAGTGCACTGTGTCCTGAAGTTTCATTA mI CAT TTCAAAGAATTCACTGGTATGGAACAGGTGATGTGGCATAAGGTGAGTGCACGGTATGTTCAGATCAC 169 WO 2004/056961 PCT/US2003/034114 AGTGCCTTATGTCCGAATACAGCAATATGTCACCGCCGCAGCCGGGGCGCACGCGTGTGAAACAACAC CGAGCTTGAATGTGGAAGTCTTTGAACCTCTTACCAAATCAGTTTGTTTTCTTTAGATTTGTCAAAAA GTTGTAATTTGAATATAAATAATTACTTTAAAATTTTAATGACACTTTACACGTAAGTGTTTTGTTC TGGGCTACCGTGTCAACGAGGCTGCTTTACAACAGCTTTATTTA1TFVTACTTTCATGCAA11T11TT ACACATCTTTTGGTGGAGTAAACTTCACCACATCCATGAATAAACTCTCAGTTATTTTGAAATGGCAA ATTTCTCATTATTTAAGTTTGGATCTGGAAAGGACATGACTTCTGAAATAGCCGCTGCTGGGTTTTAA AAGCTGAGGTCTCTCAAAGTGTGGAGGAGACGTTGCCGTCAGGCGGGAGCCAAGTGCCGGGAAGATGC CTATTTTITTTCTTGTGTATTGAAATGTAAAATCATGATGTTTGTTATGACTGCTGATGCGATTGTTT TTGTAAATTTTATTGTGGCATATACAGTATTGTCATACAGTTGAAGAGAAACAATGTTTCCTAATGTA AGTGCTCTGAAAATGTTGACACTGTATATATATATATGAGGATAGTTTGTTTTT1TITGTTTTGGGTT ITT1TT TT11CAGATTGAAAAATTAAAATAAATCCTACTATCTACC NOV9a, CG186895-01 SEQ ID NO: 68 328 aa MW at 37508. 1kD Protein Sequence__ MLEKLEFEDEAVEDSESGVYMRFMRSHKCYDIVPTSSKLVVFDTTLQVKKAFFALVANGVRAAPLWES KKQSFVGMLTITDFINILHRYYKSPMVQIYELEEHKIETWRELYLQETFKPLVNISPDASLFDAVYSL IKNKIHRLPVIDPISGNALYILTHKRILKFLQLFMSDMPKPAFMKQNLDELGIGTYHNIAFIHPDT P IKALNIFVERRISALPVVDESGKVVDIYSKFDVINLAAEKTYNNLDITVTQALQHRSQYFEGVVKCNK LEILETIVDRIVRAEVHRLVVVNEADSIVGIISLSDILQALILTPAGAKQKETETE INOV9b, SNP 13382598 of CG186895-01 |SEQ ID NO: 69 12223 bp DNA Sequence iORF Start: ATG at 160 |ORF Stop: TGA at 1144 AGGCCCCTCCTCCCGGCGGCGCGGCAGAGCCAGGCCCCAGCGCTCGGCCGGCCGCGAGCCCGCCGGCC GGGGACGAGCGTCGCAGCTCATGCTGATCGCTGTCCTCCTCCTCCCCCTCAGGCGGCGCTGGCGGCGG CCCTGGGACCCGCGGAAGCCGGCATGCTGGAGAAGCTGGAGTTCGAGGACGAAGCAGTAGAAGACTCA GAAAGTGGTGTTTACATGCGATTCATGAGGTCACACAAGTGTTATGACATCGTTCCAACCAGTTCAAA GCTTGTTGTCTTTGATACTACATTACAAGTTAAAAAGGCCTTCTTTGCTTTGGTAGCCAACGGTGTCC GAGCAGCGCCACTGTGGGAGAGTAAAAAACAAAGTTTTGTAGGAATGCTAACAATTACAGATTTCATA AATATACTACATAGATACTATAAATCACCTATGGTACAGATTTATGAATTAGAGGAACATAAAATTGA AACATGGAGGGAGCTTTATTTACAAGAAACATTTAAGCCTTTAGTGAATATATCTCCAGATGCAAGCC TCTTCGATGCTGTATACTCCTTGATCAAAAATAAAATCCACAGATTGCCCGTTATTGACCCTATCAGT GGGAATGCACTTTATATACTTACCCACAAAAGAATCCTCAAGTTCCTCCAGC1T TiATGTCTGATAT GCCAAAGCCTGCCTTCATGAAGCAGAACCTGGATGAGCTTGGAATAGGAACGTACCACAACATTGCCT TCATACATCCAGACACTCCCATCATCAAAGCCTTGAACATATTTGTGGAAAGACGAATATCAGCTCTG CCTGTTGTGGATGAGTCAGGAAAAGTTGTAGATATTTATTCCAAATTTGATGTAATTAATCTTGCTGC TGAGAAAACATACAATAACCTAGATATCACGGTGACCCAGGCCCTTCAGCACCGTTCACAGTATTTTG AAGGTGTTGTGAAGTGCAATAAGCTGGAAATACTGGAGACCATCGTGGACAGAATAGTAAGAGCTGAG GTCCATCGGCTGGTGGTGGTAAATGAAGCAGATAGTATTGTGGGTATTATTTCCCTGTCGGACATTCT GCAAGCCCTGATCCTCACGCCAGCAGGTGCCAAACAAATGGAGACAGAAACGGAGTGACCGCCGTGAA TGTAGACGCCCTAGGAGGAGAACTTGAACAAAGTCTCTGGGTCACGTTTTGCCTCATGAACACTGGCT GCAAGTGGTTAAGAATGTATATCAGGGTTTAACGATAGGTATTTCTTCCAGTGATGTTGAAATTAAGC TTAAAAAAGAAAGATTTTATGTGCTTGAAGATTCAGGCTTGCATTAAAAGACTGTTTTCAGACCTTTG TCTGAAGGATTTTAAATGCTGTATGTCATTAAAGTGCACTGTGTCCTGAAGTTTTCATTAT1TTTCAT TTCAAAGAATTCACTGGTATGGAACAGGTGATGTGGCATAAGGTGAGTGCACGGTATGTTCAGATCAC AGTGCCTTATGTCCGAATACAGCAATATGTCACCGCCGCAGCCGGGGCGCACGCGTGTGAAACAACAC CGAGCTTGAATGTGGAAGTCTTTGAACCTCTTACCAAATCAGTTTGTTTTCTTTAGATTTGTCAAAAA GTTGTAATTTGAATATAAATAATTACTTTAAAATTTTAATGACACTTTTACACGTAAGTGTTTTGTTC TGGGCTACCGTGTCAACGAGGCTGCTTACAACAGCTTTATTTA1TT1ACTTTCATGCAAT1TF1F1 ACACATCTTTTGGTGGAGTAAACTTCACCACATCCATGAATAAACTCTCAGTTATTTTGAAATGGCAA ATTTCTCATTATTTAAGTTTGGATCTGGAAAGGACATGACTTCTGAAATAGCCGCTGCTGGGTTTTAA AAGCTGAGGTCTCTCAAAGTGTGGAGGAGACGTTGCCGTCAGGCGGGAGCCAAGTGCCGGGAAGATGC CTA1TTT TTTCTTGTGTATTGAAATGTAAAATCATGATGTTTGTTATGACTGCTGATGCGATTGTTT TTGTAAATTTTATTGTGGCATATACAGTATTGTCATACAGTTGAAGAGAAACAATGTTTCCTAATGTA AGTGCTCTGAAAATGTTGACACTGTATATATATATATGAGGATAGTTTG1T1TF TIGTTTTGGGTT III1111CAGATTGAAAAATTAAAATAAATCCTACTATCTACC NOV9b, SNP 13382598 of CG186895-01 SEQ ID NO: 70 328 aa MW at 37511.2kD Protein Sequence MLEKLEFEDEAVEDSESGVYMRFMRSHKCYDIVPTSSKLVVFDTTLQVKKAFFALVANGVRAAPLWES KKQSFVGMLTITDFINILHRYYKSPMVQIYELEEHKIETWRELYLQETFKPLVNISPDASLFDAVYSL IKNKIHRLPVIDPISGNALYILTHKRILKFLQLFMSDMPKPAFMKQNLDELGIGTYHNIAFIHPDTPI 170 WO 2004/056961. PCT/US2003/034114 IKALNIFVERRISALPVVDESGKVVDIYSKFDVINLAAEKTYNNLDITVTQALQHRSQYFEGVVKCNK LEI LETIVDRIVRAEVHRLVVVNEADSIVGIISLSDILQALILTPAGAKQMETETE INOV9c, SNP 13382599 of CG186895-01 SEQ ID NO: 71 2223 bp DNA Sequence ORF Start: ATG at 160 [ORF Stop: TGA at 1144 AGGCCCCTCCTCCCGGCGGCGCGGCAGAGCCAGGCCCCAGCGCTCGGCCGGCCGCGAGCCCGCCGGCC GGGGACGAGCGTCGCAGCTCATGCTGATCGCTGTCCTCCTCCTCCCCCTCAGGCGGCGCTGGCGGCGG CCCTGGGACCCGCGGAAGCCGGCATGCTGGAGAAGCTGGAGTTCGAGGACGAAGCAGTAGAAGACTCA GAAAGTGGTGTTTACATGCGATTCATGAGGTCACACAAGTGTTATGACATCGTTCCAACCAGTTCAAA GCTTGTTGTCTTTGATACTACATTACAAGTTAAAAAGGCCTTCTTTGCTTTGGTAGCCAACGGTGTCC GAGCAGCGCCACTGTGGGAGAGTAAAAAACAAAGTTTTGTAGGAATGCTAACAATTACAGATTTCATA AATATACTACATAGATACTATAAATCACCTATGGTACAGATTTATGAATTAGAGGAACATAAAATTGA AACATGGAGGGAGCTTTATTTACAAGAAACATTTAAGCCTTTAGTGAATATATCTCCAGATGCAAGCC TCTTCGATGCTGTATACTCCTTGATCAAAAATAAAATCCACAGATTGCCCGTTATTGACCCTATCAGT GGGAATGCACTTTATATACTTACCCACAAAAGAATCCTCAAGTTCCTCCAGCTTTTTATGCCTGATAT GCCAAAGCCTGCCTTCATGAAGCAGAACCTGGATGAGCTTGGAATAGGAACGTACCACAACATTGCCT TCATACATCCAGACACTCCCATCATCAAAGCCTTGAACATATTTGTGGAAAGACGAATATCAGCTCTG CCTGTTGTGGATGAGTCAGGAAAAGTTGTAGATATTTATTCCAAATTTGATGTAATTAATCTTGCTGC TGAGAAAACATACAATAACCTAGATATCACGGTGACCCAGGCCCTTCAGCACCGTTCACAGTATTTTG AAGGTGTTGTGAAGTGCAATAAGCTGGAAATACTGGAGACCATCGTGGACAGAATAGTAAGAGCTGAG GTCCATCGGCTGGTGGTGGTAAATGAAGCAGATAGTATTGTGGGTATTATTTCCCTGTCGGACATTCT GCAAGCCCTGATCCTCACGCCAGCAGGTGCCAAACAAAAGGAGACAGAAACGGAGTGACCGCCGTGAA TGTAGACGCCCTAGGAGGAGAACTTGAACAAAGTCTCTGGGTCACGTTTTGCCTCATGAACACTGGCT GCAAGTGGTTAAGAATGTATATCAGGGTTTAACGATAGGTATTTCTTCCAGTGATGTTGAAATTAAGC TTAAAAAAGAAAGATTTTATGTGCTTGAAGATTCAGGCTTGCATTAAAAGACTGI i CAGACCTTTG TCTGAAGGATTTTAAATGCTGTATGTCATTAAAGTGCACTGTGTCCTGAAGTTTTCATTATTTTTCAT TTCAAAGAATTCACTGGTATGGAACAGGTGATGTGGCATAAGGTGAGTGCACGGTATGTTCAGATCAC AGTGCCTTATGTCCGAATACAGCAATATGTCACCGCCGCAGCCGGGGCGCACGCGTGTGAAACAACAC CGAGCTTGAATGTGGAAGTCTTTGAACCTCTTACCAAATCAGTTTGTTTTCTTTAGATTTGTCAAAAA GTTGTAATTTGAATATAAATAATTACTTTAAAATTTTAATGACACTTTTACACGTAAGTGTTTTGTTC TGGGCTACCGTGTCAACGAGGCTGCTTTACAACAGCTTTATTTATTTTAC1TTCATGCAA1T iTTT ACACATCTTTTGGTGGAGTAAACTTCACCACATCCATGAATAAACTCTCAGTTATTTTGAAATGGCAA ATTTCTCATTATTTAAGTTTGGATCTGGAAAGGACATGACTTCTGAAATAGCCGCTGCTGGGTTTTAA AAGCTGAGGTCTCTCAAAGTGTGGAGGAGACGTTGCCGTCAGGCGGGAGCCAAGTGCCGGGAAGATGC CTATTTTTTTTCTTGTGTATTGAAATGTAAAATCATGATGTTTGTTATGACTGCTGATGCGATTGTTT TTGTAAATTTTATTGTGGCATATACAGTATTGTCATACAGTTGAAGAGAAACAATGTTTCCTAATGTA AGTGCTCTGAAAATGTTGACACTGTATATATATATATGAGGATAGTTTG1TTiTTTIGTITGGGTT SI I CAGATTGAAAAATTAAAATAAATCCTACTATCTACC NOV9c, SNP 13382599 of CG186895-01 SEQ ID NO: 72 328 aa MW at 37518.2kD Protein Sequence MLEKLEFEDEAVEDSESGVYMRFMRSHKCYDIVPTSSKLVVFDTTLQVKKAFFALVANGVRAAPlLWES KKQSFVGMLTITDFINILHRYYKSPMVQIYELEEHKIETWRELYLQETFKPLVNISPDASLFDAVYSL IKNKIHRLPVIDPISGNALYILTHKRILKFLQLFMPDMPKPAFMKQNLDELGIGTYHNIAFIHPDTPI IKALNIFVERRISALPVVDESGKVVDIYSKFDVINLAAEKTYNNLDITVTQALQHRSQYFEGVVKCNK LEILETIVDRIVRAEVHRLVVVNEADSIVGIISLSDILQALILTPAGAKQKETETE A ClustaW comparison of the above protein sequences yields the following sequence alignment shown in Table D33. Table D33. Comparison of the NOV9 protein sequences. NOV9 a MLEKLEFEDEAVEDSESGVYMRFMRSHKCYDIVPTSSKLVVFDTTLQVKKAFFALVANGV NOV9b MLEKLEFEDEAVEDSESGVYMRFMRSHKCYDIVPTSSKLVVFDTTLQVKKAFFALVANGV NOV9 c MLEKLEFEDEAVEDSESGVYMRFMRSHKCYDIVPTSSKLVVFDTTLQVKKAFFALVANGV NOV9 a RAAPLWESKKQSFVGMLTITDFINILHRYYKSPMVQIYELEEHKIETWRELYLQETFKPL NOV9b RAAPLWESKKQSFVGMLTITDFINILHRYYKSPMVQIYELEEHKIETWRELYLQETFKPL NOV9 c RAAPLWESKKQSFVGMLTITDFINILHRYYKSPMVQIYELEEHKIETWRELYLQETFKPL NOV9 a VNISPDASLFDAVYSLIKNKIHRLPVIDPISGNALYILTHKRILKFLQLFMSDMPKPAFM 171 WO 2004/056961 PCT/US2003/034114 NOV9b VNISPDASLFDAVYSLIKNKIHRLPVIDPISGNALYILTHKRILKFLQLFMSDMPKPAFM NOV9c VNISPDASLFDAVYSLIKNKIHRLPVIDPISGNALYILTHKRILKFLQLFMPDMPKPAFM NOV9a KQNLDELGIGTYHNIAFIHPDTPIIKALNIFVERRISALPVVDESGKVVDIYSKFDVINL NOV9b KQNLDELGIGTYHNIAFIHPDTPIIKALNIFVERRISALPVVDESGKVVDIYSKFDVINL NOV9c KQNLDELGIGTYHNIAFIHPDTPIIKALNIFVERRISALPVVDESGKVVDIYSKFDVINL NOV9a AAEKTYNNLDITVTQALQHRSQYFEGVVKCNKLEILETIVDRIVRAEVHRLVVVNEADSI NOV9b AAEKTYNNLDITVTQALQHRSQYFEGVVKCNKLEILETIVDRIVRAEVHRLVVVNEADSI NOV9c AAEKTYNNLDITVTQALQHRSQYFEGVVKCNKLEILETIVDRIVRAEVHRLVVVNEADSI NOV9a VGIISLSDILQALILTPAGAKQKETETE NOV9b VGIISLSDILQALILTPAGAKQMETETE NOV9c VGIISLSDILQALILTPAGAKQKETETE NOV9a (SEQ ID NO: 68) NOV9b (SEQ ID NO: 70) NOV9c (SEQ ID NO: 72) Further analysis of the NOV9a protein yielded the following properties shown in Table D34. Table D34. Protein Sequence Properties NOV9a SignalP analy s Cleavage site between residues 63 and 64 PSORT 11 analysis: PSG: a new signal peptide prediction method N-region: length 10; pos.chg 1; neg.chg 5 H-region: length 2; peak value 0.00 PSG score: -4.40 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -9.08 possible cleavage site: between 59 and 60 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -3.77 Transmembrane 300 - 316 PERIPHERAL Likelihood= 3.55 (at 40) ALOM score: -3.77 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 307 Charge difference: 3.0 C( 0.0) - N(-3.0) C > N: C-terminal side will be inside >>> Single TMS is located near the C-terminus >>> membrane topology: type Nt (cytoplasmic tail 1 to 299) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 5.71 Hyd Moment(95): 8.51 G content: 0 D/E content: 2 S/T content: 0 172 WO 2004/056961 PCT/US2003/034114 Score: -6.82 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 11.3% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 26.1 %: cytoplasmic 26.1 %: nuclear 13.0 %: endoplasmic reticulum 13.0 %: Golgi 173 WO 2004/056961 PCT/US2003/034114 8.7 %: vesicles of secretory system 8.7 %: mitochondrial 4.3 %: peroxisomal >> prediction for CG186895-01 is cyt (k=23) 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 D35. Table D35. Geneseq Results for NOV9a NOV9a Identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region AA018496 Human insulin receptor signaling modifier 1.328 328/328 (100%) 0.0 SEQ ID NO: 14 - Homo sapiens, 328 aa. 1.328 328/328 (100%) [W0200255664-A2, 18-JUL-2002] AA018495 Human insulin receptor signaling modifier 1..328 328/328 (100%) 0.0 SEQ ID NO: 12 - Homo sapiens, 352 aa. 25..352 328/328 (100%) (WO200255664-A2, 18-JUL-2002] AAB93432 Human protein sequence SEQ ID 1..328 328/328 (100%) 0.0 NO:12661 - Homo sapiens, 328 aa. 1..328 328/328 (100%) {EP1074617-A2, 07-FEB-2001] AAW88438 Disease associated protein kinase DAPK- 1..328 328/328 (100%) 0.0 7 - Homo sapiens, 328 aa. [W09858052- 1..328 328/328 (100%) A2, 23-DEC-1998] L .... n .... 2.-.. .... DE.. ------ ...... ... ... . ... ~ ABG20080 Novel human diagnostic protein #20071 - 1..328 291/342 (85%) e-147 Homo sapiens, 383 aa. [W0200175067- 42..383 302/342 (88%) A2, 11-OCT-2001] I 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 D36. Table D36. Public BLASTP Results for NOV9a Protein NOV9a Identities/ Accession ProteinlOrganismlLength Residues/ Similarities for Expect Number Match the Matched Value Residues Portion AAP35791 Protein kinase, AMP-activated, gamma 2 1..328 328/328 (100%) 0.0 non-catalytic subunit - Homo sapiens 1..328 328/328 (100%) (Human), 328 aa. AAP36858 Homo sapiens protein kinase, AMP- 1..328 328/328 (100%) 0.0 activated, gamma 2 non-catalytic subunit - 1 ..328 328/328 (100%) synthetic construct, 329 aa (fragment). Q9UGJO 5'-AMP-activated protein kinase, gamma- 1.328 328/328 (100%) 0.0 2 subunit (AMPK gamma-2 chain) (AMPK 242..569 328/328 (100%) gamma2) (H91620p) - Homo sapiens (Human), 569 aa. Q8BIQ9 Similar to AMP activated protein kinase 1.328 323/328 (98%) 0.0 gamma 1 - Mus musculus (Mouse), 443 117..443 326/328 (98%) 174 WO 2004/056961 PCT/US2003/034114 AAQ55225 AMP-activated protein kinase gamma 2 1 ..328 321/328 (97%) e-180 non-catalytic subunit - Rattus norvegicus 1..326 325/328 (98%) (Rat), 326 aa. PFam analysis predicts that the NOV9a protein contains the domains shown in the Table D37. Table D37. Domain Analysis of NOV9a Identities/ Pfam Domain NOV9a Match Region Similarities Expect Value for the Matched Region CBS 33. .87 10/55 (18%) 0.031 38/55(69%) [CBS 114..168 18/55(33%) 2.1e-06 1 41/55 (75%) CBS 189..242 19/54 (35%) 8.8e-11 I 43/ 54 (8 0%) CBS 261..314 _17/54(31%) 6.1e-06 I 39/54 (72%) NOV10 - AMPK gamma 3 The laboratory cloning was performed using one or more of the methods summarized in Example Q8. The NOV10 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table D38. Table D38. NOV10 Sequence Analysis INOV1Oa, CG186913-02 SEQ ID NO: 73 11647 bp DNA Sequence ORF Start ATG at 20 ORF Stop: TGA at 1487 TTGGTCTGGGGCTGGCCACATGGAGCCCGGGCTGGAGCACGCACTGCGCAGGACCCCTTCCTGGAGCA GCCTTGGGGGTTCTGAGCATCAAGAGATGAGCTTCCTAGAGCAAGAAAACAGCAGCTCATGGCCATCA CCAGCTGTGACCAGCAGCTCAGAAAGAATCCGTGGGAAACGGAGGGCCAAAGCCTTGAGATGGACAAG GCAGAAGTCGGTGGAGGAAGGGGAGCCACCAGGTCAGGGGGAAGGTCCCCGGTCCAGGCCAGCTGCTG AGTCCACCGGGCTGGAGGCCACATTCCCCAAGACCACACCCTTGGCTCAAGCTGATCCTGCCGGGGTG GGCACTCCACCAACAGGGTGGGACTGCCTCCCCTCTGACTGTACAGCCTCAGCTGCAGGCTCCAGCAC AGATGATGTGGAGCTGGCCACGGAGTTCCCAGCCACAGAGGCCTGGGAGTGTGAGCTAGAAGGCCTGC TGGAAGAGAGGCCTGCCCTGTGCCTGTCCCCGCAGGCCCCATTTCCCAAGCTGGGCTGGGATGACGAA CTGCGGAAACCCGGCGCCCAGATCTACATGCGCTTCATGCAGGAGCACACCTGCTACGATGCCATGGC AACTAGCTCCAAGCTAGTCATCTTCGACACCATGCTGGAGATCAAGAAGGCCTTCTTTGCTCTGGTGG CCAACGGTGTGCGGGCAGCCCCTCTATGGGACAGCAAGAAGCAGAGCTTTGTGGGGATGCTGACCATC ACTGACTTCATCCTGGTGCTGCATCGCTACTACAGGTCCCCCCTGGTCCAGATCTATGAGATTGAACA ACATAAGATTGAGACCTGGAGGGAGATCTACCTGCAAGGCTGCTTCAAGCCTCTGGTCTCCATCTCTC CTAATGATAGCCTGTTTGAAGCTGTCTACACCCTCATCAAGAACCGGATCCATCGCCTGCCTGTTCTT GACCCGGTGTCAGGCAACGTACTCCACATCCTCACACACAAACGCCTGCTCAAGTTCCTGCACATCTT TGGTTCCCTGCTGCCCCGGCCCTCCTTCCTCTACCGCACTATCCAAGATTTGGGCATCGGCACATTCC GAGACTTGGCTGTGGTGCTGGAGACAGCACCCATCCTGACTGCACTGGACATCTTTGTGGACCGGCGT GTGTCTGCACTGCCTGTGGTCAACGAATGTGGTCAGGTCGTGGGCCTCTATTCCCGCTTTGATGTGAT TCACCTGGCTGCCCAGCAAACCTACAACCACCTGGACATGAGTGTGGGAGAAGCCCTGAGGCAGAGGA CACTATGTCTGGAGGGAGTCCTTTCCTGCCAGCCCCACGAGAGCTTGGGGGAAGTGATCGACAGGATT GCTCGGGAGCAGGTACACAGGCTGGTGCTAGTGGACGAGACCCAGCATCTCTTGGGCGTGGTCTCCCT CTCCGACATCCTTCAGGCACTGGTGCTCAGCCCTGCTGGCATCGATGCCCTCGGGGCCTGAGAAGATC TGAGTCCTCAATCCCAAGCCACCTGCACACCTGGAAGCCAATGAAGGGAACTGGAGAACTCAGCCTTC ATCTTCCCCCACCCCCATTTGCTGGTTCAGCTATGATTCAGGTAGGCTCTGCCCTGGGCCATGACACC 175 WO 2004/056961 PCT/US2003/034114 IAGCCTCTTAGTCTTC

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NOV10a, CG186913-02 SEQ ID NO: 74 489 aa MW at 54257.4kD Protein Sequence MEPGLEHALRRTPSWSSLGGSEHQEMSFLEQENSSSWPSPAVTSSSERIRGKRRAKALRWTRQKSVEE GEPPGQGEGPRSRPAAESTGLEATFPKTTPLAQADPAGVGTPPTGWDCLPSDCTASAAGSSTDDVELA TEFPATEAWECELEGLLEERPALCLSPQAPFPKLGWDDELRKPGAQYMRFMQEHTCYDAMATSSKLV IFDTMLEIKKAFFALVANGVRAAPLWDSKKQSFVGMLTITDFILVLHRYYRSPLVQIYEIEQHKIETW REIYLQGCFKPLVSISPNDSLFEAVYTLIKNRIHRLPVLDPVSGNVLHILTHKRLLKFLHIFGSLLPR PSFLYRTIQDLGIGTFRDLAVVLETAPILTALDI FVDRRVSALPVVNECGQVVGLYSRFDVIHLAAQQ TYNHLDMSVGEALRQRTLCLEGVLSCQPHESLGEVIDRIAREQVHRLVLVDETQHLLGVVSLSDLQA LVLSPAGIDALGA F09V10b, G186913-01 SEQ ID NO: 75 2290 bp DNA Sequence ORF Start: ATG at 22 IORF Stop: TGA at 1498 GTTGGTCTGGGGCTGGCCACATGGAGCCCGGGCTGGAGCACGCACTGCGCAGGACCCTTCCTGGAG CAGCCTTGGGGGTTCTGAGCATCAAGAGATGAGCTTCCTAGAGCAAGAAAACAGCAGCTCATGGCCAT CACCAGCTGTGACCAGCAGCTCAGAAAGAATCCGTGGGAAACGGAGGGCCAAAGCCTTGAGATGGACA AGGCAGAAGTCGGTGGAGGAAGGGGAGCCACCAGGTCAGGGGGAAGGTCCCCGGTCCAGGCCAGCTGC TGAGTCCACCGGGCTGGAGGCCACATTCCCCAAGACCACACCCTTGGCTCAAGCTGATCCTGCCGGGG TGGGCACTCCACCAACAGGGTGGGACTGCCTCCCCTCTGACTGTACAGCCTCAGCTGCAGGCTCCAGC ACAGATGATGTGGAGCTGGCCACGGAGTTCCCAGCCACAGAGGCCTGGGAGTGTGAGCTAGAAGGCCT GCTGGAAGAGAGGCCTGCCCTGTGCCTGTCCCCGCAGGCCCCATTTCCCAAGCTGGGCTGGGATGACG AACTGCGGAAACCCGGCGCCCAGATCTACATGCGCTTCATCGAGGAGCACACCTGCTACGATGCCATG GCAACTAGCTCCAAGCTAGTCATCTTCGACACCATGCTGGAGATCAAGAAGGCCTTCTTTGCTCTGGT GGCCAACGGTGTGCGGGCAGCCCCTCTATGGGACAGCAAGAAGCAGAGCTTTGTGGGGATGCTGACCA TCACTGACTTCATCCTGGTGCTGCATCGCTACTACAGGTCCCCCCTGGTCCAGATCTATGAGATTGAA CAACATAAGATTGAGACCTGGAGGGAGATCTACCTGCAAGGCTGCTTCAAGCCTCTGGTCTCCATCTC TCCTAATGATAGCCTGTTTGAAGCTGTCTACACCCTCATCAAGAACCGGATCCATCGCCTGCCTGTTC TTGACCCGGTGTCAGGCAACGTACTCCACATCCTCACACACAAACGCCTGCTCAAGTTCCTGCACATC TTTGGTTCCCTGCTGCCCCGGCCCTCCTTCCTCTACCGCACTATCCAAGATTTGGGCATCGGCACATT CCGAGACTTGGCTGTGGTGCTGGAGACAGCACCCATCCTGACTGCACTGGACATCTTTGTGGACCGGC GTGTGTCTGCACTGCCTGTGGTCAACGAATGTGGTCAGGTCGTGGGCCTCTATTCCCGCTTTGATGTG ATTCACCTGGCTGCCCAGCAAACCTACAACCACCTGGACATGAGTGTGGGAGAAGCCCTGAGGAAGAG GACACTATGTCTGGAGGGAGTCCTTTCCTGCCAGCCCCACGAGAGCTTGGGGGAAGTGATCGACAGGA TTGCTCGGGAGCAGGTACACAGGCTGGTGCTAGTGGACGAGACCCAGCATCTCTTGGGCGTGGTCTCC CTCTCCGACATCCTTCAGGCACTGGTGCTCAGCCCTGCTGGCATCGATCCCTCGGGGCCTGAGAAGAT CTGTAACTCAGCCTT CATCTTCCCCCACCCCCATTGCTGGTTCAGCTATGA-TCAGGCTCTCAGGCCCTCCCAAATTGCC CTTGCCCTACCAGAGCTCCCAGAAGCCCTCGGCATGCCAGTGCACCATGGGATGATGAAATTAAGGAG AACAGCTGAGTCAAGCTTGGAGGTCCCTAAGCCAGAGGCACTAGGAACCCCAGGGCCATCTGTGCT CATGCCCGCCCATCCCCGCCGCCTGACTGGGTCGGATGGCCCCCAGTGGG.AGTCAGGGCC TGGATCCTCGGTTUCTGGGCTACCTATGCTTCACCTTCAGCTCCTGGGAGTCCCAGCAACGTCGCCA CTGCCCCTCCTACTCTCCAGGGGTTGGTCATTTCAAGGCTGCTGAAATGCTGCATUTCAGGGGGCCAC CATGGAGCAGCCGTTATATAGAACTGCCCTG11GGAGGTGGGGAGTCCTCCCTCCAUOUTGTCCA GAAAACTCCTTAGCTCTCGCAGTGAGCCCATGTTCUTAGTCTCCAGGGATGGATGGCCU-GTATATGG ACCCCTGAGAATGAGCAATTGAGAAAACAAAACAAGGAACAATCCATGAACTAGAThTTAUGGT TTCACTCAAAATGCTGAGTCATTGACCTGAACTGTGGCAAGAGACGTGCCTAMTCA

GACTAGAAGGGAAATGGATAAAAATCACAAGTGCCGTTTCTCTTGC

INOV10b, CG186913-01 5SQI N:7 492 aa MW at 54636.8kD Protein Sequence .. _ _ MEPGLEHALRRTPSWSSLGGSEHQEMSFLEQENSSSWPSPAVTSSSERIRGKRRAKLRWTRQKSVEE GEPPGQGEGPRSRPAAESTGLEATFPKTTPLAQADPAGVGTPPTGWDCLPSDCTASAAGSSTDDVELA TEFPATEAWECELEGLLEERPALCLSPQAPFPKLGWDDELRKPGAOIYMRFIEEHTCYDAMATSSKLV IFDTMLEIKKAFFALVANGVRAAPLWDSKKQSFVGMLTITDFILVLHRYYRSPLVQIYEIEQHKIETW REIYLQGCFKPLVSISPNDSLFEAVYTLIKNRIHRLPVLDPVSGNVLHILTHKRLLKFLHIFGSLLPR PSFLYRTIQDLGIGTFRDLAVVLETAPILTALDIFVDRRVSALPVVNECGQVVGLYSRFDVIHLAAQQ TYNHLDMSVG EALRKRTLCLEGVLSCQPHESLG EVIDRIAREQVHRLVLVDETQHLLGVVSLSDILQA LVLSPAGIDPSGPEKI 176 WO 2004/056961 PCT/US2003/034114 A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table D39. Table D39. Comparison of the NOV10 protein sequences. NOV10a MEPGLEHALRRTPSWSSLGGSEHQEMSFLEQENSSSWPSPAVTSSSERIRGKRRAKALRW NOV10b MEPGLEHALRRTPSWSSLGGSEHQEMSFLEQENSSSWPSPAVTSSSERIRGKRRAKALRW NOV10a TRQKSVEEGEPPGQGEGPRSRPAAESTGLEATFPKTTPLAQADPAGVGTPPTGWDCLPSD NOV10b TRQKSVEEGEPPGQGEGPRSRPAAESTGLEATFPKTTPLAQADPAGVGTPPTGWDCLPSD NOV10a CTASAAGSSTDDVELATEFPATEAWECELEGLLEERPALCLSPQAPFPKLGWDDELRKPG NOV10b CTASAAGSSTDDVELATEFPATEAWECELEGLLEERPALCLSPQAPFPKLGWDDELRKPG NOV10a AQIYMRFMQEHTCYDAMATSSKLVIFDTMLEIKKAFFALVANGVRAAPLWDSKKQSFVGM NOV10b AQIYMRFIEEHTCYDAMATSSKLVIFDTMLEIKKAFFALVANGVRAAPLWDSKKQSFVGM NOV10a LTITDFILVLHRYYRSPLVQIYEIEQHKIETWREIYLQGCFKPLVSISPNDSLFEAVYTL NOV10b LTITDFILVLHRYYRSPLVQIYEIEQHKIETWREIYLQGCFKPLVSISPNDSLFEAVYTL NOV10a IKNRIHRLPVLDPVSGNVLHILTHKRLLKFLHIFGSLLPRPSFLYRTIQDLGIGTFRDLA NOV10b IKNRIHRLPVLDPVSGNVLHILTHKRLLKFLHIFGSLLPRPSFLYRTIQDLGIGTFRDLA NOV10a VVLETAPILTALDIFVDRRVSALPVVNECGQVVGLYSRFDVIHLAAQQTYNHLDMSVGEA NOV10b VVLETAPILTALDIFVDRRVSALPVVNECGQVVGLYSRFDVIHLAAQQTYNHLDMSVGEA NOV10a LRQRTLCLEGVLSCQPHESLGEVIDRIAREQVHRLVLVDETQHLLGVVSLSDILQALVLS NOV10b LRKRTLCLEGVLSCQPHESLGEVIDRIAREQVHRLVLVDETQHLLGVVSLSDILQALVLS NOV10a PAGIDALGA-- NOV10b PAGIDPSGPEKI NOV10a (SEQ ID NO: 74) NOV10b (SEQ ID NO: 76) Further analysis of the NOV10a protein yielded the following properties shown in Table D40. Table D40. Protein Sequence Properties NOV10a SignP analysis: No Known Signal Sequence Predicted PSORT 1I analysis: PSG: a new signal peptide prediction method N-region: length 11; pos.chg 2; neg.chg 2 H-region: length 10; peak value 4.75 PSG score: 0.35 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -8.63 possible cleavage site: between 20 and 21 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 2 INTEGRAL Likelihood = -2.28 Transmembrane 360 - 376 INTEGRAL Likelihood = -2.66 Transmembrane 464 - 480 PERIPHERAL Likelihood= 1.80 (at 235) 177 WO 2004/056961 PCT/US2003/034114 ALOM score: -2.66 (number of TMSs: 2) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 367 Charge difference: 2.0 C( 0.0) - N(-2.0) C > N: C-terminal side will be inside >>>Caution: Inconsistent mtop result with signal peptide >>> membrane topology: type 3b MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 7.57 Hyd Moment(95): 9.87 G content: 1 D/E content: 2 S/T content: 0 Score: -6.88 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 9.6% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none 1 RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination 178 WO 2004/056961 PCT/US2003/034114 Prediction: cytoplasmic Reliability: 89 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 44.4 %: endoplasmic reticulum 11.1 %: vacuolar 11.1 %: vesicles of secretory system 11.1 %: nuclear 11.1 %: Golgi 11.1 %: mitochondrial >> prediction for CG186913-02 is end (k=9) A search of the NOV1 Oa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table D41. Table D41. Geneseq Results for NOV10a NOV10a Identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region AAE32034 Human kinase and phosphatase (KPP)-15 1..489 489/489 (100%) 0.0 - Homo sapiens, 489 aa. [W0200283709- 1..489 489/489 (100%) A2, 24-OCT-2002 AAB47679 PRKAG3 - Homo sapiens, 489 aa. 1..489 489/489 (100%) 0.0 [W02001 77305-A2, 18-OCT-2001] 1 .. 489 489/489 (100%) ABP43929 AMP activated protein kinase gamma 3 1..489 487/489 (99%) 0.0 subunit - Homo sapiens, 489 aa. 1..489 489/489 (99%) [W0200231 111 -A2, 18-APR-2002] II AAE00223 Human AMPK gamma subunit muscle- 26..489 463/464 (99%) 0.0 specific isoform, complete PRKAG3 - 1..464 463/464 (99%) Homo sapiens, 464 aa. [W0200120003 A2, 22-MAR-2001] AAE00224 Sus scrofa Prkag3 splice variant - Sus 12..489 412/479 (86%) 0.0 scrofa, 514 aa. [W0200120003-A2, 22- 37.514 432/479 (90%) MAR-2001] In a BLAST search of public sequence databases, the NOVI 0a protein was found to have homology to the proteins shown in the BLASTP data in Table D42. Table D42. Public BLASTP Results for NOVI 0a Protein NOV10a identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion CAD10589 Sequence 5 from Patent WO0177305 - 1..489 489/489 (100%) 0.0 Homo sapiens (Human), 489 aa. 1..489 489/489 (100%) 179 WO 2004/056961 PCT/US2003/034114 Q9UGI9 5'-AMP-activated protein kinase, gamma- 26..489 463/464 (99%) 0.0 3 subunit (AMPK gamma-3 chain) (AMPK 1..464 463/464 (99%) gamma3) - Homo sapiens (Human), 464 aa. Q8BGM7 AMP-activated protein kinase gamma 3 1..489 415/490 (84%) 0.0 subunit long form (5'-AMP-activated 1..89 432/490 (87%) protein kinase) - Mus musculus (Mouse), 489 aa. Q9MYP4 5'-AMP-activated protein kinase, gamma- 12..489 412/479 (86%) 0.0 3 subunit (AMPK gamma-3 chain) (AMPK 37..514 432/479 (90%) gamma3) - Sus scrofa (Pig), 514 aa. Q80WK8 AMP-activated protein kinase gamma 1..489 415/491 (84%) 0.0 subunit - Mus musculus (Mouse), 490 aa. 1..490 432/491 (87%) PFam analysis predicts that the NOVI 0a protein contains the domains shown in the Table D43. Table D43. Domain Analysis of NOVI Oa Identities/ Pfam Domain NOV1Oa Match Region Similarities Expect Value for the Matched Region CBS 197..251 11/55(20%) 0.0022 37/55 (67%) BS 278..332 19/55 (35%) 7.6e-09 CBS. .. ... 2 3 .. . . 43/55 (78%) 1 CBS 353..406 15/54 (28%) 5.1 e-09 40/54 (74%) CBS 425..478 18/54 (33%) 5.5e-10 43/54 (80%) Example D3. Human AMP-activated Protein Kinase Gene Variants and SNPs The protocol for obtainment of gene variants and SNPs is disclosed in Example Q1 1. The variants of the human AMP-activated Protein Kinase were obtained from direct cloning and/or public databases. In addition to the human version of the AMP-activated Protein Kinase identified as being differentially expressed in the experimental study, other variants have been identified by direct sequencing of cDNAs derived from many different human tissues and from sequences in public databases. Table D43-1 below demonstrates discovered SNP sequences, wherein nucleotide N 1 is C or G, and wherein residue X 1 is T or S. SNP of CG186882-01 SEQ ID NO: 148 1578 bp DNA Sqence [9RF Start: ATG at 68 ORF Stop: TGA at 1088 GCGCCCTTAAAGATGGTGAGGGGGCTCATGCTCTGAGTAGAAGGTGGTGACCTCCAGGAGCGGTGGGA TGATGAGGGCCCGGGCGCCTCTTGCAATGGAGACGGTCATTTCTTCAGATAGCTCCCCAGCTGTGGAA AATGAGCATCCTCAAGAGACCCCAGAATCCAACAATAGCGTGTATACTTCCTTCATGAAGTCTCATCG CTGCTATGACCTGATTCCCACAAGCTCCAAATTGGTTGTATTTGATACGTCCCTGCAGGTGAAGAAAG CTITTTTGCTTTGGTGACTAACGGTGTACGAGCTGCCCCTTTATGGGATAGTAAGAAGCAAAGTTTT GTGGGCATGCTGACCATCANITGATTTCATCAATATCCTGCACCGCTACTATAAATCAGCCTTGGTACA 180 WO 2004/056961 PCT/US2003/034114 GATCTATGAGCTAGAAGAACACAAGATAGAAACTTGGAGAGAGGTGTATCTCCAGGACTCCTTTAAAC CGCTTGTCTGCATTTCTCCTAATGCCAGCTTGTTTGATGCTGTCTCTTCATTAATTCGGAACAAGATC CACAGGCTGCCAGTTATTGACCCAGAATCAGGCAATACTTTGTACATCCTCACCCACAAGCGCATTCT GAAGTTCCTCAAATTGTTTATCACTGAGTTCCCCAAGCCAGAGTTCATGTCCAAGTCTCTGGAAGAGC TACAGATTGGCACCTATGCCAATATTGCTATGGTTCGCACTACCACCCCCGTCTATGTGGCTCTGGGG AlIIIGTACAGCATCGAGTCTCAGCCCTGCCAGTGGTGGATGAGAAGGGGCGTGTGGTGGACATCTA CTCCAAGTTTGATGTTATCAATCTGGCAGCAGAAAAGACCTACAACAACCTAGATGTATCTGTGACTA AAGCCTTGCAACATCGATCACATTACTTTGAGGGTGTTCTCAAGTGCTACCTGCATGAGACTCTGGAG ACCATCATCAACAGGCTAGTGGAAGCAGAGGTTCACCGACTTGTAGTGGTGGATGAAAATGATGTGGT CAAGGGAATTGTATCACTGTCTGACATCCTGCAGGCCCTGGTGCTCACAGGTGGAGAGAAGAAGCCCT GAGCTGGGGGAAGGGGTCATGCAGCACCAGGGGATATGCCCAACTCACTGCCTGCTGGAMGCTCTGTG GGAATCAGATGAAACTTGAGGGAATTGTGACTCTGTTCCC-GTTCAGGGTCCCCTGCCCTTCTATCTG GGAGCTAGGGAAGGTATGGGGGAGGAAAGAGAATGGATTTATAGCTACCCTTACCCTCACACATACAC TTGAAAAAACTTTCAGCCTAGCCAGTiCTAGCCCCTGTCCTCTTAGATATATCCCCCTTTCTGGGTGA A TATAGGCTCTGTGCCTCTCAGACAATTCTACTCTAAGAGATCCCCAGACCTCACTTGCCTCTG CCTCACTGCCTGTCAACGTAAAAGGAcAAAATCTTCATAAGATATm--T-IA 1rCACCTGTTICCGTGCTATATGGAGGAGGCCAAGTCCAT-nAGTGACAmGUGTTCCATAATGTGAGT GGGGAGGATTGTGG [Wherein nucleotide N 1 is C or G] SNP of CG 186882-01 fSEQ ID NO: 149 14 a at 38577.2kD Protein Sequence___MW___ MMRARAPLAMETVISSDSSPAVENEHPQETPESNNSVYTSFMKSHRCYDLIPTSSKLVVFDTSLQV

AFFALVTNGVRAAPLWDSKKQSFVGMLTX

1 DFINILHRYYKSALVQIYELEEHKIETWREVYLQDSFK PLVCISPNASLFDAVSSLIRNKIHRLPVIDPESGNTLYILTHKRILKFLKLFITEFPKPEFMSKSLEE LQIGTYANIAMVRTTTPVYVALGIFVQHRVSALPVVDEKGRVVDIYSKFDVINLAAEKTYNNLDVSVT KALQHRSHYFEGVLKCYLHETLETIINRLVEAEVHRLVVVDENDVVKGIVSLSDILQALVLTGGEKKP [Wherein residue X,_is T orS.) Table D43-2 below demonstrates discovered SNP sequences, wherein N 1 is T or C; N 2 is A or T, and wherein X 1 is S or P; X 2 is K or M. ISNPof CG ,1868"95-0;1 - TSEQ ID NO: 150 f2223 bp _DNA Sequence _ ORF Start: ATG at 160 IORF Stop: TGA at 1144 AGGCCCCTCCTCCCGGCGGCGCGGCAGAGCCAGGCCCCAGCGCTCGGCCGGCCGCGAGCCCGCCGGCC GGGGACGAGCGTCGCAGCTCATGCTGATCGCTGTCCTCCTCCTCCCCCTCAGGCGGCGCTGGCGGCGG CCCTGGGACCCGCGGAAGCCGGCATGCTGGAGAAGCTGGAGUTTCGAGGACGAAGCAGTAGAAGACTCA GAAAGTGGTGTTTACATGCGATTCATGAGGTCACACAAGTGTTATGACATCGTTCCAACCAGTTCAAA GCTTGTTGTCTTTGATACTACATTACAAGTTAAAAAGGCCTTCTTTGCTTTGGTAGCCAACGGTGTCC GAGCAGCGCCACTGTGGGAGAGTAAAAAACAAAGTTTTGTAGGAATGCTAACAATTACAGATTTCATA AATATACTACATAGATACTATAAATCACCTATGGTACAGATTTATGAATTAGAGGAACATAAAATTGA AACATGGAGGGAGCTTTATTTACAAGAAACATTTAAGCCTTTAGTGAATATATCTCCAGATGCAAGCC TCTTCGATGCTGTATACTCCTTGATCAAAAATAAAATCCACAGATTGCCCGTTATTGACCCTATCAGT GGGAATGCACTTTATATACTTACCCACAAAAGAATCCTCAAGTTCCTCCAGC iiATGN1CTGATAT GCCAAAGCCTGCCTTCATGAAGCAGAACCTGGATGAGCTTGGAATAGGAACGTACCACAACATTGCCT TCATACATCCAGACACTCCCATCATCAAAGCCTTGAACATATTTGTGGAAAGACGAATATCAGCTCTG CCTGTTGTGGATGAGTCAGGAAAAGTTGTAGATATTTATTCCAAATTTGATGTAATTAATCTTGCTGC TGAGAAAACATACAATAACCTAGATATCACGGTGACCCAGGCCCTTCAGCACCGTTCACAGTATTTTG AAGGTGTTGTGAAGTGCAATAAGCTGGAAATACTGGAGACCATCGTGGACAGAATAGTAAGAGCTGAG GTCCATCGGCTGGTGGTGGTAAATGAAGCAGATAGTATTGTGGGTATTATTTCCCTGTCGGACATTCT

GCAAGCCCTGATCCTCACGCCAGCAGGTGCCAAACAAAN

2 GGAGACAGAAACGGAGTGACCGCCGTGAA TGTAGACGCCCTAGGAGGAGAACTTGAACAAAGTCTCTGGGTCACGTTTTGCCTCATGAACACTGGCT GCAAGTGGTTAAGAATGTATATCAGGGTTAACGATAGGTATTTCTTCCAGTGATGTTGAAATTAAGC TTAAAAAAGAAAGATTTTATGTGCTTGAAGATTCAGGCTTGCATTAAAAGACTGTTTTCAACTTTG TCTGAAGGATTTTAAATGCTGTATGTCATTAAAGTGCACTGTGTCCTGAAGTTTTCATTATTTTTCAT TTCAAAGAATTCACTGGTATGGAACAGGTGATGTGGCATAAGGTGAGTGCACGGTATGTTCAGATCAC 181 WO 2004/056961 PCT/US2003/034114 AGTGCCTTATGTCCGAATACAGCAATATGTCACCGCCGCAGCCGGGGCGCACGCGTGTGAAACAACAC CGAGCTTGAATGTGGAAGTCTTTGAACCTCTTACCAAATCAGTTTGTTTTCTTTAGATTTGTCAAAAA GTTGTAATTTGAATATAAATAATTACTTTAAAATTTTAATGACACTTTTACACGTAAGTGTTTTGTTC TGGGCTACCGTGTCAACGAGGCTGCTTTACAACAGCTTTATTTA1TrTTACTTTCATGCAA 1TFFFT ACACATCTTTTGGTGGAGTAAACTTCACCACATCCATGAATAAACTCTCAGTTATTTTGAAATGGCAA ATTTCTCATTATTTAAGTTTGGATCTGGAAAGGACATGACTTCTGAAATAGCCGCTGCTGGGTTTTAA AAGCTGAGGTCTCTCAAAGTGTGGAGGAGACGTTGCCGTCAGGCGGGAGCCAAGTGCCGGGAAGATGC CTATIrTTTTTCTTGTGTATTGAAATGTAAAATCATGATGTTTGTTATGACTGCTGATGCGATTGTTT TTGTAAATTTTATTGTGGCATATACAGTATTGTCATACAGTTGAAGAGAAACAATGTTTCCTAATGTA AGTGCTCTGAAAATGTTGACACTGTATATATATATATGAGGATAGTTTGTTTTTTFTGTTTTGGGTT iii iiiii i TCAGATTGAAAAATTAAAATAAATCCTACTATCTACC [Wherein N 1 is T or C; N 2 is A or T.j SNf oG18689s-i SEQ 6 NO 151 328 aa Mat 37505.ko Protein Sequence MLEKLEFEDEAVEDSESGVYMRFMRSHKCYDIVPTSSKLVVFDTTLQVKKAFFALVANGVRAAPLWES KKQSFVGMLTITDFINILHRYYKSPMVQIYELEEHKIETWRELYLQETFKPLVNISPDASLFDAVYSL

IKNKIHRLPVIDPISGNALYLTHKRILKFLQLFMX

1 DMPKPAFMKQNLDELGIGTYHNIAFIHPDTPI IKALNIFVERRISALPVVDESGKVVDIYSKFDVINLAAEKTYNNLDITVTQALQHRSQYFEGVVKCNK LEILETIVDRIVRAEVHRLVVVNEADSIVGIISLSDI LQALILTPAGAKQX 2 ETETE [Wherein X, is S or P; X 2 is K or M.] Example D4: Expression Profile of the Human AMP-activated Protein Kinase The protocol for quantitative expression analysis is disclosed in Example Q9. To determine skeletal muscle specific composition of AMP-activated kinase, the expression of two catalytic alpha subunits, two regulatory beta subunits and three regulatory gamma subunits have been analyzed by RTQ-PCR. CG91149-01: AMP-activated protein kinase - alpha 1 Expression of gene CG91149-01 was assessed using the primer-probe set ag3673, described in Table D44. Results of the RTQ-PCR runs are shown in Tables D45 and D46. Table D44. Probe Name ag3673 Primers Sequences Length, Start Position SEQ ID No Forward 5'-aacagaaatcaccaggatcctt-3' 22 966 116 Probe. TET-5'-tggcagttgcctaccatctcataata-3'-TAMRA 26 988 1 117 Reverse 5'-tgtcgccaaatagaaatctttg-3' 22 1040 118 Table D45. General-screening-panel-v1.4 Column A - Rel. Exp.(%) a93673, Run 218901791 Tissue Name A Tissue Name A Adipose -- -- - - - 10.7 [Renal ca. TK-10 --- 2. Melanoma* Hs688(A).T 41.5 Bladder 30.1 Melanoma* Hs688(B).T 39.0 Gastric ca. (liver met.) NCI-N87 72.2 Melanoma* M14 23.3 IGastric ca. KATO Ill 61.6 Melanoma* LOXIMVI 47. Colon ca. SW-948 9.5 j~lnoa I 4a3 C5olon ca. SW480 j-I7 jSquamous cell carcinoma SCC-4 39.5 Colon ca.* (SW480 met) SW620 F40.6 ITestis Pool 24.5 Colon ca. HT29 48.3 Prostate ca.* (bone met) PC-3 49.7 Colon ca. HCT-1 16 41.2 182 WO 2004/056961 PCT/US2003/034114 Prostate Pool 12.7 Colon ca. CaCo-2 50.0 Placenta 3.2 Colon cancer tissue 25.5 Uterus Pool 7.6 Colon ca. SW1116 5.__6 Ovarian ca. OVCAR-3 28.5 Colon ca. Colo-205 8.7 Ovarian ca. SK-OV-3 41.5 Colon ca. SW-48 13.8 Ovarian ca. OVCAR-4 11.9 Colon Pool 29.3 Ovarian ca. OVCAR-5 55.5 Small Intestine Pool 25.0 -(~nnca GO- 24.5 IjStomach Pool 1. [Ovaian ca. IGOV1 4 . -st -~ -- ~5-7~ [ovarian ca. OVCAR-8 12.7 Bone Marrow Pool Ovary 12.4 Fetal Heart 119.5 Breast ca. MCF-7 19.8 Heart Pool 13.4 Breast ca. MDA-MB-231 56.3 Lymph Node Pool 34.4 Breast ca. BT 549 69.7 Fetal Skeletal Muscle 9.6 Breast ca. T47D 100.0 [~eletal Muscle Pool8.8 [Breast ca. MDA-N* 1 .....--- ------- 17.0 jSpleen Pool _ _ _ _ _ _ _ _ _ 1. Breast Pool 26.6 Thymus Pool 20.0 Trachea 21.2 CNS cancer (glio/astro) U87-MG 35.6 Lung 6.7 CNS cancer (glio/astro) U-1 18-MG 73.7 Fetal Lung 66.4 CNS cancer (neuro;met) SK-N-AS 34.9 .a .C...1 . ..... .. 1 1 5 .4. .................... - ..... ....... Lung ca. NCl-N417 6.6 1CNS cancer (astro) SF-539 15.4 Lung ca. LX-1 42.3 CNS cancer (astro) SNB-75 69.3 Lung ca. NCI-H146 6.2 CNS cancer (glio) SNB-19 27.0 11-un~gca. SHP-77 1-41.5 dCNS cancer (giio) SF-295 - 179.0 Lung ca. A549 46.7 Brain (Amygdala) Pool 7.9 1Lung ca. NCI-H526 7.8 Brain (cerebellum) 14.1 Lung ca. NCI-H23 65.5 Bra in (fetal) 10.3 Lung ca. NCI-H460 27.4 Brain (Hippocampus) Pool 78 Lung ca. HOP-62 21.8 Cerebral Cortex Pool 12.2 1Lung ca. NCI-H522 31.6 Brain (Substantia nigra) Pool 8.1 Liver 1.8 Brain (Thalamus) Pool 15.5 Fetal Liver 37.1 Brain (whole) 8.5 Liver ca. HepG2 19.5 Spinal Cord Pool 10.2 1Kidne' Pool-"* .1. . 41.2 l14drenal Gland 111.7 ]Fetal Kidney 41.5 Pituitary gland Pool 6.0 Renal c786. 683 Salivary Gland 6.2 - -------- * .. -------- Renal ca. A498 1 16.5 Th ro 1 er )8. 3 Renal ca. ACHN 16.5 IPancreatic ca. CAPAN2 34.2 Rena--a.---3 - - --- lPancre -as' Poo 130.8 Table D46. Panel 5D - Column A - Rel. Exp.(%) ag3673, Run 169315835 Tissue Name A Tissue Name A 97457 Patient-02go adipose 50.3 94709 Donor 2 AM -A adipose 76.3 97476 Patient-07sk skeletal muscle 31.4 94710 Donor 2 AM - B adipose 46.7 97477 Patient-07ut uterus 39.5 94711 Donor 2 AM - C adipose 34.2 97478 Patient-07pl placenta 33.4 94712 Donor 2 AD - A adipose 52.1 ............ 197.48.1Patient-8skske'letalmusclef.13 Donor 2 AD - B adipose 78.5 183 WO 2004/056961 PCT/US2003/034114 97482 Patient-O8ut uterus 27.4 194714 Donor 2 AD - C adipose 5 97483 Patient-08pl placenta 41.8 Cell2 Donor 3 U - A Mesenchymal Stem 1.6 P n9s 94743 Donor 3 U - B Mesenchymal Stem [97486 Patient-O9sk skeletal muscle 12. 4el 3. 97487 Patient-09ut uterus 76.3 94730 Donor 3 AM - A adipose 71.2 97488 Patient-09pl placenta 19.8 94731 Donor 3 AM - B adipose 47.0 [97492 Patient-1 Out uterus 64.6 94732 Donor 3 AM - C adipose 179.0 97493 Patient-10pl placenta 47.6 94733 Donor 3 AD - A adipose 72.2 97495 Patient-11 go adipose 46.0 94734 Donor 3 AD - B adipose 45.1 197496 Patient-11 sk skeletal muscle F25.7 94735 Donor 3 AD - C adipose 57.4 97497 Patient- 11 ut uterus 60.7 77138 Liver HepG2untreated 73.7 97498 Patient-i 1 p) placenta 25.53556 Ieart cardiac stromal cells primaryr y) 48.6 [97500 Patient-12go adipose ) 54.7 81735 Small Intestine 76.3 97501 Patient-12sk skeletal muscle 140.9 72409 Kidney Proximal Convoluted Tubule 42.6 97502 Patient-12ut uterus 100.0 82685 Small intestine Duodenum 39.5 97503 Patient-12pl placenta 16.7 90650 Adrenal Adrenocortical adenoma 13.5 94721 Donor 2 U -A Mesenchymal Stem 43. 572410 Kidney HRCE 64.2 Cells __ _ _ __ _ _1 Kine C 94722 Donor 2 U - B Mesenchymal Stem 26.4 72411 Kidney HRE 52.1 Cells 94723 Donor 2 U - C Mesenchymal Stem 1133 oCells 0.5 73139 Uterus Uterine smooth muscle cells 42.9 Generalscreening-paneLv1.4 Summary: Ag3673 The highest expression of this gene was detected in the breast cancer cell line T47D (CT=27). This gene was upregulated in cell lines derived from melanoma, breast cancer, lung cancer, colon cancer, ovarian cancer, and various brain cancers. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of these cancers. Among tissues with metabolic or endocrine function, this gene was expressed at moderate to low 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. Panel 5D Summary: Ag3673 The highest expression of this gene was detected in a uterus sample (CT=30). This gene was expressed at moderate to low levels in all tissues with metabolic or endocrine function represented on this panel. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. CG186855-01: Protein kinase, AMP-activated, alpha 2 catalytic subunit. Expression of gene CG186855-01 was assessed using the primer-probe set Ag7384, described in Table D47. Results of the RTQ-PCR runs are shown in Tables D48 and D49. Table D47. Probe Name Ag7384 [PrImers Ij Sequences LengthjStarti Positionf SEQ ID No [Forward 5' -ctacagacgattaacacaccacact-3' 25 2002 T 119 [Probe jTET-5'-accacccttacattgagatggttcgc-3'-TAMRAI 26 _ 2028 120 184 WO 2004/056961 PCT/US2003/034114 reversee 21-taaactagat Table D48. Generalscreening panel v1.7 Column A - Rel. Exp.(%) Ag7384, Run 318345346 Tissue Name A Tissue Name A pose 11.3 Gastric ca. (liver met.) NCI-N87 0.4 HUVEC 4.8 Stomach 1.3 *-elanoma* Hs688(A).T O.ola S fMelanoma* Hs6B8(B).T 0. ~0Colon ca. SW-48 0. Melanoma (met)_SK-MEL-5 f 0.5 l~lo ca 540mt W620 __ i 8.5 T~estis....--I 3.1 Colon ca. HT29 _ ________10.0 Prostate ca. (bone met) PC-3 0.0 Colon ca. HCT-1 16 3.8 [Prostate ca. DU145 11.5 Colon cancer tissue 0.1 [rostie I pool I c' . '5 Colon a. SW116 0.0 Uterus pool 1.3 jColon ca. Colo-205 0.0 Ovarian ca. OVCAR-3 8.0 IColon ca. SW-48 0.0 Ovarian ca. (ascites) SK-OV-3 0.3 Colon 5.6 [Ovarian ca. OVCAR-4 [31.4 Small Intestine 3.2 Ovarian ca. OVCAR-5 12.8 Fetal Heart 50.0 Ovarian ca. IGROV-1 33.9 Heart 15,8 narian ca. OVCAR-8 11.3 Lymph Node Pool 1.4 Ovary 9.7 Lymph Node pool 2 3.4 [Breast ca. MCF-7 0.1 Fetal Skeletal Muscle 4.3 [Beast ca. MDA-MB-231 17.0 Skeletal Muscle pool 21.5 Breast ca. BT 549 - 2.4 Skeletal Muscle 100.0 IBreast ca. T47D 5 ~ ~e e n129 113452 mammary gland 2.3 Thymus 1.3 Trachea 321 CNS cancer (glio/astro) SF-268 9.6 Lung 10.3 IONS cancer (glio/astro) T98G 0.1 Fetal Lung 5.9 CNS cancer (neuro;met) SK-N-AS 0.1 Lung ca. NCI-N417 1 1 .3 FCNS cancer (astro) SF-539 [Lung ca. LX-1 F1 6.2 [ONS cancer (astro) SNB:7'50. Lung ca. NCI-H146 0.1 CNS cancer (glio) SNB-19 8.4 Lg ca. SHP-77 - 1 -43 INS cancer (glio) SF-295 122 Lungca.~NCI-H23 1-1 .3 Brain (Amygdala) 11.9 ung ca. NC-H460 18.6 1Brain (Cerebellum) 26.1 Lung ca. HOP-62 2.7 Brain (Fetal) 14.4 Lung ca. NCI-H522 0.6 Brain (Hippocampus) 6.4 [Lung ca. DMS-114 .. 1 1.4 Cerebral Cortex pool 6.9 Liver 0.2 Brain (Substantia nigra) 2.7 Fetal Liver 1.2 Brain (Thalamus) 7.4 Kidney pool 55.1 IBrain (Whole) 63.3 lFetal Kidney 5.9 Spinal Cord 1.9 Renal ca. 786-0 330.1 Adrenal Gland 2.3 Renal ca. A498 11.0 Pituitary Gland 4.7 Renal ca. ACHN 115.7 Salivary Gland 3.8 FRenal ca. UO-31 F12.2 Thyroid 2 185 WO 2004/056961 PCT/US2003/034114 Rena .a...4. Pancreatic ca. PANG-i 6.6 a eI pancreas pool 0.9 Table D49. Panel 5 Islet SColumn A - Re Exp (%) Ag7384, Run 304686277 .ssue Name JA -Tissue Name. - I 97457 Patient-02go adipose 4.7 94709 Donor 2 AM - A adipose3 19747'6"Patient-O7sk skeletal muscle 0.0 194710 Donor 2 AM - B adipose 17 97477 Patient-07ut uterus 7 94711 Donor 2 AM - C adipose 0.0 97478 Patiet-07pl p_ 0.1 94712 Donor2 AD -A adipose 2.2 99167 Bayer Patient 1 0 0]94713 Donor 2 AD -B adipose 97482 Patient-08ut uterus f 1.6 94714 Donor i AD - C adipose 1.6 97483 Patient-08pl placenta 0.6 94742 Donor 3 U - A Mesenchymal Stem 0.0 ___ ___ _ _____Cells 1. 97486 Patient-09sk skeletal muscle 21.9 94743 Donor 3 U - B Mesenchymal Stem 0.2 -I_ Cells 97487 Patient-O9ut uterus 14.5 94730 Donor 3 AM - A adipose 0.9 97488 Patient-09pl placenta 0.3 94731 Donor 3 AM - B adipose T. 97492 Patient-1Out uterus 10.3 94732 Donor 3 AM - C adipose 0.6 97493 Patient-10pl placenta 0.8 94733 Donor 3 AD - A adipose 1.4 j97495 Patient-l1go adipose 4.1 94734 Donor 3 AD -B adipose 2 .1 97496 Patient-1 1sk skeletal muscle 51.8 94735 Donor 3 AD - C adipose 97497 Patient-11 ut uterus 9.2 77138 Liver HepG2untreated 40.9 97498 Patient- 11pl placenta 0.2 73556 Heart Cardiac stromal cells (primary) 4.4 7500 Patient-12go adipose 5.1 81735 Small Intestine 24.5 197501 Patient-12sk skeletal musc e 100.0 72409 Kidney Proximal Convoluted Tubule .2 97502 Patient-12ut uterus 4.5 82685 Small intestine Duodenum 97503 Patient-12pl placenta 07 90650 Adrena Adrenocortical adenom. 94721 Donor 2 U - A Mesenchymal Stem 0, J72410 Kidney HRCE 1 94722 Donor 2 U - B Mesenchymal Stem 0.2 72411 Kidney HRE 7.5 Cells - _____ 94723 Donor 2 U - C Mesenchymal Stem 0.4 i 7 313 9 Uterus Uterine smooth muscle cells 3.3 lC ells _________________ General screening panelvi.7 Summary: Ag7384 The highest expression of this gene was detected in a skeletal muscle sample (CT=25). This gene was widely expressed in tissues and cell lines represented on this panel. 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, brain, liver and the gastrointestinal tract. Panel 5 Islet Summary: Ag7384 The highest expression of this gene was detected in a skeletal muscle sample. This gene showed a muscle specific expression pattern among tissues on this panel. Low levels of expression was also detected in heart, intestine, kidney and uterus. CG127397-01: AMP-activated protein kinase, Beta 1. Expression of gene CG127397-01 was assessed using the primer-probe set Ag7392, described in Table D50. Results of the RTQ-PCR runs are shown in Table D51 and D52. Table D50. Probe Name Ag7392 186 WO 2004/056961 PCT/US2003/034114 Primers Sequences Length Start Position SEQ ID No Forward 5'-aagtttacttatctgggtccttcaac-3' 26 544 122 Probe TET-5'-tggagtaaacttcccctcaccagaagc-3'-TAMRA 271 573 123 Reverse 5'-caggatggctacaaagttattgtg-3' 24 600 124 Table D51. General-screening.panelvl.7 Column A - Rel. Exp.(%) Ag7392, Run 318345642 Tissue Name A Tissue Name A [Adipose 9.7 Gastric ca. (liver met.) NCI-N87 1.5 HUVEC 23.3 Stomach 1.6 VMelanoma* Hs688(A).T ( 0.0 Colon ca. SW-948 18.7 Melanoma* Hs688(B).T 24.5 Colon ca. SW480 0.8 Melanoma (met) SK-MEL-5 63 Colon ca. (SW480 met) SW620 129.5 Testis 20.3 Colon ca. HT29 28.5 Prostate ca. (bone met) PC-3 0.4 Colon ca. HCT-1 16 20.7 Prostate ca. DU145 10.7 Colon cancer tissue 2.1 Prostate pool 2.9 Colon ca. SW1116 3.8 Uterus pool 1.4 Colon ca. Colo-205 9.4 Ovarian ca. OVCAR-3 8.1 Colon ca. SW-48 8.2 IOvarian ca. (ascites) SK-OV-3 0.8 .Colon 115.7 Ovarian ca. OVCAR-4 14.1 Small Intestine (2.0 Ovarian ca. OVCAR-5 46.7 (Fetal Heart 6.7 (Ovarian ca. IGROV-1 51.8 Heart 2.3 Ovarian ca. OVCAR-8 30.6 Lymph Node Pool 1.8 Ovary______10.5___ yph Node pool 22. Breast ca. MCF-7 18.3 lFetal Skeletal Muscle 5.8 Breast ca. MDA-MB-231 20.3 Skeletal Muscle pool 0.7 (Breast ca. BT 549 .5.4 Skeletal Muscle 4.7 (Breast ca. T47D 10.2 Spleen 10.2 113452 mammary gland 3.0 Thymus 5.6 Trachea 36.1 NS cancer (glio/astro) SF-268 4 7 Lung 59.0 IONS cancer (glio/astro) T98G (Fetal Lung . 29.1 CNS cancer (neuro;met) SK-N-AS F6.0 Lung ca. NOI-N417 1 3.6 ICNS cancer (astro) SF-539 14.7 Lung ca. LX-1 6.0 ICNS cancer (astro) SNB-75 6.0 Lung ca. NCI-H146 22.1 ICNS cancer (glio) SNB-19 14.8 g ~ca. SHP-77 -~182.4 (C&S cancer (glio) SF-295 7.2 Lung ca. NCI-H23 14.3 IBrain (Amygdala) 5 1 Lung ca. NCI-H460 16.6 Brain (Cerebellum) 16.2 (Lung ca. HOP-62 Brain__(Fetal)__2__,_4_7_1 Lung ca. NCI-H522 12.6 Brain (Hippocampus) 3.9 Lung ca. DMS-114 10.2 Cerebral Cortex pool 5.0 iver in n5siantia nigra) 1.8 Fetal Liver 17.9 (Brain (Thalamus) 6.3 Kiney pool 100.0 (Brain (Whole) 135.4 [FtlKde 41]pnlCord j. 187 WO 2004/056961 PCT/US2003/034114 Renal ca. 786-0 29.5 Adrenal Gland 28.5 Renal1ca: -a.-A498 .... 9 ....... 3 Pituitary Gand 7.5 Renal ca. ACHN 17.0 Salivary Gland 9.0 (Renal ca. UO-31 39.2 Thyroid 28.1 Renal ca. TK-10 18.9 (Pancreatic ca. PANC-1 14.8 (Bladder 1 11.1 (Pancreas pool 4.8 Table D52. Panel 5 Islet Column A - Rel. Exp(%) Ag7392, Run 305256721 Tissue Name A Tissue Name A 97457.Patient-02go adipose 7.3094709 Donor 2 AM - A adipose 9.3 (97476 Patient-07sk skeletal musce 0.0 194710 Donor 2 AM - B adipose 8.0 (97477 Patient-07ut uterus 4.7 94711 Donor 2 AM - C adipose 4.7 9778 Patient-07p Iplacenta 94712 Donor 2AD - A adipose 16 (99167 Bayer Patient 1 0.0 94713 Donor 2 AD -B adipose 23.3 97482 Patient-08ut uterus 1 .9 ]94714 Donor 2 AD - C adipose 16.0 97483 Patient-08pl placenta 9.9 94742 Donor 3 U - A Mesenchymal Stem 3.6 Cells 97486 Patient-09sk skeletal muscle 2.5 94743 Donor 3 U - B Mesenchymal Stem 3.1 Cells 97487 Patient-O9ut uterus 8.7 4730 Donor 3AM-Aadipose 5.2 [97488 Patient-09pl placenta 5.2 94731 Donor 3 AM - B adipose 18.7 (97492 Patient-i Out uterus [5.0 (9473"2 Donor 3 AM - C adipose [15.1 F97493 Patient-1 OpI placenta 12.3 94733 Donor 3 AD - A adipose [8. 97495 Patient- 11go adipose 4.4 94734 Donor 3 AD - B adipose 17.4 197496 Patient-i 1isk skeletal muscle [4.2 j94 35 Donor 3 AD - C adipose 7. 97497 Patient- 11ut uterus 12.1177138 Liver HepG2untreated 100.0 .7498 Patient-11 pl placenta 4.0]73556 Heart Cardiac stromal cells (primary) 9.8 97500 Patient-1 2go adipose 6.8 81735 Small Intestine 12.9 [97501 Patient-12sk skeletal muscle 4.9 72409 Kidney Proximal Convoluted Tubule 67.8 [97502 Patient-12ut uterus 7.0 82685 Small intestine Duodenum 8.7 9 7503Patient-12p placenta 1f0.4 90650 Adrenal Adrenocortical adenoma 2.9 94721 Donor 2 U - A Mesenchymal Stem 12.3 72410 Kidney HRCE 20.0 Cells Cells94722 Donor 2 U - B Mesenchymal Stem 8.4 72411 Kidney HRE 11.1 94723 Donor 2 U - C Mesenchymal Stem 11.1 73139 Uterus Uterine smooth muscle cells 17.1 Generalscreening-panel-vl.7 Summary: Ag7392 Highest expression of this gene was detected in kidney (CT=23.38). Moderate to high expression of this gene was detected in number of tissues with metabolic/endocrine function including pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, and liver. 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. 188 WO 2004/056961 PCT/US2003/034114 Panel 5 Islet Summary: Ag7392 The highest expression of this gene was detected in untreated HepG2 liver cells (CT=29). This gene was expressed at low levels in adipose, skeletal muscle, uterus, placenta, mesenchymal stem cells, heart cardiac stromal cells, intestine and kidney. CG186873-01: Protein kinase, AMP-activated, beta 2 non-catalytic subunit. Expression of gene CG186873-01 was assessed using the primer-probe set Ag7385, described in Table D53. Results of the RTQ-PCR runs are shown in Tables D54 and D55. Table D53. Probe Name Ag7385 InImers Lequence CiL5i Start PostionSE I o forward 5'-cttggcacaattaacaatttgatc-3' 24 436 125 Probe TET-5'-cgaacacctcaaaatcagatttcttgaca-3'-TAMRA1 29 462 126 Reverse [5'-agaactttccatagaatctaactttaaagc-3' 30 493 127 Table D54. General-screening-panel-v1.7 Column A - Rel. Exp.(%) Ag7385, Run 318345348 Tissue Name A)Tissue Nam [A C A T s Na Adipose 23.8 Gastric ca. (liver met.) NCi-N87 0.8 HUVEC [11 .3 Stomach 1.7 Melanoma* Hs688(A).T 0.0 Colon ca. SW-948 7.1 IMelanoma* Hs688(B).T 18.8 [Colon ca. SW480 0.2 Melanoma (met) SK-MEL-5 24.7 Colon ca. (SW480 met) SW620 17.3 Tests 14.3 Colon ca. HT29 17.0 [Prostate ca. (bone met) PC-3 0.9 Colon ca. HCT-1 16 18.6 Prostate ca. DU145 20.4 Colon cancer tissue 1.4 [Prostate pool 6.9 Colonca.SW116 5.2 Uterus pool .1 Colon ca. Colo-205 2.4 [Ovarian ca. OVCAR-3 7.0 C6lon ca. SW-48 2.4 varian ca. (ascies) SK-OV-3 0.9 Colon 10.0 Ovarian ca. OVCAR-4 35.1 Smal Intestine 4.9 Ovarian ca. OVCAR-5 13.2 Fetal Heart 7.4 Ovarian ca. IGROV-1 59.0 Heart 8.8 Ovari a n ca A R- I I Node Poo 3.6 Ovary 18.3 Lymph Node pool 2 16.0 Breast ca. MCF-7 17.6 Fetal Skeletal Muscle 8.2 Breast ca. MDA-MB-231 16.0 Skeletal Muscle pool 9.5 Breast ca. BT 549 14.7 Skeletal Muscle 100.0 Breast ca. T47D 12.2 Spleen 4.9 [113452 mammary gland 6.0 Thymus 8.5 Trache...... .. a 23.2 CNS cancer (glio/astro) SF-268 5.0 [LuYng 132.5 CNS cancer (glio/astro) T98G 7.4 [Fetal Lung 27.2 CNS cancer (neuro;met) SK-N-AS 0.8 Lung ca. NC.-N417 9.7 CNS cancer (astro) SF-539 40.6 Lung ca. LX-1 6.9 CNS cancer (astro) SNB-75 25.7 Lung ca. NCI-H146 13.9 CNS cancer (glio) SNB-19 34.9 Lung ca. SHP-77 [63.3 CNS cancer (glio) SF-295 4.1 189 WO 2004/056961 PCT/US2003/034114 ILung ca. NCI-H23 919.5 Brain (Amygdala) 9.6 ILung ca. NCI-H460 19.9 Brain (Cerebellum) 50.0 Lung ca. HOP-62 18.6 Brain (Fetal) 63.7 Lung ca. NCI-H522 20.9 Brain (Hippocampus) 11.7 jLung ca. DMS-114 10.7 jCerebral Cortex pool 8.5 Liver 21.3 IBrain (Substantia nigra) 3.7 Fetal Liver 30.4 Brain (Thalamus) 12.2 IKidey Il.27'rain Whole) 45.7 Fetal Kidney 16.9 Spinal Cord 4.2 Renal ca. 786-0 16.0 Adrenal Gland 28.3 IRenal ca. A498 17.0 Pituitary Gland 9.3 lRenal ca. ACHN 16.0 Salivary Gland 4.8 Renal ca. UO-31 15.5 Thyroid 20.6 Renal ca. TK-10 12.5 jPancreatic ca. PANC-1 5.4 fBlder32.8 10ancreaspool Table D55. Panel 5 Islet .- Column A - Rel. Exp.(%) Ag7385, Run 304686279 Tissue Name A Tissue Name A 19747 Patient-O2go adipose 1.8 94709 Donor 2 AM - A adipose 6.3 97476 Patient-07sk skeletal muscle 0.0 9471-0 Donor 2 AM - B adipose 4.0 97477 Patient-O7ut uterus 4.2 94711 Donor 2 AM - C adipose 13.0 9f478 Patient-07pl placenta 1.6 94712 Donor 2 AD - A adipose 12.4 99I67Bayer Patient 1 0.0 94713 Donor 2 AD - B adipose 16.7 97482 Patient-O8ut uterus 45 94714 Donor 2 AD - C adipose 112.9 194742 Donor 3 U - A Mesenchymal Stem 97483 Patient-08p1 placenta 1.5 ICells 1.2 97486 Patient-O9sk skeletal muscle 4.2 94743 Donor 3 U - B Mesenchymal Stem 1.3 9 7 6 PC e lls 1 97487 Patient-09ut uterus 9.0 94730 Donor 3 AM - A adipose 8.2 J97488 Patient-09pl placenta 0.5 94731 Donor 3 AM - B adipose 113.6 97492 Patient-1 Out uterus 6.6 194732 Donor 3 AM - C adipose 12.2 97493 Patient-10pl placenta 2.7 94733 Donor 3 AD -A adipose 13.1 9i495 Patient- 11go adipose 100.0 94734 Donor 3 AD -B adipose 12.2 97496 Patient- 11sk skeletal muscle 5.1 94735 Donor 3 AD - C adipose 3.9 9 atient-1 1ut uterus 11.7 77138 Liver HepG2untreated 17.9 f974 Patint- ueunta___________ ___ 97498 Patient-i 1 pi placenta 0.6 173556 Heart Cardiac stromal cells (primary) 11,.2 f97500Patient-12go adipose 11.0 81735 Small Intestine 6.2 J97501 Patient-12sk skeletal muscle 15.1 72409 Kidney Proximal Convoluted Tubule 2.7 97502 Patient-1 2ut uterus 12.6 82685 Small intestine Duodenum 17.2 97503 Patient-12pl placenta 2.0 90650 Adrenal Adrenocortical adenoma 0.2 94721 Donor 2 U - A Mesenchymal Stem 63 72410 Kidney HRCE 2.3 9472 Door U B esechyal tem 3. 172410 Kidney HRE -. Cells 94723 Donor 2 U -C Mesenchymal Stem 4.5 73139 Uterus Uterine smooth muscle cells 2.8 1Cells 190 WO 2004/056961 PCT/US2003/034114 General screeningpanel-vl.7 Summary: Ag7385 The highest expression of this gene was detected in a skeletal muscle sample (CT=26). This gene was widely expressed in tissues and cell lines represented on this panel. Among tissues with metabolic or endocrine function, this gene was expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, brain, liver and the gastrointestinal tract. Panel 5 Islet Summary: Ag7385 The highest expression of this gene was detected in a visceral adipose sample (CT=28). The expression of this gene was increased in differentiated adipose cells as compared to the mesenchymal stem cells that gave rise to them. CG186882-01: Protein kinase, AMP-activated, gamma 1 non-catalytic subunit. Expression of gene CGI 86882-01 was assessed using the primer-probe set Ag7400, described in Table D56. Results of the RTQ-PCR runs are shown in Tables D57 and D58. Table D56. Probe Name Ag7400 Primers[ Sequences Length [Sart Position'SEQ ID No Forward 5'-ggggaggaaagagaatggat-3' 20 1243 128 Probe YFY-5'-cccttaccctcacacatacacttgaa-3-TAMRA 26 1272 129 Reverse 5'-gaggacaggggctagaactg-3 20 1315 130 Table D57. General screening-panelvl.7 Column A - Rel. Exp.() Ag7400, Run 318345646 Tissue Name A Tissue Name A Adipose 29.5 Gastric ca. (liver met.) NCI-N87 0.6 HUVEC . . . 118.0 [Stomach 0 . .. 8 F 0elanoma* Hs688(A).T 0.0 ColoncaSW-948 12.5 IMelanoma* Hs688(B).T 41.2 Colon ca. SW480 0.4 melanoma (met) SK-MEL-5 '42.3 olon ca. (SW480 met) SW620 46.7 Testis 7.3 Colon ca. HT29 36.1 rostate ca. (bone met) PC-3 1 I0 Colon ca. HCT-1 16 100. Prostate ca. DU145 15.7 Colon cancer tissue 1 2 Prostate pool [42 Colon ca. SW1116 14.1 Uterus pool 1.5 Colon ca. Colo-205 11.0 Ovarian ca. OVCAR-3 1 9.1 Colon ca. SW-48 17.1 FOvarian ca. (ascites) SK-OV-3 0.7[Con-10.2 Ovarian ca. OVCAR-4 69.3 Small Intestine 2.2 [Ovarian ca. OVCAR-5 T15.6 [Fetal Heart 14.4 Ovarian ca. IGROV-1 -- [90.8 [Heart 4.7 Ovarian ca. OVCAR-8 19.8 [Lymph Node Pool 2.0 [Ovary [14.3 [Lymph Node pool 2.1 18.2 Breast ca. MCF-7 18.0 Fetal Skeletal Muscle 5.4 Breast ca. MDA-MB-231 40.1 Skeletal Muscle pool 2.0 Breast ca. BT 549 21.2 Skeletal Muscle 20.2 Breast ca. T47D 50.0 Spleen 4.0 113452 mammary gland 3.0 Thymus 3.8 [Trachea 11.3 CNS cancer (glio/astro) SF-268 26.1 Lung 12.4 [CNS cancer (glio/astro) T98G 12.4 191 WO 2004/056961 PCT/US2003/034114 [Fetal Lung 12 [ONS cancer (neuro;met) 5K-N-AS 7 Lung ca. NCI-N417 7.2 [CNS cancer (astro) SF-539 j 31.9 [Lung ca. LX-1 13.5 [CNS cancer (astro) SNB-75 22.2 Lung ca. NCI-H146 24.1 CNS cancer (glio) SNB-19 30.1 Lung ca. SHP-77 23.7 CNS cancer (glio) SF-295 10.9 Lung ca. NCI-H23 24.5 Brain (Amygdala) 9.5 Lung ca. NCI-H460 28.7 Brain (Cerebellum) 11.7 Lung ca. HOP-62 25.2 Brain (Fetal) 9.8 FLung ca. NCI-H522 23.3 Brain (Hippocampus) 7.9 ILn a. DMS-114 15.6 erebra Cortex pool 6.3 [Liver 2.5 Brain (Substantia nigra) 6.9 Fetal Liver 5.5 Brain (Thalamus) 9 Kidney pool 26.2 Brain (Whole) 21.9 Fetal Kidney 4.0 Spinal Cord 4.7 Real ca. 786-0 [29.9 ~r e nal GlIa nd 18....... Renal ca. A498 [8.8 Pituitary Gland 1 .9 Renal ca. ACHN 24.0 Salivary Gland 6.2 [Renal ca. UO-31 35.6 [Thyroid 3.7 Renal ca. TK-10 16.6 [Pancreatic ca. PANC-1 17.9 [Bdd 5..6...-.. 0_- Table D58. Panel 5 Islet Column A - Rel. Exp.(%) Ag7400, Run 305256724 Tissue Name A Tissue Name A [97457 Patient-02go adipose 12.6[94709 Donor 2 AM - A adipose. 37.9 97476 Patient-07sk skeletal muscle 6 0.0 [9-47"l 0D6o-n-or 2-AM . B... adpse31.6 [97477 Patient-07ut uterus 10.6 94711 Donor 2 AM - C adipose 28.5 97478 Patient-07pI placenta 1OI.2 412 Donor 2 AD - A adipose [99167 Bayer Patient 1 0.0 194713 Donor 2 AD - B adipose 59.0 97482 Patient-08ut uterus 7.9 94714 Donor 2 AD - C adipose 43.2 97483 Patient-08pl placenta 13.1 94742 Donor 3 U - A Mesenchymal Stem 24.0 Cells 97486 Patient-09sk skeletal muscle 11.4 94743 Donor 3 U - B Mesenchymal Stem 20.2 Cells [97487 Patient-O9ut uterus.......10.2 94730 Donor 3 AM - A adipose [52.5 [97488 Patient-09pl placenta 7.7194731 Donor 3 AM - B adipose 75.8 [9i492 Patient-10ut uterus 15.5 94732 Donor 3AM - C adipose 61.6 97493 Patient-10pl placenta 10.5794733 Donor 3 AD - A adipose 1100.0 197495 Patient-11go adipose 13.1 941734 Donor 3 AD - B adipose 63.7 97496 Patient- 11sk skeletal muscle 2.6 94735 Donor 3 AD - C adipose 25.5 97497 Patient-11ut uterus 18.6177138 Liver HepG2untreated 39.8 97498 Patient- 1pl placenta 7.9 73556 Heart Cardiac stromal cells (primary) 15.0 [97500 Patient-12go adipose 19.2 81735 Small Intestine 28.1 [i5~Tait- 2skskeletal muscle - 33.472409 Kidney Proximal Convoluted Tuiule 72.2 [9702 Patient-12ut uterus 18.4 82685 Small intestine Duodenum 13.7 [97503 Patient-12pl placenta 20.6 90650 Adrenal Adrenocortical adenoma 17.3 94721 Donor 2 U - A Mesenchymal Stem 159.572410 Kidney HRCE 47.0 192 WO 2004/056961 PCT/US2003/034114 Oells ' Hb - esncyml te--f 94722 Donor 2 U - B Mesenchymal Stem 41.5 72411 Kidney HRE 12.0 Cells 1. Cells 51.873139 Uterus Uterine smooth muscle cells 47.3 Generalscreening-panelvl.7 Summary: Ag7400 The highest expression of this gene was detected in a colon cancer cell line (HCT-1 16)(CT=25). The expession of this gene was higher in breast cancer cell lines than in normal breast tissue. The expession of this gene was higher in lung cancer cell lines than in normal lung tissue. The expession of this gene was higher in 7 of 8 colon cancer cell lines, as compared to normal colon tissue. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of breast cancer, lung cancer and colon cancer. Among tissues with metabolic or endocrine function, this gene was expressed at high to moderate levels in brain, pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Panel 5 Islet Summary: Ag7400 The highest expression of this gene was detected in fully differentiated adipose cells (CT=31). The gene was expressed at low levels in skeletal muscle, uterus, placenta and adipose. CG186895-01: Protein kinase, AMP-activated, gamma 2 non-catalytic subunit. Expression of gene CG1 86895-01 was assessed using the primer-probe set Ag7398, described in Table D59. Results of the RTQ-PCR runs are shown in Tables D60 and D61. Table D59. Probe Name Ag7398 Primers Sequences ILength Start Position SEQ ID No F-orward 5'-ttgcccgttattgaccctat-3 20 589 131 Probe TET-5'-tgggaatgcactttatatacttacccaca-3'-TAMRAj 29 612 132 [Reiyeerse[5.gctggaggaacttgaggatt-3' 20j 645 133 _ Table D60. General-screening-panelvl.7 Column A - Rel. Exp.(%) Ag7398, Run 318345644 Tissue Name A Tissue Name A lAdipose 1 13.1 Gastric ca. (liver met.) NCI-N87 0.3 HUVEC 122.1 Stomach 11.0 lMelanoma* Hs688(A).T 1 0.0 Colon ca. SW-948 8.4 IMelanoma* Hs688(B).T 1 7.8 Colon ca. SW480 0.5 Imelano m-a- ( -met) 5K-MEL- 15.1 {Colon ca. (SW480 met) SW620 r1. jTestis 1 5.0 lColon ca. HT29 40.6 .rostaie ca. (bone met) OP-3 I.37Colon ca. HCT-116 53. Prostate ca. DU145 27.9 Colon cancer tissue 0.6 Prostate pool 14.7 Colon ca. SW1 11 66. Uterus pool J 1.3 Colon ca. Colo-205 3.6 193 WO 2004/056961 PCT/US2003/034114 Ovarian ca. OVCAR-3 14.5 Colon ca. SW-48 5.0 Ovarian ca. (ascites) SK-OV-3 0 .7Colon 9.8 Ovarian ca. OVCAR-4 32.5 Small Intestine 1.5 6vaan 6 a. VCAR-5 29 5 Fetal Heart 2. Ovarian ca. IGROV-1 27.9 Heart 8.7 ovarian ca. OVCAR-8 41.2 Lymph Node Pool 1.9 vary 15Lymph Node pool 2 16. Breast ca. MCF-7 5.8 Fetal Skeletal Muscle 1.1 Breast ca. MDA-MB-231 64.2 Skeletal Muscle pool 0.7 [Breast ca B-T 5496 6. .7 ---S-ke. Ie .t .alI M.;us .cl.I.e .... 5.9 IBreast ca. T47D 5.5 Spleen 6.1 113452 mammary gland 1.8 Thymus 2.9 Trachea 17.8 CNS cancer (glio/astro) SF-268 109 1Lung -- 19.1 CNS cancer (glio/astro) T98G 3.2 IFe ung........ . 11.7 IONS cancer (neuro;met) SK-N-AS 1 .3 [Lung ca. NCI-N417 J 4.7 CNS cancer (astro) SF-539 9.0 I ung ca. LX-1 1 2.1 CNS cancer (astro) SNB-75 -- - 6.2 ILung ca. NCI-H146 3.7 CNS cancer (glio) SNB-19 27.7 Lung ca. SHP-77 1.8 ICNS cancer (glio) SF-295 2.4 ILung ca. NCI-H23 9.0 Brain (Am.ygdala) 15.3 [Lung ca. NCI-H460 18.4 1Brain (Cerebellum) 25.7 Lung ca. HOP-62. 15.3 Brain (Fetal) 26.8 1Lung ca. NCI-H522 I00. Brain (Hippocampus) 112.4 Lung ca. DMS-1 14 f3.3 lCerebral Cortex pool 10.7 Liver 2.5 Brain (Substantia nigra) [3.8 Fetal Liver 2.6 Brain (Thalamus) [15.1 KIdney poo 24.0 Brain (Whole) [61.1 lIetal Kidney 3.3 Spinal Cord 4.5 lRenal ca. 786-0 16.6 Adrenal Gland 5.2 Fenal ca. A498 6.3 Pituitary Gland 4.0 Renal ca. ACHN 63.7 Salivary Gland 5.7 Rena ca. UO-31 20.6 IThyroid 18.2 Renal ca. TK-10 186 Pancreatic ca. PANC-1 12.2 30.1 Pancreas 2.7 ..... r.. .. ._ _ ._....__..._...... Table D61. Panel 5 Islet Column A - Rel. Exp.(%) Ag7398, Run 305256722 Tissue Name A Tissue Name 97457 Patient-02go adipose 5.2 94709 Donor 2 AM - A adipose 12.4 7476 Patient-07sk skeletal muscle 0.0 94710 Donor 2 AM - B adipose 9.4 97477 Patient-07ut uterus 25.2 94711 Donor 2 AM - C adipose 8.8 97478 Patient-07pI placenta 28,3 94712 Donor 2 AD - A adipose 25.5 99167 Bayer Patient 1 0.0 94713 Donor 2 AD - B adipose 36.6 97482 Patient-08ut uterus 32.3 94714 Donor 2 AD - C adipose 27.0 97483 Patient-08pf placenta 31.2 94742 Donor 3 U - A Mesenchymal Stem 9.0 C-jells - -. 97486-Patient-O9sk skeletal muscle 2.6 94743 Donor 3 U - B Mesenchymal Stem 1 4 .5 194 WO 2004/056961 PCT/US2003/034114 Cells 97488 Patient-09pi placenta 50.0 94731 Donor 3 AM - B adipose 67.8 [97492 Patient-10ut uterus 37.9 4732 Donor 3 AM - C adipose F5.6 974=93 Patient-iOpI placenta 1 73.7 94733 Donor 3 AD - A adipose 156.3 97495 Patient-i 1 go adipose 7.4 94734 Donor 3 AD - B adipose 44.4 97496 Patient-11 sk skeletal muscle 2.5 94735 Donor 3 AD - C adipose 11.0 97i497 Patient- 1ut utrs100I 73 ie HeGutre 8w. 197498 Patient-i1 ipI placenta 125.7 173556 Heart Cardiac stromal cells (primary) 19.1 97500 Patient-12go adipose . . 7.6 81735 Small Intestine 36.1 97501 Patient-12sk skeletal muscle 13.3 72409 Kidney Proximal Convoluted Tubule 80.1 97502 Patient-l2ut uterus 68.8 82685 Small intestine Duodenum 34.6 97503 Patient-1 2pl placenta 90.8 90650 Adrenal Adrenocortical adenoma 2.7 94721 Donor 2 U - A Mesenchymal Stem 27.2 72410 Kidney HRCE 70.2 lCells IKde 9472 ono 2U -IBlesenchymal Stem 139121 inyHE2. 94723 Donor 2 U - C Mesenchymal Stem Cellss13.9 72411 Kidney HIRE 28.3 25.0 73139 Uterus Uterine smooth muscle cells 25.7 Cells I General screening-panel-vl.7 Summary: Ag7398 The highest expression of this gene was detected in a lung cancer cell line (CT=23). Among tissues with metabolic or endocrine function, this gene was expressed at high to moderate levels in brain, pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Panel 5 Islet Summary: Ag7398 The highest expression of this gene was detected in a uterus sample (CT=31). This gene was expressed at low levels in uterus, placenta, mesenchymal stem cells, adipose, liver, primary cardiac stromal cells, small intestine and kidney. CG186913-01: Protein kinase. - gamma 3 Expression of gene CG186913-01 was assessed using the primer-probe set Ag7532, described in Table D62. Results of the RTQ-PCR runs are shown in Tables D63 and D64. Table D62. Probe Name Ag7532 O rmes Sequences Length Start Position SEQ ID No Forward 5'-actgcctgtggtcaacgaat-3 20 1167 134 Probe JTET5'-cctctatcccgcttgatgtgattc-3'-TAMRA 26 135 Reverse 5'-ccaggtggttgtaggtttgc-3' 2 1242 136 Table D63. General-screening-panel-v1.7 Column A - Rel. Exp.(%) Ag7532, Run 318841721 ssue ame Tissue NameA Adipose 0.0 Gastric ca. (liver met.) NCI-N87 0.0 {HUVEC 0.0Stomach .0 195 WO 2004/056961 PCT/US2003/034114 Melanoma* Hs688(A).T 0.0 Colonca. SW-948 -0.0 Melanoma* Hs688(B).T 0.0 lon ca. SW480 0.0 Meoma rnet) K-MEL 5 0.0 Colon ca. (SW480 met) SW620 0.0 Ifestis 1 0.0 Colon ca. HT29 0.0 Prostate ca. (bone met) PC-3 0.0 Colon ca. HCT-1 16 O.0 Prostate ca. DU145 0.0 Colon cancer tissue 0.0 Prostate pool 0.0 Colon ca. SW 1116 0.0 Uterus pool 0.0 Colon ca. Colo-205 0.0 Ovarian ca. OVCAR-3 0.0 Colon ca. SW-48 0.0 Ori an a (a-sc i t-e s)j - SK--O-3 . 1. ..- 10 -0 Colon f0.0 Ovarian ca. OVCAR-4 0.0 Small Intestine 0.0 Ovarian ca. OVCAR-5 0.0 Fetal Heart 0.0 Ovarian ca. IGROV-1 0.0 Heart 0.0 [ovarian ca. OVCAR-8 0.0 Lymph Node Pool [60 [Ovary-" .... . f 00-J ILym p h- N-- o,d e p l-o ol " 2 [..... ..0. Breast ca.MCF-7 0.0 Fetal Skeletal Muscle 0.0 Breast ca. MDA-MB-231 0.0 Skeletal Muscle pool 01 [Breast ca. BT 549 0.0 Skeletal Muscle 067 [Breast ca. T47D 1 0.0 JSpleen [o.0 113452 mammary gland 0.6 Ifhymus 0.0 [Trachea 0.0 ICNS cancer (glio/astro) SF-268 0.0 [Lung 1 0.0 CNS cancer (glio/astro) T98G 0.0 Fetal Lung - . ancer (neuro;met) SK-N-AS 6 .0 1Lung ca. NCI-N417 0.0 ONS cancer (astro) SF-539 0.0 1-ung ca. LX-1 0.0 CNS cancer (astro) SNB-75 f0.0 Lung ca. NCI-H146 [0.0 CNS cancer (glio) SNB-19 0.0 Lung ca. SHP-77 [ 0 NS cancer (glio) SF-295 6.0 fLung ca. NC-H23 0.0 Brain (Amygdala) 0.0 fLung ca. NC-H460 0.0 Brain (Cerebellum) 0.0 Lung ca. HOP-62 0.0 rain (Fetal) 0.0 Lung ca. NCI-H522 0.0 Brain (Hippocampus) 10.0 ung ca. DMS-114 0.0 Cerebral Cortex pool 0.0 Liver 0.0 Brain (Substantia nigra) 0.0 I Fetal Liver ____ 0.0 Brain (Thalamus) 0 0 Kidney pool 0.0 Brain (Whole) l0.0 Fetal Kidney 0.0 Spinal Cord [-.0 Renal ca. 786-0 0.0 Adrenal Gland 0.0 Renal ca. A498 0.0 Pituitary Gland 0.0 [Renal ca. ACHN 00 Salivary Gland 0.0 Renal ca. UO-31 1 0 Thyroid 0.0 Renal ca. TK-10 0.0 Pancreatic ca. PANC-1 0.0 Blaer 0__ 0. Pancreas pool 0.0 Table 064. Panel 5 Islet Column A - Rel. Exp.(%) Ag7532, Run 308743741 Tissue Name A Tissue Name A 97457 Patient-02go adipose 0.0 94709 Donor 2 AM - A adipose 0.0 196 WO 2004/056961 PCT/US2003/034114 97476 Patient-07sk skeletal muscle 0.0 94710 Donor 2 AM -B adipose 0.0 97477 Patient-07ut uterus 0.0 94711'Donor 2 AM - C adipose 0.0 97478 Patient-7pl placenta 0.0 94712 Donor 2 AD - A adipose 0.0 99167 Bayer Patient 1 0.0194713 Donor 2 AD - B adipose 0.0 97482 Patient-08ut uterus 0.0 94714 Donor 2 AD - C adipose 0. 97483 Patient-08pl placenta 0.0 Cells Donor 3 U - A Mesenchyma0 Stem 00 97486 Patient-09sk skeletal muscle 30.1 94743 Donor 3 U - B Mesenchymal Stem 0.0 [97487 Patient-09ut uterus 0.0 94730 Donor 3 AM - A adipose 0.0 97488 Patient-09pl placenta 0.0 94731 Donor 3 AM - B adipose 0.0 197492 Patient-1Out uterus 0.0 94732 Donor 3 AM -C adipose 0.0 97493 Patient-10pl placenta f 0.0 j94733 Donor 3 AD - A adipose 0.0 j945Patient-i 1Igo adipose 0.0 1 ~onor 3AD-B adipose 10.0 197496 Patient- 11sk skeletal muscle 37.9 [94735 Donor 3 AD -C adipose o610 97497 Patient- 11ut uterus 0.0 77138 Liver HepG2untreated 0.0 97498 Patient-i I placenta 0.0 73556 Heart Cardiac stromal cells (primary) 0.0 97500 Patient-ggo adipose 0.0 81735 Small Intestine 0.6 197501 Patient-12sk skeletal muscle 1160.0 72409 Kidney Proximal Convoluted Tubule 0.0 952Patient-i12ut uterus _____ 0.0 182685 Small intestineDuodenum [0.0 97503 Patient-12pl placenta 0.0 190650 Adrenal Adrenocortical adenoma 0 0 9471 Donor 2 U - A Mesenchymal Stem Kidney Cells ______ ___ 0.0_ V 172410 KinyHRCE 00 94722 Donor 2 U - B Mesenchymal Stem I-____________ n 0.0 72411 Kidney HRE .0O 94723 Donor 2 U - C Mesenchy nal Stem Cells 0.0 73139 Uterus Uterine smooth muscle cells 0.0 General-screening-panel-vl.7 Summary: Ag7532 The highest expession of this gene was detected in an ovarian cancer line (SK-OV-3)(CT=18). Significant expression was also detected in adipose, skeletal muscle and thyroid. Panel 5 Islet Summary: Ag7532 The highest expression of this gene was detected in a skeletal muscle sample (CT=29). On the present panel, significant expression was detected exclusively in skeletal muscle. Example D4. Pathways Relevant to the Etiology and Pathogenesis of Obesity and/or Diabetes Protein-protein interactions were assayed using PathCalling@ technology disclosed in Example Q10. Our data showed that AMPKA1, alphal catalytic subunit preferentially interacts with betal, gammal and gamma2 subunits. The alpha2 subunit therefore is expected to interact more specifically with beta2 and gamma3 subunits, particularly in view of the RTQ-PCR data, showing enriched expression of alpha2, beta 2 and gamma3 subunits in skeletal muscle. Example D5. Assays Screening for Modulators of AMP-activated Protein Kinase Assays for screening for antibody therapeutics or small molecule drugs targeting human AMP-activated protein kinase can be formulated utilizing the non-exhaustive list of cell lines that express the AMP-activated Protein Kinase from the RTQ-PCR results shown above. To assay the enzymatic activity of AMP-activated kinase the active heterotrimer consisting of alpha, beta and gamma subunits could be reconstituted in vitro. The enzymatic activity of heterotrimer could be monitored by measurement of 32 P-incorporation in general kinase peptide 197 WO 2004/056961 PCT/US2003/034114 substrate, which is a common method in the art (see for example US. Patent No.: 6,514,719, Example 5, Columns 47-48). Typically this would be carried out by combining the kinase with radiolabeled

[

3 2 P]ATP in working buffer solution containing peptide or protein substrate. Peptide substrates are generally from 8-30 amino acids in length and may terminate at N- or C-terminus with three or more lysine or arginine residues to facilitate binding of the peptide to phosphocellulose paper. After incubation of this reaction mixture for a suitable time, the transfer of radioactive phosphate from ATP to substrate may be monitored by acidifying the reaction mixture then spotting it into phosphocellulose paper, and subsequent washing of the paper with dilute solution of phosphoric acid. To assess the selectivity of the compounds, endogenous protein known to be phosphorylated by AMP-activated kinase may be used as a substrate, like AMP-adenylate kinase, phosphofructokinase, cdc25c, mark3. Our results indicate that a modulator of AMP-activated protein kinase activity, such as an inhibitor, activator, antagonist, or agonist of AMP-activated protein kinase may be useful for treatment of such disorders as obesity, diabetes, and insulin resistance, as well as for enhancement of insulin secretion. In one preferred embodiment, the modulator is an activator or agonist of AMP-activated protein kinase activity. The screening for antibody and small molecule drugs could be performed using only the catalytic alpha subunit. In a preferred embodiment of the invention, the heterotrimeric protein composed of alpha 2, beta 2 and gamma 3 subunits is the target for screening. The following Table D65 indicates the SEQ ID numbers and corresponding CuraGen accession numbers (CGUID#) of the subunits of the AMP-activated protein kinase. Table D65 Subunit CGUID # SEQ ID NO: Alpha 1 CG91149-01 48 Alpha 2 CG186855-01 54 Beta 1 CG127397-01 60 Beta 2 CG186873-01 62 Gamma 1 CG186882-01 64 Gamma 2 CG186895-01 68 Gamma 3 CG186913-02 74 Alternatively, screening for modulators could be done using non-human orthologs of human AMPK. For example, one can use rat ortholog sequences listed in Table D66 below. Table D66. Amino acid sequence Rat ortholog of AMPK Rat alpha 2 (NP076481; SEQ ID NO:137) 1 MAEKQKHDGR VKIGHYVLGD TLGVGTFGKV KIGEHQLTGH KVAVKILNRQ KIRSLDVVGK 61 IKREIQNLKL FRHPHIIKLY QVISTPTDFF MVMEYVSGGE LFDYICKHGR VEEVEARRLF 121 QQILSAVDYC HRHMVVHRDL KPENVLLDAQ MNAKIADFGL SNMMSDGEFL RTSCGSPNYA 181 APEVISGRLY AGPEVDIWSC GVILYALLCG TLPFDDEHVP TLFKKIRGGV FYIPEYLNRS 241 IATLLMHMLQ VDPLKRATIK DIREHEWFKQ DLPSYLFPED PSYDANVIDD EAVKEVCEKF 301 ECTESEVMNS LYSGDPQDQL AVAYHLIIDN RRIMNQASEF YLASSPPTGS FMDDMAMHIP 361 PGLKPHPERM PPLIADSPKA RCPLDALNTT KPKSLAVKKA KWHLGIRSQS KPYDIMAEVY 421 RAMKQLDFEW KVVNAYHLRV RRKNPVTGNY VKMSLQLYLV DNRSYLLDFK SIDDEVVEOR 481 SGSSTPQRSC SAAGLHRPRS SVDSSTAENH SLSGSLTGSL TGSTLSSASP RLGSHTMDFF 541 EMCASLITALAR Rat beta 2 (NP 072149; SEQ ID NO:138) 198 WO 2004/056961 PCT/US2003/034114 1 MGNTTSERVS GERHGAKAAR AEGGGHGPGK EHKIMVGSTD DPSVFSLPDS KLPGDKEFVP 61 WQQDLDDSVK PTQQARPTVI RWSEGGKEVF ISGSFNNWST KIPLIKSHND FVAILDLPEG 121 EHQYKFFVDG QWVHDPSEPV VTSQLGTINN LIHVKKSDFE VFDALKLDSM ESSETSCRDL 181 SSSPPGPYGQ EMYVFRSEER FKSPPILPPH LLQVILNKDT NISCDPALLP EPNHVMLNHL 241 YALSTKDSVM VLSATHRYKK KYVTTLLYKP I Rat gamma 3 (CG212022-01; SEQ ID NO:139) MEPELEHTLPGTLTWSHSGGPESQEMDFLEPEENSWPSPTVATSSERTCAIRGVKASRWTRQEAVEEAEP PGLGEGAQSGPAAESTRQKATFPKATPLAQAVPLADAETSTTGWDLFLPDCAASAVGSSTGDLELTIEFP GPEVWDCELKGLEQDRPRPCPSPQAPLLSLSWDDELQKPGAQYMHFMQEHTCYDAMATSSKLVIFDTTL EIKKAFFAMVANGVRAAPLWDSKKQSFVGMLTITDFILVLHRYYRSPLVQIYEIEEHKIETWREIYLQGC FKPLVSISPNDSLFEAVYALIKNRIHRLPVLDPVSGTVLYILTHKRLLKFLHIFGALLPRPSFLCRTIQD LGIGTFRDLAVVLETAPILTALDIFVDRRVSALPVVNESGQVVGLYSRFDVIHLAAQQTYNHLDMSVGEA LRQRTLCLEGVLSCQPHESLGEVIDRIAREQVHRLVLVDETQHLLGVVSLSDILQALVLSPAGIDALSA E. NOV11 -- Adenosine monophosphate deaminase 1 (AM PD1) Adenosine monophosphate deaminase 1 (AMPD1) catalyzes the deamination of AMP to inosine monophosphate (IMP) in skeletal muscle and plays an important role in the purine nucleotide cycle. Deficiency of the muscle-specific AMPD1 is a common cause of exercise-induced myopathy due to impairment in utilization of protein catabolism for energy production in skeletal muscle (Arch Neurol. 38(5):279 (1981); Science. 5;200(4341):545 (1978)). In particular the invention relates to the use of AMPD1 protein, genes and antibodies thereto in diagnostic applications and/or AMPD1 genes, gene products and antibodies as targets for small molecule drugs and antibody therapeutics. The inventors discovered that AMPD1 is up-regulated in diabetic skeletal muscle, implicating a role for AMPD1 in the early stages of diabetes. The inventors discovered that AMPD1 has higher expression in glycolytic compared to oxidative skeletal muscle fibers in rat and mouse skeletal muscle. As a result of its expression in skeletal muscle fibers, inhibition of AMPD1 may favor oxidative muscle phenotype thus facilitating fatty acid utilization and improving muscle metabolism. AMPD1 (AMP deaminase) is one of the enzymes in purine nucleotide cycle that links amino acid/protein catabolism with citric acid cycle (TCA) involved in energy production. AMPD1 catalyses the conversion of adenosine monophosphate (AMP) to inosine monophosphate (IMP). Generated IMP is used for production of fumarate via adenylsuccinate by the subsequent action of two enzymes: adenylsuccinate synthase and adenylosuccinate lyase. Fumarate is shuttled to TCA cycle for energy production. It is proposed that inhibition of AMPD1 would decrease cellular levels of IMP thereby impairing the production of fumarate, the major anaplerotic substrate for TCA cycle from protein catabolism, Figure 1 schematically shows the purine nucleotide cycle that together with fatty acid beta-oxidation is thought to be one of the major pathways for energy generation in skeletal muscle during exercises. Attenuating protein catabolism by inhibition of AMPD1 might promote fatty acid beta-oxidation and glucose oxidation for energy generation that is beneficial in treatment or amelioration of conditions causing obesity and diabetes. In addition, the inhibition of AMPD1 would increase cellular AMP level that in turn would lead to prolonging of activation of AMP-activated kinase (AMPK). Activation of AMPK is known to have many beneficial effects on skeletal muscle metabolism, including an increase in fatty acid beta-oxidation and glucose utilization. The current invention embodies the use of recombinantly expressed and/or 199 WO 2004/056961 PCT/US2003/034114 endogenously expressed protein in various screens to identify AMPD1 antagonist, therapeutic antibodies and/or therapeutic small molecules beneficial in the treatment of obesity. Not to be limited by a particular mechanism of action, the inventors nevertheless have discovered that inhibition of AMPD1 has beneficial effects for treating diabetes/obesity by acting in many metabolic tissues, including skeletal muscle. Furthermore, our results indicate that a modulator of AMPD1 activity, such as an inhibitor, activator, antagonist, or agonist of AMPD1 may be useful for treatment of such disorders as obesity, diabetes, and insulin resistance, as well as for enhancement of insulin secretion. In a preferred embodiment, the modulator of AMPD1 activity is antagonist or inhibitor of AMPD1 activity. Discovery Process The following sections describe the study design(s) used to identify the AMPD1 -encoded protein and any variants, thereof, as being suitable as diagnostic markers, AMPD1 s for an antibody therapeutic and AMPD1 s for a small molecule drugs for Obesity and Diabetes. Example El. Mouse Dietary - Induced Obesity Study The predominant cause for obesity in clinical populations is excess caloric intake. This so called diet-induced obesity (DIO) is mimicked in animal models by feeding high fat diets of greater than 40% fat content. The DIO study was established to identify the gene expression changes contributing to the development and progression of diet-induced obesity. In addition, the study design sought to identify the factors that lead to the ability of certain individuals to resist the effects of a high fat diet and thereby prevent obesity. The sample groups for the study were selected from C57BU6J mice and had body weights +1 S.D. (sdl), + 4 S.D. (sd4) and + 7 S.D. of the chow-fed controls (below). In addition, the biochemical profile of the + 7 S.D. mice revealed a further stratification of these animals into mice that retained a normal glycemic profile in spite of obesity (ngsd7) and mice that demonstrated hyperglycemia (hgsd7). Tissues examined included hypothalamus, brainstem, liver, retroperitoneal white adipose tissue (WAT), epididymal WAT, brown adipose tissue (BAT), gastrocnemius muscle (fast twitch skeletal muscle) and soleus muscle (slow twitch skeletal muscle). The differential gene expression profiles for these tissues revealed genes and pathways that can be used as therapeutic AMPD1s for obesity. The protocol for Mouse Dietary-Induced Obesity Study is disclosed in Example 01. A fragment of the mouse Adenosine monophosphate deaminase 1 gene was initially found to be up-regulated by 1.7 fold in soleus (oxidative) skeletal muscle of obese/hyperglycemic (hgsd7) mice compared to resistant to diabetes and obesity (sdl) mice using CuraGen's GeneCalling@ method of differential gene expression (disclosed in Example Q7). The same gene fragment was found to be up-regulated by 3 and 2.2 fold, respectively in gastrocnemius (glycolytic) skeletal muscle relative to soleus (oxidative) skeletal muscle of hgsd7 and sdl mice. A differentially expressed mouse gene fragment migrating at approximately 71 nucleotides in length (shown in Table El) was definitively identified as a component of the mouse AMPD1 cDNA. The method of competitive PCR was used for confirmation of the gene assessment. The electropherographic peaks corresponding to the gene fragment of the mouse AMPD1 were ablated when a gene-specific primer (shown in Table El) competes with primers in the linker-adaptors during the PCR amplification. The peaks at 71 nt in 200 WO 2004/056961 PCT/US2003/034114 length were ablated in the sample from soleus muscle from both hgsd7 and sdl mice. Taken together, these data show that inhibition of AMPD1 would promote the oxidative muscle phenotype to increase glucose uptake and fatty acid oxidation and therefore improve insulin sensitivity and hyperglycemia. In addition, the finding that AMPD1 is up-regulated in diabetic skeletal muscle supports the hypothesis that inhibition of AMPD1 would be beneficial for the treatment of diabetes. Table El. The direct sequence of the 319 nucleotide-long gene fragment and the gene-specific primers used for competitive PCR are indicated on the cDNA sequence of AMPD1 (SEQ ID NO:140) and are shown below in bold (fragment from 136 to 206 in bold; band size: 71). The gene-specific primers at the 5' and 3' ends of the fragment are underlined. 1 CGATGACCCG ATGCAGTTCC ATTTCACCCA GGAGCCCCTG ATGGAAGAAT ACCCCTTCCC 61 TGCGCAAGTC TTCAAGCTGA GCACCTGTGA AATGTGTGAG GTGGCAAGGA ACAGTTTCCT 121 CCAGTATGGG ATTTCTCATG AGGAAAAACC AAAGTTTTTG GGCAACAATT ACCTTGAGGA 181 AGGCCCTGTT GGAAATGACA TCCGGAGGAC AAATGTCGCT CAGATTCGCA TGGCCCATCG 241 TTATGAAACT TGGTGTTATG AACTCAATTT AATTGCTGAG GTTCTTAAAG CAACAGAATG 301 AATAAAGTAA ATAGACTAA Example E2. Rat Insulin Sensitivity Study Type 2 diabetes is a strongly genetic disorder resulting from inadequate compensatory insulin secretion in the face of insulin resistance. The Zucker diabetic fatty (ZDF) rat is a model of type 2 diabetes and, like the human disease, has both insulin resistance (from a mutant leptin receptor causing obesity) and inadequate beta-cell compensation. ZDF rats or their lean littermates were treated with a variety of agents that are known to alter insulin sensitivity. Metformin, vanadate, and AICAR enhance tissue response to insulin, while the free fatty acids generated by Liposyn (intravenous lipid infusion treatment) reduces the response. A variety of tissues were harvested, including gastrocnemius and soleus muscles, liver, retroperitoneal and epididymal WAT, and intrascapular BAT. The protocol for Rat Insulin Sensitivity Study is disclosed in Example 03. A fragment of the rat Adenosine monophosphate deaminase 1 gene was initially found to be up-regulated by 2.7 fold in gastrocnemius (glycolytic) skeletal muscle relative to soleus (oxidative) skeletal muscle of diabetic rats using GeneCalling® method of differential gene expression (disclosed in Example Q7). A differentially expressed rat gene fragment migrating at approximately 321 nucleotides in length was definitively identified as a component of the rat AMPD1 cDNA (shown in Table E2). The method of competitive PCR was used for confirmation of the gene assessment. The electropherographic peaks corresponding to the gene fragment of the rat AMPD1 were ablated when a gene-specific primer (shown I Table E2) competes with primers in the linker-adaptors during the PCR amplification. The peaks at 321 nt in length were ablated in the sample from both gastrocnemius and soleus skeletal muscle from diabetic rats. Notably, rat beta 2 subunit of AMP-activated protein kinase (AMPK) gene has been found dysregulated in the similar comparison. The co-regulation of AMPD1 and AMPK kinase further supports the hypothesis that AMPD1 may influence activity of AMPK. Taken together, these data are in agreement with dysregulation observed in the Mouse Diet 201 WO 2004/056961 PCT/US2003/034114 Induced Obesity Study (disclosed in Example El) and support the hypothesis that inhibition of AMPD1 would be beneficial for the treatment of diabetes/obesity. Table E2. The direct sequence of the 1081 nucleotide-long gene fragment and the gene-specific primers used for competitive PCR are indicated on the cDNA sequence of AMPD1 (SEQ ID NO:141) and are shown below in bold (fragment from 281 to 601 in bold; band size: 321; full gene length: 2358). The gene-specific primers at the 5' and 3' ends of the fragment are underlined. 1 TGTCACAGAG TCAGTCTGCC ATCCCCACAG TCTCTCTCCT TCCTCTGCTG TGCTGTCCTA 61 GAATCCAGGA TCCCAGTCAC AATGCCTCTG TTCAAACTTA CAGGTCAAGG AAAACAAATT 121 GATGATGCAA TGCGTAGCTT TGCTGAAAAA GTATTTGCCT CAGAAGTCAA AGATGAGGGA 181 GGTCGGCACG AGATCTCCCC CTTCGACGTG GATGAGATCT GCCCAATTTC CCTCCGTGAG 241 ATGCAGGCCC ACATATTCCA CATGGAGAAC CTGTCCATGT CCATGGATGG CAGGAGGAAA 301 AGGCGCTTCC AAGGACGGAA GACTGTTAAT TTGTCCATTC CGCAAAGTGA AACGTCTTCT 361 ACCAAACTGT CCCACATTGA AGAATTTATT TCTTCATCCC CGACCTATGA GAGTGTGCCT 421 GACTTCCAGA GGGTGCAGAT CACTGGTGAC TATGCCTCTG GGGTAACTGT TGAAGACTTT 481 GAGGTGGTTT GTAAAGGTCT CTATCGGGCT TTGTGTATAC GAGAGAAATA CATGCAGAAG 541 TCATTCCAGA GGTTCCCCAA GACCCCCTCC AAGTACCTGA GGAACATCGA CGGCGAAGCT 601 TTGGTAGCAA TCGAAAGCTT CTATCCAGTA TTTACCCCTC CTCCGAAGAA GGGAGAAGAC 661 CCCTTTCGCA GAGAAGACCT TCCCGCAAAC CTGGGCTATC ACCTCAAGAT GAAGGGTGGT 721 GTGATTTACA TCTACCCTGA TGAAGCAGCA GCCAGCAGAG ATGAGCCCAA GCCCTACCCT 781 TACCCAAATC TGGATGACTT CCTGGATGAC ATGAATTTTT TGCTTGCTCT AATTGCACAA 841 GGGCCTGTGA AGACTTACAC TCACCGCCGT CTGAAGTTCC TCTCCTCCAA GTTCCAGGTC 901 CATCAGATGC TGAATGAGAT GGACGAGCTA AAGGAGCTGA AGAACAACCC CCACCGGGAC 961 TTTTATAACT GCAGGAAGGT GGATACTCAC ATCCACGCAG CTGCCTGCAT GAACCAGAAG 1021 CACCTGCTGC GCTTTATTAA GAAATCTTAC CATATTGATG CTGACAGAGT GGTCTACAGC 1081 A Example E3. Identification of Human AMPD1 sequence. The sequence of Human AMPD2 was 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, were 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 protocol for identification of human sequence(s) is disclosed in Example Q8. Table E3 shows an alignment (ClustalW) of the protein sequences of the human (CG192154 01; SEQ ID NO:78) and rat homologs (SEQ ID NO:142) of the AMPD1. Table E4 shows protein sequence of rat homolog of the AMPD1. Table E3. An alignment (ClustalW) of the protein sequences of the human (CG 192154-01) and rat homologs of the AMPD1. 202 WO 2004/056961 PCT/US2003/034114 AMPDI mt 1 G QG S S 60 CG192154-01 1 AE IDM FK AE PADE'EGGQ lP FN VDE 60 AMPDI mt 61 I M DG kIF RE 120 C0192154-01 61 t jrgTTEZA .FR T PEDY ISSPWiPQT D R 120 AMPDIat 121 L I F 180 C0192154-01 121 180 AMPD1rat 181 F P RED *AIGLMK ; I-TED A EP 240 CG192154-01 181 P TDN EL HVVN K LP240 AMPD1rat 241 L DDM F 300 C0192154-01 241 300 AMPDImt 301 DETH UI M LFl K5IDRVYSE KNT ELF 360 CG192154-01 301 DH A C LR K QA SENLE FKK 360 AMPDIrat 361 420 C0192154-01 361 420 AMPDIrat 421 H R R W WP MIQ I 480 c192154-01 421 HERLIY SDW LW uuCPMT P R IFKLPFMLE 480 AMPDIrat 481 L A H LTKN 540 C0192154-01 481 NIP vAINPQD F L D D H M PK 540 AMPD1 mt 541 Y T 600 C0192154.01 541 600 AMPD1_mt 601 660 C0192154-01 601 660 AMPDI mt 661 LN 720 C0192154-01 661 L I F DQI HE : D E D I RR T NV 720 AMPDIrat 721 A IA E E IE LT 747 C0192154.01 721 IRMYYE E ENIL 747 Table E4. Protein sequence of rat homolog of the AMPD1 (NP_620231; SEQ ID NO:142). 1 mplfkltgqg kqiddamrsf aekvfasevk deggrheisp fdvdeicpis Iremqahifh 61 menlsmsmdg rrkrrfqgrk tvnisipqse tsstklshie efisssptye svpdfqrvqi 121 tgdyasgvtv edfevvckgl yralcireky mqksfqrfpk tpskylrnid gealvaiesf 181 ypvftpppkk gedpfrredl panlgyhlkm kggviyiypd eaaasrdepk pypypnlddf 241 lddmnfilal iaqgpvktyt hrrlkflssk fqvhqmlnem delkelknnp hrdfyncrkv 301 dthihaaacm nqkhlrfik ksyhidadrv vystkeknlt lkelfaqlnm hpydltvdsl 361 dvhagrqtfq rfdkfndkyn pvgaselrdl ylktdnying eyfatiikev gadlvdakyq 421 haeprlsiyg rspdewskls swfvgnriyc pnmtwmiqvp riydvfrskn flphfgkmle 481 niflpvfeat inpqthpdIs vflkhitgfd svddeskhsg hmfsskspkp eewtmennps 541 ytyyayymya nimvlncirk ergmntfifr phcgeagalt hlmtafmiad nishglnlkk 601 spvlqylffI aqipiamspl snnslfleya knpfldflqk glmislstdd pmqfhftkep 661 Imeeyaiaaq vfklstcdmc evarnsvlqc gisheekakf Ignnyieegp vgndirrtnv 721 aqirmayrye twcyelnlia eglkste The laboratory cloning was performed using one or more of the methods summarized in Example Q8. The NOV11 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table E5. Table E5. NOV11 Sequence Analysis jNOV11a, CG192154-01 jSEQ ID NO: 77 2341 bp )DNA Sequence IORF Start: ATG at 85 ORF Stop: TAA at 2326 iTaAAGoGioaGioAGToACCCCACAGTCTCCTCTCTCTTCTTT CTACTGTGCTATCCTAGAATC 203 WO 2004/056961 PCT/US2003/034114 AAGGATTTCAGCAACAATGCCTCTGTTCAAACTCCCAGCTGAAGAGAAACAAATTGATGATGCAATGC GCAACTTTGCTGAAAAAGTGTTTGCCTCTGAAGTCAAAGATGAAGGAGGTCGTCAGGAGATTTCCCCC TTTGATGTGGATGAGATCTGTCCGATCTCATCATGAGATGCAAGCACACATATTCCATCTGGAGAC TCTGTCCACCTCCACAGAAGCCAGGAGAAAAAAGCGTTTCCAAGGACGGAAGACTGTTAATTTGTCCA TTCCACTAAGTGAAACATCTTCCACCAAACTGTCCCACATTGATGAATACATTTCCTCATCTCCAACC TACCAGACCGTGCCTGATTTTCAGAGAGTGCAGATTACTGGTGACTATGCCTCTGGGGTTACAGTTGA AGATTTTGAAATTGTTTGCAAAGGTCTGTATCGGGCACTATGCATACGTGAGAAATACATGCAGAAGT CGTTTCAGAGGTTCCCTAAAACCCCTTCCAAATACTTGCGGAACATTGATGGTGAGGCTTGGGTAGCA AATGAGAGCTTCTATCCAGTCTTTACTCCTCCTGTGAAGAAGGGAGAGGACCCCTTCCGAACAGACAA CCTTCCTGAAAACCTGGGCTATCACCTCAAAATGAAGGACGGTGTAGTTTACGTCTATCCTAATGAAG CAGCAGTCAGCAAAGATGAGCCTAAGCCACTTCCTTACCCAAATCTGGACACCTTCTTAGACGATATG AAT1 11TACTTGCTTTAATTGCTCAAGGACCTGTTAAGACCTATACCCACCGGCGCCTGAAGTTCCT CTCCTCCAAGTTCCAGGTCCATCAGATGCTTAACGAGATGGACGAGTTAAAGGAGCTGAAAAACAACC CCCACCGAGA1TTATAACTGCAGGAAGGTGGACACCCATATCCATGCAGCCGCTTGCATGAACCAG AAACATCTGCTGCGTTTTATTAAGAAATCTTACCAAATTGATGCTGACAGAGTGGTCTATAGCACCAA AGAGAAGAATCTGACCCTAAAGGAACTTTTTGCTAAATTAAAAATGCATCCTTATGACCTGACTGTTG ATTCTCTGGATGTTCATGCTGGACGCCAGACCTTCCAGCGTTTTGATAAGTTCAATGACAAATATAAT CCTGTAGGAGCAAGTGAGCTACGGGACCTCTACTTGAAGACAGACAATTACATTAATGGGGAATATTT TGCCACTATCATCAAGGAGGTAGGTGCGGACCTGGTGGAGGCCAAGTACCAGCATGCTGAGCCCCGCCI TGTCCATCTATGGCCGCAGTCCTGATGAGTGGAGCAAACTCTCCTCCTGGTTCGTCTGCAATCGCATC CACTGCCCCAACATGACATGGATGATCCAGGTTCCCAGGATCTATGATGTGTTCCGTTCCAAGAATTT CCTTCCACATTTTGGAAAAATGCTGGAGAATATTTTCATGCCAGTGTTTGAGGCCACCATCAACCCCC AGGCTGACCCAGAACTCAGTGTCTTCCTCAAGCATATCACTGGCTTTGACAGTGTGGATGATGAGTCC AAACACAGTGGCCACATGTTCTCCTCCAAGAGTCCCAAGCCCCAGGAGTGGACATTGGAAAAGAATCC ATCTTACACTTACTATGCCTACTACATGTATGCAAACATCATGGTGCTCAACAGCCTGAGAAAGGAAC GAGGCATGAATACGTTTCTGTTCCGACCTCACTGTGGAGAAGCTGGAGCCCTCACCCATCTCATGACA GCATTCATGATAGCAGATGATATCTCTCATGGCCTAAATTAAAAAAGAGTCCCGTGCTACAGTACTT G1TTCTTAGCCCAAATTCCCATCGCCATGTCACCACTAAGTAACAATAGCCTATTTCTAGAGTATG CCAAAAATCCTTTTTTGGATTTCCTTCAGAAAGGGCTAATGATCTCACTGTCTACAGATGACCCAATG CAATTCCACTTTACCAAGGAGCCCCTAATGGAAGAATATGCTATTGCTGCACAAGTCTTCAAGCTGAG CACCTGTGATATGTGCGAAGTGGCAAGGAACAGTGTCTTGCAGTGTGGAATTTCTCATGAGGAGAAAG TAAAGTTTCTGGGCGACAATTACCTTGAGGAAGGCCCTGCTGGAAATGATATCCGGAGGACAAATGTA GCCCAAATCCGCATGGCCTATCGCTATGAAACCTGGTGTTATGAACTCAATAATTGCTGAGGGTCT TAAATCAACAGAATAAAAAAAAGTAAACC OVila, CG192154-01 OSSEQ ID NO: 78 -47 aa W at 86488.9kD Protein Sequence MPLFKLPAEEKQIDDAMRNFAEKVFASEVKDEGGRQEISPFDVDEICPISHHEMQAHIFHLETLSTST EARRKKRFQG RKTVNLSIPLSETSSTKLSHIDEYISSSPTYQTVPDFQRVQITGDYASGVTVEDFEIV CKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVANESFYPVFTPPVKKGEDPFRTDNLPENL GYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQ VHQMLNEMDELKELKNNPHRDFYNCRKVDTHIHAAACMNQKHLLRFKKSYQIDADRVVYSTKEKNLT LKELFAKLKMHPYDLTVDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIlK EVGADLVEAKYQHAEPRLSIYGRSPDEWSKLSSWFVCNRIHCPNMTWMIQVPRIYDVFRSKNFLPHFG KMLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLEKNPSYTYY AYYMYANIMVLNSLRKERGMNTFLFRPHCGEAGALTHLMTAFMIADDISHGLNLKKSPVLQYLFFLAQ IPIAMSPLSNNSLFLEYAKNPFLDFLQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVFKLSTCDMC EVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIRRTNVAQI RMAYRYETWCYELNLIAEGLKSTE NOV11b, CG192154-02 SEQ ID NO: 79 12284 bp tDNA Sequence ORF Start: at 2 IORF Stop: TAA at 2255 CACCGGATCCACCATGCCTCTG1-TCAAACTCCCAGCTGAAGAGAAACAAATTGATGATGCAATGCGCA ACTTTGCTGAAAAAGTGTTTGCCTCTGAAGTCAAAGATGAAGGAGGTCGTCAGGAGATTTCCCCCTTT GATGTGGATGAGATCTGTCCGATTTCTCATCATGAGATGCAAGCACACATATTCCATCTGGAGACTCT GTCCACCTCCACAGAAGCCAGGAGAAAAAAGCGTTTCCAAGGACGGAAGACTGTTAATTTGTCCATTC CACTAAGTGAAACATCTTCCACCAAACTGTCCCACATTGATGAATACATTTCCTCATCTCCAACCTAC CAGACCGTGCCTGATTTTCAGAGAGTGCAGATTACTGGTGACTATGCCTCTGGGGTTACAGTTGAAGA TTTTGAAATTGTTTGCAAAGGTCTGTATCGGGCACTATGCATACGTGAGAAATACATGCAGAAGTCGT TTCAGAGGTTCCCTAAAACCCCTTCCAAATACTTGCGGAACATTGATGGTGAGGCTTGGGTAGCAAAT GAGAGCTTCTATCCAGTCTTTACTCCTCCTGTGAAGAAGGGAGAGGACCCCTTCCGAACAGACAACCT 204 WO 2004/056961 PCT/US2003/034114 TCCTGAAAACCTGGGCTATCACCTCAAAATGAAGGACGGTGTAGTTTACGTCTATCCTAATGAAGCAG CAGTCAGCAAAGATGAGCCTAAGCCACTTCCTTACCCAAATCTGGACACCTTCTTAGACGATATGAAT 1T11TACTTGCTTTAATTGCTCAAGGACCTGTTAAGACCTATACCCACCGGCGCCTGAAGTTCCTCTC CTCCAAGTTCCAGGTCCATCAGATGCTTAACGAGATGGACGAGTTAAAGGAGCTGAAAAACAACCCCC ACCGAGATTTTTATAACTGCAGGAAGGTGGACACCCATATCCATGCAGCCGCTTGCATGAACCAGAAA CATCTGCTGCGTTTTATTAAGAAATCTTACCAAATTGATGCTGACAGAGTGGTCTATAGCACCAAAGA GAAGAATCTGACCCTAAAGGAACTTTTGCTAAATTAAAAATGCATCCTTATGACCTGACTGTTGATT CTCTGGATGTTCATGCTGGACGCCAGACCTTCCAGCGTTTTGATAAGTTCAATGACAAATATAATCCT GTAGGAGCAAGTGAGCTACGGGACCTCTACTTGAAGACAGACAATTACATTAATGGGGAATATTTTGC CACTATCATCAAGGAGGTAGGTGCGGACCTGGTGGAGGCCAAGTACCAGCATGCTGAGCCCCGCCTGT CCATCTATGGCCGCAGTCCCGATGAGTGGAGCAAACTCTCCTCCTGGTTCGTCTGCAATCGCATCCAC TGCCCCAACATGACATGGATGATCCAGGTTCCCAGGATCTATGATGTGTTCCGTTCCAAGAATTTCCT TCCACATTTTGGAAAAATGCTGGAGAATATTTTCATGCCAGTGTTTGAGGCCACCATCAACCCCCAGG CTGACCCAGAACTCAGTGTCTTCCTCAAGCATATCACTGGCTTTGACAGTGTGGATGATGAGTCCAAA CACAGTGGCCACATGTTCTCCTCCAAGAGTCCCAAGCCCCAGGAGTGGACATTGGAAAAGAATCCATC TTACACTTACTATGCCTACTACATGTATGCAAACATCATGGTGCTCAACAGCCTGAGAAAGGAACGAG GCATGAATACGTTTCTGTTCCGACCTCACTGTGGAGAAGCTGGAGCCCTCACCCATCTCATGACAGCA TTCATGATAGCAGATGATATCTCTCATGGCCTAAATTTAAAAAAGAGTCCCGTGCTACAGTACTTGTT TTTCTTAGCCCAAATTCCCATCGCCATGTCACCACTAAGTAACAATAGCCTATTTCTAGAGTATGCCA AAAATCCTTTTTTGGATTTCCTTCAGAAAGGGCTAATGATCTCACTGTCTACAGATGACCCAATGCAA TTCCACTTTACCAAGGAGCCCCTAATGGAAGAATATGCTATTGCTGCACAAGTCTTCAAGCTGAGCAC CTGTGATATGTGCGAAGTGGCAAGGAACAGTGTCTTGCAGTGTGGAATTTCTCATGAGGAGAAAGTAA AGTTTCTGGGCGACAATTACCTTGAGGAAGGCCCTGCTGGAAATGATATCCGGAGGACAAATGTAGCC CAAATCCGCATGGCCTATCGCTATGAAACCTGGTGTTATGAACTCAATTTAATTGCTGAGGGTCTTAA ATCAACAGAATAAGTCGACGGCAAGGGCGAATTCTGCAGA NOV 11b, CG192154-02 SEQ ID NO: 80 751 aa MW at 86835.3kD Protein Sequence TGSTMPLFKLPAEEKOIDDAMRNFAEKVFASEVKDEGGRQEISPFDVDEICPISHHEMQAHIFHLETL STSTEARRKKRFQGRKTVNLSIPLSETSSTKLSHIDEYISSSPTYQTVPDFQRVQITGDYASGVTVED FEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVANESFYPVFTPPVKKGEDPFRTDNL PENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHRRLKFLS SKFQVHQMLNEMDELKELKNNPHRDFYNCRKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYSTKE KNLTLKELFAKLKMHPYDLTVDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFA TIIKEVGADLVEAKYQHAEPRLSIYGRSPDEWSKLSSWFVCNRIHCPNMTWMIQVPRIYDVFRSKNFL PHFGKMLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLEKNPS YTYYAYYMYANIMVLNSLRKERGMNTFLFRPHCGEAGALTHLMTAFMIADDISHGLNLKKSPVLQYLF FLAQIPIAMSPLSNNSLFLEYAKNPFLDFLQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVFKLST CDMCEVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIRRTNVAQIRMAYRYETWCYELNLIAEGLK STE [NOV11 c, CG192154-03 JSEQ ID NO: 81 2248 bp DNA Sequence _ _ _ .ORF Start: at 1 [ORF Stop: TAA at 2245 ACCATGCCTCTGTTCAAACTCCCAGCTGAAGAGAAACAAATTGATGATGCAATGCGCAACTTTGCTGA AAAAGTGTTTGCCTCTGAAGTCAAAGATGAAGGAGGTCGTCAGGAGATTTCCCCCTTTGATGTGGATG AGATCTGTCCGATTTCTCATCATGAGATGCAAGCACACATATTCCATCTGGAGACTCTGTCCACCTCC ACAGAAGCCAGGAGAAAAAAGCGTTTCCAAGGACGGAAGACTGTTAATTTGTCCATTCCACTAAGTGA AACATCTTCCACCAAACTGTCCCACATTGATGAATACATTTCCTCATCTCCAACCTACCAGACCGTGC CTGATTTTCAGAGAGTGCAGATTACTGGTGACTATGCCTCTGGGGTTACAGTTGAAGATTTTGAAATT GTTTGCAAAGGTCTGTATCGGGCACTATGCATACGTGAGAAATACATGCAGAAGTCGTTTCAGAGGTT CCCTAAAACCCCTTCCAAATACTTGCGGAACATTGATGGTGAGGCTTGGGTAGCAAATGAGAGCTTCT ATCCAGTCTTTACTCCTCCTGTGAAGAAGGGAGAGGACCCCTTCCGAACAGACAACCTTCCTGAAAAC CTGGGCTATCACCTCAAAATGAAGGACGGTGTAGTTTACGTCTATCCTAATGAAGCAGCAGTCAGCAA AGATGAGCCTAAGCCACTTCCTTACCCAAATCTGGACACCTTCTTAGACGATATGAATTT1TTACTTG CTTTAATTGCTCAAGGACCTGTTAAGACCTATACCCACCGGCGCCTGAAGTTCCTCTCCTCCAAGTTC CAGGTCCATCAGATGCTTAACGAGATGGACGAGTTAAAGGAGCTGAAAAACAACCCCCACCGAGATTT TTATAACTGCAGGAAGGTGGACACCCATATCCATGCAGCCGCTTGCATGAACCAGAAACATCTGCTGC GTTTTATTAAGAAATCTTACCAAATTGATGCTGACAGAGTGGTCTATAGCACCAAAGAGAAGAATCTG ACCCTAAAGGAACT1T11GCTAAATTAAAAATGCATCCTTATGACCTGACTGTTGATTCTCTGGATGT TCATGCTGGACGCCAGACCTTCCAGCGTTTTGATAAGTTCAATGACAAATATAATCCTGTAGGAGCAA 205 WO 2004/056961 PCT/US2003/034114 GTGAGCTACGGGACCTCTACTTGAAGACAGACAATTACATTAATGGGGAATATTTTGCCACTATCATC AAGGAGGTAGGTGCGGACCTGGTGGAGGCCAAGTACCAGCATGCTGAGCCCCGCCTGTCCATCTATGG CCGCAGTCCCGATGAGTGGAGCAAACTCTCCTCCTGGTTCGTCTGCAATCGCATCCACTGCCCCAACA TGACATGGATGATCCAGGTTCCCAGGATCTATGATGTGTTCCGTTCCAAGAATTTCCTTCCACATTTT GGAAAAATGCTGGAGAATATTTTCATGCCAGTGTTTGAGGCCACCATCAACCCCCAGGCTGACCCAGA ACTCAGTGTCTTCCTCAAGCATATCACTGGCTTTGACAGTGTGGATGATGAGTCCAAACACAGTGGCC ACATGTTCTCCTCCAAGAGTCCCAAGCCCCAGGAGTGGACATTGGAAAAGAATCCATCTTACACTTAC TATGCCTACTACATGTATGCAAACATCATGGTGCTCAACAGCCTGAGAAAGGAACGAGGCATGAATAC GTTTCTGTTCCGACCTCACTGTGGAGAAGCTGGAGCCCTCACCCATCTCATGACAGCATTCATGATAG CAGATGATATCTCTCATGGCCTAAATAAAAAAGAGTCCCGTGCTACAGTACTTGTTT1TCTTAGCC CAAATTCCCATCGCCATGTCACCACTAAGTAACAATAGCCTATTTCTAGAGTATGCCAAAAATCCTTT TTTGGATTTCCTTCAGAAAGGGCTAATGATCTCACTGTCTACAGATGACCCAATGCAATTCCACTTTA CCAAGGAGCCCCTAATGGAAGAATATGCTATTGCTGCACAAGTCTTCAAGCTGAGCACCTGTGATATG TGCGAAGTGGCAAGGAACAGTGTCTTGCAGTGTGGAATTTCTCATGAGGAGAAAGTAAAGTTTCTGGG CGACAATrACCTTGAGGAAGGCCCTGCTGGAAATGATATCCGGAGGACAAATGTAGCCCAAATCCGCA TGGCCTATCGCTATGAAACCTGGTGTTATGAACTCAATTTAATTGCTGAGGGTCTTAAATCAACAGAA TAAG NOVI1 c, CG192154-03 SEQ ID NO: 82 748 aa MW at 86590.OkD Protein Sequence TMPLFKLPAEEKQIDDAMRNFAEKVFASEVKDEGGRQEISPFDVDEICPISHHEMQAHIFHLETLSTS TEARRKKRFQG RKTVNLSI PLSETSSTKLSHI DEYlSSSPTYQTVPDFQRVQlTG DYASGVTVEDFEI VCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVANESFYPVFTPPVKKGEDPFRTDNLPEN LGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKF QVHQMLNEMDELKELKNNPHRDFYNCRKVDTHI HAAACMNQKHLLRFI KKSYQIDADRVVYSTKEKNL TLKELFAKLKMHPYDLTVDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATII KEVGADLVEAKYQHAEPRLSIYGRSPDEWSKLSSWFVCNRHCPNMTWMIQVPRIYDVFRSKNFLPHF GKMLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLEKNPSYTY YAYYMYANIMVLNSLRKERGMNTFLFRPHCGEAGALTHLMTAFMIADDISHGLNLKKSPVLQYLFFLA QIPIAMSPLSNNSLFLEYAKNPFLDFLQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVFKLSTCDM CEVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIRRTNVAQIRMAYRYETWCYELNLIAEGLKSTE NOV11 d, CG192154-04 SEQ ID NO: 83 1965 bp DNA Sequence ORF Start: at 1 fOR Stop: TAA at 1963 ACCATGCTGTCCCACATTGATGAATACATTTCCTCATCTCCAACCTACCAGACCGTGCCTGATTTTCA GAGAGTGCAGATTACTGGTGACTATGCCTCTGGGGTTACAGTTGAAGATTTTGAAATTGTTTGCAAAG GTCTGTATCGGGCACTATGCATACGTGAGAAATACATGCAGAAGTCGTTTCAGAGGTTCCCTAAAACC CCTTCCAAATACTTGCGGAACATTGATGGTGAGGCTTGGGTAGCAAATGAGAGCTTCTATCCAGTCTT TACTCCTCCTGTGAAGAAGGGAGAGGACCCCTTCCGAACAGACAACCTTCCTGAAAACCTGGGCTATC ACCTCAAAATGAAGGACGGTGTAGTTTACGTCTATCCTAATGAAGCAGCAGTCAGCAAAGATGAGCCT AAGCCACTTCCTTACCCAAATCTGGACACCTTCTTAGACGATATGAATTTTTTACTTGCTTTAATTGC TCAAGGACCTGTTAAGACCTATACCCACCGGCGCCTGAAGTTCCTCTCCTCCAAGTTCCAGGTCCATC AGATGCTTAACGAGATGGACGAGTTAAAGGAGCTGAAAAACAACCCCCACCGAGAT1TTTATAACTGC AGGAAGGTGGACACCCATATCCATGCAGCCGCTTGCATGAACCAGAAACATCTGCTGCGTTTTATTAA GAAATCTTACCAAATTGATGCTGACAGAGTGGTCTATAGCACCAAAGAGAAGAATCTGACCCTAAAGG AAC111TTGCTAAATTAAAAATGCATCCTTATGACCTGACTGTTGATTCTCTGGATGTTCATGCTGGA CGCCAGACCTTCCAGCGTTTTGATAAGTTCAATGACAAATATAATCCTGTAGGAGCAAGTGAGCTACG GGACCTCTACTTGAAGACAGACAATTACATTAATGGGGAATATTTTGCCACTATCATCAAGGAGGTAG GTGCGGACCTGGTGGAGGCCAAGTACCAGCATGCTGAGCCCCGCCTGTCCATCTATGGCCGCAGTCCC GATGAGTGGAGCAAACTCTCCTCCTGGTTCGTCTGCAATCGCATCCACTGCCCCAACATGACATGGAT GATCCAGGTTCCCAGGATCTATGATGTGTTCCGTTCCAAGAATTTCCTTCCACATTTTGGAAAAATGC TGGAGAATATTTTCATGCCAGTGTTTGAGGCCACCATCAACCCCCAGGCTGACCCAGAACTCAGTGTC TTCCTCAAGCATATCACTGGCTTTGACAGTGTGGATGATGAGTCCAAACACAGTGGCCACATGTTCTC CTCCAAGAGTCCCAAGCCCCAGGAGTGGACATTGGAAAAGAATCCATCTTACACTTACTATGCCTACT ACATGTATGCAAACATCATGGTGCTCAACAGCCTGAGAAAGGAACGAGGCATGAATACGTTTCTGTTC CGACCTCACTGTGGAGAAGCTGGAGCCCTCACCCATCTCATGACAGCATTCATGATAGCAGATGATAT CTCTCATGGCCTAAATTTAAAAAAGAGTCCCGTGCTACAGTACTTG I I I I I CTTAGCCCAAATTCCCA TCGCCATGTCACCACTAAGTAACAATAGCCTATTTCTAGAGTATGCCAAAAATCCTTTTTTGGATTTC CTTCAGAAAGGGCTAATGATCTCACTGTCTACAGATGACCCAATGCAATTCCACTTTACCAAGGAGCC CCTAATGGAAGAATATGCTATTGCTGCACAAGTCTTCAAGCTGAGCACCTGTGATATGTGCGAAGTGG 206 WO 2004/056961 PCT/US2003/034114 CAAGGAACAGTGTCTTGCAGTGTGGAATTTCTCATGAGGAGAAAGTAAAGTTTCTGGGCGACAATTAC CTTGAGGAAGGCCCTGCTGGAAATGATATCCGGAGGACAAATGTAGCCCAAATCCGCATGGCCTATCG CTATGAAACCTGGTGTTATGAACTCAATTTAATTGCTGAGGGTCTTAAATCAACAGAATAA NOV11d, CG192154-04 SEQ D NO 84 654 aa MW at 75866.1kD Protein Sequence . .. . .M.a.7.8.6.l. TMLSHI DEYISSSPTYQTVPDFQRVQITG DYASGVTVEDFEIVCKG LYRALCI REKYMQKSFQRFPKT PSKYLRNIDGEAWVANESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEP KPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYNC RKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYSTKEKNLTLKELFAKLKMHPYDLTVDSLDVHAG RQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEVGADLVEAKYQHAEPRLSIYGRSP DEWSKLSSWFVCNRIHCPNMTWMIQVPRIYDVFRSKNFLPHFGKMLENIFMPVFEATINPQADPELSV FLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLEKNPSYTYYAYYMYANIMVLNSLRKERGMNTFLF RPHCGEAGALTHLMTAFMIADDISHGLNLKKSPVLQYLFFLAQIPIAMSPLSNNSLFLEYAKNPFLDF LQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNY LEEGPAGNDIRRTNVAQIRMAYRYETWCYELNLIAEGLKSTE NOV11e, CG192154-05 SEQ ID NO: 85 1986 bp DNA Sequence ORF Start: at 1 ORE Stop TAA at 1984 ACCATGGGACATCATCACCACCATCACCTGTCCCACATTGATGAATACATTTCCTCATCTCCAACCTA CCAGACCGTGCCTGATTTTCAGAGAGTGCAGATTACTGGTGACTATGCCTCTGGGGTTACAGTTGAAG ATTTTGAAATTGTTTGCAAAGGTCTGTATCGGGCACTATGCATACGTGAGAAATACATGCAGAAGTCG TTTCAGAGGTTCCCTAAAACCCCTTCCAAATACTTGCGGAACATTGATGGTGAGGCTTGGGTAGCAAA TGAGAGCTTCTATCCAGTCTTTACTCCTCCTGTGAAGAAGGGAGAGGACCCCTTCCGAACAGACAACC TTCCTGAAAACCTGGGCTATCACCTCAAAATGAAGGACGGTGTAGTTTACGTCTATCCTAATGAAGCA GCAGTCAGCAAAGATGAGCCTAAGCCACTTCCTTACCCAAATCTGGACACCTTCTTAGACGATATGAA TT1TTACTTGCTTTAATTGCTCAAGGACCTGTTAAGACCTATACCCACCGGCGCCTGAAGTTCCTCT CCTCCAAGTTCCAGGTCCATCAGATGCTTAACGAGATGGACGAGTTAAAGGAGCTGAAAAACAACCCC CACCGAGATTTTTATAACTGCAGGAAGGTGGACACCCATATCCATGCAGCCGCTTGCATGAACCAGAA ACATCTGCTGCGTTTTATTAAGAAATCTTACCAAATTGATGCTGACAGAGTGGTCTATAGCACCAAAG AGAAGAATCTGACCCTAAAGGAACTTTTTGCTAAATTAAAAATGCATCCTTATGACCTGACTGTTGAT TCTCTGGATGTTCATGCTGGACGCCAGACCTTCCAGCGTTTTGATAAGTTCAATGACAAATATAATCC TGTAGGAGCAAGTGAGCTACGGGACCTCTACTTGAAGACAGACAATTACATTAATGGGGAATATTTTG CCACTATCATCAAGGAGGTAGGTGCGGACCTGGTGGAGGCCAAGTACCAGCATGCTGAGCCCCGCCTGI TCCATCTATGGCCGCAGTCCCGATGAGTGGAGCAAACTCTCCTCCTGGTTCGTCTGCAATCGCATCCA CTGCCCCAACATGACATGGATGATCCAGGTTCCCAGGATCTATGATGTGTTCCGTTCCAAGAATTTCC TTCCACATTTTGGAAAAATGCTGGAGAATATTTTCATGCCAGTGTTTGAGGCCACCATCAACCCCCAG GCTGACCCAGAACTCAGTGTCTTCCTCAAGCATATCACTGGCTTTGACAGTGTGGATGATGAGTCCAA ACACAGTGGCCACATGTTCTCCTCCAAGAGTCCCAAGCCCCAGGAGTGGACATTGGAAAAGAATCCAT CTTACACTTACTATGCCTACTACATGTATGCAAACATCATGGTGCTCAACAGCCTGAGAAAGGAACGA GGCATGAATACGTTTCTGTTCCGACCTCACTGTGGAGAAGCTGGAGCCCTCACCCATCTCATGACAGC ATTCATGATAGCAGATGATATCTCTCATGGCCTAAATTTAAAAAAGAGTCCCGTGCTACAGTACTTGT TTTTCTTAGCCCAAATTCCCATCGCCATGTCACCACTAAGTAACAATAGCCTATTTCTAGAGTATGCC AAAAATCCTTTTTTGGATTTCCTTCAGAAAGGGCTAATGATCTCACTGTCTACAGATGACCCAATGCA ATTCCACTTTACCAAGGAGCCCCTAATGGAAGAATATGCTATTGCTGCACAAGTCTTCAAGCTGAGCA CCTGTGATATGTGCGAAGTGGCAAGGAACAGTGTCTTGCAGTGTGGAATTTCTCATGAGGAGAAAGTA AAGTTTCTGGGCGACAATTACCTTGAGGAAGGCCCTGCTGGAAATGATATCCGGAGGACAAATGTAGC CCAAATCCGCATGGCCTATCGCTATGAAACCTGGTGTTATGAACTCAATTTAATTGCTGAGGGTCTTA AATCAACAGAATAA NOV11e, CG192154-05 SEQ ID NO: 86 661 aa MW at 76746.OkD Protein Sequence TMGHHHHHHLSHIDEYISSSPTYQTVPDFQRVQTGDYASGVTVEDFEIVCKGLYRALCIREKYMQKS FQRFPKTPSKYLRNIDGEAWVANESFYPVFTPPVKKG EDPFRTDNLPENLGYHLKMKDGVVYVYPNEA AVSKDEPKPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNP HRDFYNCRKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYSTKEKNLTLKELFAKLKMHPYDLTVD SLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEVGADLVEAKYQHAEPRL SIYGRSPDEWSKLSSWFVCNRIHCPNMTWMQVPRIYDVFRSKNFLPHFGKMLENIFMPVFEATINPQ ADPELSVFLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLEKNPSYTYYAYYMYANIMVLNSLRKER GMNTFLFRPHCGEAGALTHLMTAFMIADDISHGLNLKKSPVLQYLFFLAQI PIAMSPLSNNSLFLEYA KNPFLDFLQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKV 207 WO 2004/056961 PCT/US2003/034114 KFLGDNYLEEGPAGNDIRRTNVAQI RMAYRYETWCYELNLIAEGLKSTE lVIN CG192154-06 SEQ ID NO: 87 1983 bp DNA Sequence (ORF Start: at 1 ORF Stop: TAA at 1981 ACCATGCTGTCCCACATTGATGAATACATTTCCTCATCTCCAACCTACCAGACCGTGCCTGATTTTCA GAGAGTGCAGATTACTGGTGACTATGCCTCTGGGGTTACAGTTGAAGATTTTGAAATTGTTTGCAAAG GTCTGTATCGGGCACTATGCATACGTGAGAAATACATGCAGAAGTCGTTTCAGAGGTTCCCTAAAACC CCTTCCAAATACTTGCGGAACATTGATGGTGAGGCTTGGGTAGCAAATGAGAGCTTCTATCCAGTCTT TACTCCTCCTGTGAAGAAGGGAGAGGACCCCTTCCGAACAGACAACCTTCCTGAAAACCTGGGCTATC ACCTCAAAATGAAGGACGGTGTAGTTTACGTCTATCCTAATGAAGCAGCAGTCAGCAAAGATGAGCCT AAGCCACTTCCTTACCCAAATCTGGACACCTTCTTAGACGATATGAATTJTrTACTTGCTTTAATTGC TCAAGGACCTGTTAAGACCTATACCCACCGGCGCCTGAAGTTCCTCTCCTGCAAGTTCCAGGTCCATC AGATGCTTAACGAGATGGACGAGTTAAAGGAGCTGAAAAACAACCCCCACCGAGATT-I ATAACTGC AGGAAGGTGGACACCCATATCCATGCAGCCGCTTGCATGAACCAGAAACATCTGCTGCGTTTTATTAA GAAATCTTACCAAATTGATGCTGACAGAGTGGTCTATAGCACCAAAGAGAAGAATCTGACCCTAAAGG AAC111TrGCTAAATTAAAAATGCATCCTTATGACCTGACTGTTGATTCTCTGGATGTTCATGCTGGA CGCCAGACCTTCCAGCGTTTTGATAAGTTCAATGACAAATATAATCCTGTAGGAGCAAGTGAGCTACG GGACCTCTACTTGAAGACAGACAATTACATTAATGGGGAATATTTTGCCACTATCATCAAGGAGGTAG GTGCGGACCTGGTGGAGGCCAAGTACCAGCATGCTGAGCCCCGCCTGTCCATCTATGGCCGCAGTCCC GATGAGTGGAGCAAACTCTCCTCCTGGTTCGTCTGCAATCGCATCCACTGCCCCAACATGACATGGAT GATCCAGGTTCCCAGGATCTATGATGTGTTCCGTTCCAAGAATTTCCTTCCACATTTTGGAAAAATGC TGGAGAATATTTTCATGCCAGTGTTTGAGGCCACCATCAACCCCCAGGCTGACCCAGAACTCAGTGTC TTCCTCAAGCATATCACTGGCTTTGACAGTGTGGATGATGAGTCCAAACACAGTGGCCACATGTTCTC CTCCAAGAGTCCCAAGCCCCAGGAGTGGACATTGGAAAAGAATCCATCTTACACTTACTATGCCTACT ACATGTATGCAAACATCATGGTGCTCAACAGCCTGAGAAAGGAACGAGGCATGAATACGTTTCTGTTC CGACCTCACTGTGGAGAAGCTGGAGCCCTCACCCATCTCATGACAGCATTCATGATAGCAGATGATAT CTCTCATGGCCTAAATTTAAAAAAGAGTCCCGTGCTACAGTACTTG1TFU CTTAGCCCAAATTCCCA TCGCCATGTCACCACTAAGTAACAATAGCCTATTTCTAGAGTATGCCAAAAATCCTTTTTGGATTTC CTTCAGAAAGGGCTAATGATCTCACTGTCTACAGATGACCCAATGCAATTCCACTTTACCAAGGAGCC CCTAATGGAAGAATATGCTATTGCTGCACAAGTCTTCAAGCTGAGCACCTGTGATATGTGCGAAGTGG CAAGGAACAGTGTCTTGCAGTGTGGAATTTCTCATGAGGAGAAAGTAAAGTTTCTGGGCGACAATTAC CTTGAGGAAGGCCCTGCTGGAAATGATATCCGGAGGACAAATGTAGCCCAAATCCGCATGGCCTATCG CTATGAAACCTGGTGTTATGAACTCAATTTAATTGCTGAGGGTCTTAAATCAACAGAACATCATCACC ATCACCATTAA NOV1f, CG192154-06 SEQID NO: 88 660 aa MW at 76688.9kD Protein Sequence TMLSHIDEYISSSPTYQTVPDFQRVQTGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKT PSKYLRNIDGEAWVANESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEP KPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYNC RKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYSTKEKNLTLKELFAKLKMHPYDLTVDSLDVHAG RQTFORFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEVGADLVEAKYQHAEPRLSIYGRSP DEWSKLSSWFVCNRIHCPNMTWMIQVPRIYDVFRSKNFLPHFGKMLENIFMPVFEATINPQADPELSV FLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLEKNPSYTYYAYYMYANIMVLNSLRKERGMNTFLF RPHCGEAGALTHLMTAFMIADDISHGLNLKKSPVLQYLFFLAQIPIAMSPLSNNSLFLEYAKNPFLDF LQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNY LEEGPAGNDIRRTNVAQIRMAYRYETWCYELNLIAEGLKSTEHHHHHH -NOV11g, 319077055 SEQ ID NO: 89 1986 bp DNA Sequence ORF Start: at 1 RF Stop: TAA at 1984 ACCATGGGACATCATCACCACCATCACCTGTCCCACATTGATGAATACATTTCCTCATCTCCAACCTA CCAGACCGTGCCTGAUTTTCAGAGAGTGCAGATTACTGGTGACTATGCCTCTGGGGTTACAGTTGAAG ATTTTGAAATTGTTTGCAAAGGTCTGTATCGGGCACTATGCATACGTGAGAAATACATGCAGAAGTCG TTTCAGAGGTTCCCTAAAACCCCTTCCAAATACTTGCGGAACATTGATGGTGAGGCTTGGGTAGCAAA TGAGAGCTTCTATCCAGTCTTTACTCCTCCTGTGAAGAAGGGAGAGGACCCCTTCCGAACAGACAACC TTCCTGAAAACCTGGGCTATCACCTCAAAATGAAGGACGGTGTAGTTTACGTCTATCCTAATGAAGCA GCAGTCAGCAAAGATGAGCCTAAGCCACTTCCTTACCCAAATCTGGACACCTTCTTAGACGATATGAA T11TTTACTTGCTTTAATTGCTCAAGGACCTGTTAAGACCTATACCCACCGGCGCCTGAAGTTCCTCT CCTCCAAGTTCCAGGTCCATCAGATGCTTAACGAGATGGACGAGTTAAAGGAGCTGAAAAACAACCCC CACCGAGA TFVATAACTGCAGGAAGGTGGACACCCATATCCATGCAGCCGCUGCATGAACCAGAA 208 WO 2004/056961 PCT/US2003/034114 ACATCTGCTGCGTTTTATTAAGAAATCTTACCAAATTGATGCTGACAGAGTGGTCTATAGCACCAAAG AGAAGAATCTGACCCTAAAGGAACTITTGCTAAATTAAAAATGCATCCTTATGACCTGACTGTTGAT TCTCTGGATGTTCATGCTGGACGCCAGACCTTCCAGCGTTTTGATAAGTTCAATGACAAATATAATCC TGTAGGAGCAAGTGAGCTACGGGACCTCTACTTGAAGACAGACAATTACATTAATGGGGAATATTTTG CCACTATCATCAAGGAGGTAGGTGCGGACCTGGTGGAGGCCAAGTACCAGCATGCTGAGCCCCGCCTG TCCATCTATGGCCGCAGTCCCGATGAGTGGAGCAAACTCTCCTCCTGGTTCGTCTGCAATCGCATCCA CTGCCCCAACATGACATGGATGATCCAGGTTCCCAGGATCTATGATGTGTTCCGTTCCAAGAATTTCC TTCCACATTTTGGAAAAATGCTGGAGAATATTTTCATGCCAGTGTTTGAGGCCACCATCAACCCCCAG GCTGACCCAGAACTCAGTGTCTTCCTCAAGCATATCACTGGCTTTGACAGTGTGGATGATGAGTCCAA ACACAGTGGCCACATGTTCTCCTCCAAGAGTCCCAAGCCCCAGGAGTGGACATTGGAAAAGAATCCAT CTTACACTTACTATGCCTACTACATGTATGCAAACATCATGGTGCTCAACAGCCTGAGAAAGGAACGA GGCATGAATACGTTTCTGTTCCGACCTCACTGTGGAGAAGCTGGAGCCCTCACCCATCTCATGACAGC ATTCATGATAGCAGATGATATCTCTCATGGCCTAAATTTAAAAAAGAGTCCCGTGCTACAGTACTTGT TTTTCTTAGCCCAAATTCCCATCGCCATGTCACCACTAAGTAACAATAGCCTATTTCTAGAGTATGCC AAAAATCCI1T1TTGGATTTCCTTCAGAAAGGGCTAATGATCTCACTGTCTACAGATGACCCAATGCA ATTCCACTTTACCAAGGAGCCCCTAATGGAAGAATATGCTATTGCTGCACAAGTCTTCAAGCTGAGCA CCTGTGATATGTGCGAAGTGGCAAGGAACAGTGTCTTGCAGTGTGGAATTTCTCATGAGGAGAAAGTA AAGTTTCTGGGCGACAATTACCTTGAGGAAGGCCCTGCTGGAAATGATATCCGGAGGACAAATGTAGC CCAAATCCGCATGGCCTATCGCTATGAAACCTGGTGTTATGAACTCAATTTAATTGCTGAGGGTCTTA AATCAACAGAATAA NOV11g, 319077055 .SEQ D NO: 90 661 aa W at 76746.0kD Protein Sequence TMGHHHHHHLSHIDEYISSSPTYQTVPDFQRVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKS FORFPKTPSKYLRNIDG EAWVANESFYPVFTPPVKKG EDPFRTDNLPENLGYHLKMKDGVVYVYPN EA AVSKDEPKPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNP HRDFYNCRKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYSTKEKNLTLKELFAKLKMHPYDLTVD SLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEVGADLVEAKYQHAEPRL SIYGRSPDEWSKLSSWFVCNRIHCPNMTWMQVPRIYDVFRSKNFLPHFGKMLENIFMPVFEATINPQ ADPELSVFLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLEKNPSYTYYAYYMYANIMVLNSLRKER GMNTFLFRPHCGEAGALTHLMTAFMIADDISHGLNLKKSPVLQYLFFLAQPIAMSPLSNNSLFLEYA KNPFLDFLQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKV KFLGDNYLEEGPAGNDIRRTNVAQIRMAYRYETWCYELNLIAEGLKSTE N11 h, 319077084 1*E IDNO: 91* 1965 bp DNA Sequence -.ORF Start: at 1 ORF Stop: TAA at 1963 ACCATGCTGTCCCACATTGATGAATACATTTCCTCATCTCCAACCTACCAGACCGTGCCTGATTTTCA GAGAGTGCAGATTACTGGTGACTATGCCTCTGGGGTTACAGTTGAAGATTTTGAAATTGTTTGCAAAG GTCTGTATCGGGCACTATGCATACGTGAGAAATACATGCAGAAGTCGTTTCAGAGGTTCCCTAAAACC CCTTCCAAATACTTGCGGAACATTGATGGTGAGGCTTGGGTAGCAAATGAGAGCTTCTATCCAGTCTT TACTCCTCCTGTGAAGAAGGGAGAGGACCCCTTCCGAACAGACAACCTTCCTGAAAACCTGGGCTATC ACCTCAAAATGAAGGACGGTGTAGTTTACGTCTATCCTAATGAAGCAGCAGTCAGCAAAGATGAGCCT AAGCCACTTCCTTACCCAAATCTGGACACCTTCTTAGACGATATGAA1 1TIT ACTTGCTTTAATTGC TCAAGGACCTGTTAAGACCTATACCCACCGGCGCCTGAAGTTCCTCTCCTCCAAGTTCCAGGTCCATC AGATGCTTAACGAGATGGACGAGTTAAAGGAGCTGAAAAACAACCCCCACCGAGATTTrTATAACTGC AGGAAGGTGGACACCCATATCCATGCAGCCGCTTGCATGAACCAGAAACATCTGCTGCGTTTrATTAA GAAATCTTACCAAATTGATGCTGACAGAGTGGTCTATAGCACCAAAGAGAAGAATCTGACCCTAAAGG AACTTTTTGCTAAATTAAAAATGCATCCTTATGACCTGACTGTTGATTCTCTGGATGTTCATGCTGGA CGCCAGACCTTCCAGCGTTTTGATAAGTTCAATGACAAATATAATCCTGTAGGAGCAAGTGAGCTACG GGACCTCTACTTGAAGACAGACAATTACATTAATGGGGAATATTTTGCCACTATCATCAAGGAGGTAG GTGCGGACCTGGTGGAGGCCAAGTACCAGCATGCTGAGCCCCGCCTGTCCATCTATGGCCGCAGTCCC GATGAGTGGAGCAAACTCTCCTCCTGGTTCGTCTGCAATCGCATCCACTGCCCCAACATGACATGGAT GATCCAGGTTCCCAGGATCTATGATGTGTTCCGTTCCAAGAATTTCCTTCCACATTTTGGAAAAATGC TGGAGAATATTTTCATGCCAGTGTTTGAGGCCACCATCAACCCCCAGGCTGACCCAGAACTCAGTGTC TTCCTCAAGCATATCACTGGCTTTGACAGTGTGGATGATGAGTCCAAACACAGTGGCCACATGTTCTC CTCCAAGAGTCCCAAGCCCCAGGAGTGGACATTGGAAAAGAATCCATCTTACACTTACTATGCCTACT ACATGTATGCAAACATCATGGTGCTCAACAGCCTGAGAAAGGAACGAGGCATGAATACGTTTCTGTTC CGACCTCACTGTGGAGAAGCTGGAGCCCTCACCCATCTCATGACAGCATTCATGATAGCAGATGATAT CTCTCATGGCCTAAATTTAAAAAAGAGTCCCGTGCTACAGTACTTG1TTTTCTTAGCCCAAATTCCCA TCGCCATGTCACCACTAAGTAACAATAGCCTATTTCTAGAGTATGCCAAAAATCCTT1T-rTGGATTTC 209 WO 2004/056961 PCT/US2003/034114 CTTCAGAAAGGGCTAATGATCTCACTGTCTACAGATGACCCAATGCAATTCCACTTTACCAAGGAGOC CCTAATGGAAGAATATGCTATTGCTGCACAAGTCTTCAAGCTGAGCACCTGTGATATGTGCGAAGTGG CAAGGAACAGTGTCTTGCAGTGTGGAATTTCTCATGAGGAGAAAGTAAAGTTTCTGGGCGACAATTAC CTTGAGGAAGGCCCTGCTGGAAATGATATCCGGAGGACAAATGTAGCCCAAATCCGCATGGCCTATCG CTATGAAACCTGGTGTTATGAACTCAATTTAATTGCTGAGGGTCTTAAATCAACAGAATAA j NOV1 1h, 31 9077084 ISEQ ID NO: 92....... 1 654 a** a..MW.at........ Protein Sequence _ TMLSHIDEYISSSPTYQTVPDFORVQITGDYASGVTVEDFEVCKGLYRALCIREKYMQKSFQRFPKT PSKYLRNIDGEAWVANESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEP KPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYNC RKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYSTKEKNLTLKELFAKLKMHPYDLTVDSLDVHAG RQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEVGADLVEAKYQHAEPRLSIYGRSP DEWSKLSSWFVCNRIHCPNMTWMIQVPRIYDVFRSKNFLPHFGKMLENIFMPVFEATINPQADPELSV FLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLEKNPSYTYYAYYMYANIMVLNSLRKERGMNTFLF RPHCGEAGALTHLMTAFMIADDISHGLNLKKSPVLQYLFFLAQIPIAMSPLSNNSLFLEYAKNPFLDF LQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNY LEEGPAGNDIRRTNVAQIRMAYRYETWCYELNLIAEGLKSTE NOV11i,320155888 SEQ ID NO: 93 1983 bp DNA Sequence ORF Start: at 1 JORF Stop: TAA at 1981 ACCATGCTGTCCCACATTGATGAATACATTTCCTCATCTCCAACCTACCAGACCGTGCCTGATTTTCA GAGAGTGCAGATTACTGGTGACTATGCCTCTGGGGTTACAGTTGAAGATTTTGAAATTGTTTGCAAAG GTCTGTATCGGGCACTATGCATACGTGAGAAATACATGCAGAAGTCGTTTCAGAGGTTCCCTAAAACC CCTTCCAAATACTTGCGGAACATTGATGGTGAGGCTTGGGTAGCAAATGAGAGCTTCTATCCAGTCTT TACTCCTCCTGTGAAGAAGGGAGAGGACCCCTTCCGAACAGACAACCTTCCTGAAAACCTGGGCTATC ACCTCAAAATGAAGGACGGTGTAGTTTACGTCTATCCTAATGAAGCAGCAGTCAGCAAAGATGAGCCT AAGCCACTTCCTTACCCAAATCTGGACACCTTCTTAGACGATATGAA 1TFACTTGCTTTAATTGC TCAAGGACCTGTTAAGACCTATACCCACCGGCGCCTGAAGTTCCTCTCCTCCAAGTTCCAGGTCCATC AGATGCTTAACGAGATGGACGAGTTAAAGGAGCTGAAAAACAACCCCCACCGAGA 1 i1ATAACTGC AGGAAGGTGGACACCCATATCCATGCAGCCGCTTGCATGAACCAGAAACATCTGCTGCGTTTTATTAA GAAATCTTACCAAATTGATGCTGACAGAGTGGTCTATAGCACCAAAGAGAAGAATCTGACCCTAAAGG AACTTTTTGCTAAATTAAAAATGCATCCTTATGACCTGACTGTTGATTCTCTGGATGTTCATGCTGGA CGCCAGACCTTCCAGCGTTTTGATAAGTTCAATGACAAATATAATCCTGTAGGAGCAAGTGAGCTACG GGACCTCTACTTGAAGACAGACAATTACATTAATGGGGAATATTTTGCCACTATCATCAAGGAGGTAG GTGCGGACCTGGTGGAGGCCAAGTACCAGCATGCTGAGCCCCGCCTGTCCATCTATGGCCGCAGTCCC GATGAGTGGAGCAAACTCTCCTCCTGGTTCGTCTGCAATCGCATCCACTGCCCCAACATGACATGGAT GATCCAGGTTCCCAGGATCTATGATGTGTTCCGTTCCAAGAATTTCCTTCCACATTTTGGAAAAATGC TGGAGAATATTTTCATGCCAGTGTTTGAGGCCACCATCAACCCCCAGGCTGACCCAGAACTCAGTGTC TTCCTCAAGCATATCACTGGCTTTGACAGTGTGGATGATGAGTCCAAACACAGTGGCCACATGTTCTC CTCCAAGAGTCCCAAGCCCCAGGAGTGGACATTGGAAAAGAATCCATCTTACACTTACTATGCCTACT ACATGTATGCAAACATCATGGTGCTCAACAGCCTGAGAAAGGAACGAGGCATGAATACGTTTCTGTTC CGACCTCACTGTGGAGAAGCTGGAGCCCTCACCCATCTCATGACAGCATTCATGATAGCAGATGATAT CTCTCATGGCCTAAATTTAAAAAAGAGTCCCGTGCTACAGTACTTGTTCTTAGCCCAAATTCCCA TCGCCATGTCACCACTAAGTAACAATAGCCTATTTCTAGAGTATGCCAAAAATCCI 1 GGATTTC CTTCAGAAAGGGCTAATGATCTCACTGTCTACAGATGACCCAATGCAATTCCACTTTACCAAGGAGCC CCTAATGGAAGAATATGCTATTGCTGCACAAGTCTTCAAGCTGAGCACCTGTGATATGTGCGAAGTGG CAAGGAACAGTGTCTTGCAGTGTGGAATTTCTCATGAGGAGAAAGTAAAGTTTCTGGGCGACAATTAC CTTGAGGAAGGCCCTGCTGGAAATGATATCCGGAGGACAAATGTAGCCCAAATCCGCATGGCCTATCG CTATGAAACCTGGTGTTATGAACTCAATTTAATTGCTGAGGGTCTTAAATCAACAGAACATCATCACC ATCACCATTAA NOVi i, 320155888 SEQ ID NO: 94 660 aa MW at 76688.9kD Protein Sequence TMLSHI DEYISSSPTYQTVPDFQRVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFRFPKT PSKYLRNIDGEAWVANESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEP KPLPYPNLDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYNC RKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYSTKEKNLTLKELFAKLKMH PYDLTVDSLDVHAG RQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEVGADLVEAKYQHAEPRLSIYGRSP DEWSKLSSWFVCNRIHCPNMTWMIQVPRIYDVFRSKNFLPHFGKMLENIFMPVFEATINPQADPELSV FLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLEKNPSYTYYAYYMYANIMVLNSLRKERGMNTFLF 210 WO 2004/056961 PCT/US2003/034114 RPHCGEAGALTHLMTAFMIADDISHGLNLKKSPVLQYLFFLAQIPIAMSPLSNNSLFLEYAKNPFLDF LQKGLMISLSTDDPMQFHFTKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNY LEEGPAGNDIRRTNVAQIRMAYRYETWCYELNLIAEGLKSTEHHHHHH A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table E6. Table E6. Comparison of the NOV11 protein sequences. NOV11a ---- MPLFKLPAEEKQIDDAMRNFAEKVFASEVKDEGGRQEISPFDVDEICPISHHEMQA NOVIlb TGSTMPLFKLPAEEKQIDDAMRNFAEKVFASEVKDEGGRQEISPFDVDEICPISHHEMQA NOV11c ---TMPLFKLPAEEKQIDDAMRNFAEKVFASEVKDEGGRQEISPFDVDEICPISHHEMQA NOV11d ----- NOV11e ----- NOV11f -- NOVl1g -------------------------------- - - - NOV11h ------------------------------- NOV11i ------- NOV11a HIFHLETLSTSTEARRKKRFQGRKTVNLSIPLSETSSTKLSHIDEYISSSPTYQTVPDFQ NOV11b HIFHLETLSTSTEARRKKRFQGRKTVNLSIPLSETSSTKLSHIDEYISSSPTYQTVPDFQ NOV11c HIFHLETLSTSTEARRKKRFQGRKTVNLSIPLSETSSTKLSHIDEYISSSPTYQTVPDFQ NOV11d ------------------------------------- TMLSHIDEYISSSPTYQTVPDFQ NOV1le ------------------------------ TMGHHHHHHLSHIDEYISSSPTYQTVPDFQ NOV11f ------------------------------------- TMLSHIDEYISSSPTYQTVPDFQ NOVllg ------------------------------ TMGHHHHHHLSHIDEYISSSPTYQTVPDFQ NOV11h ------------------------------------- TMLSHIDEYISSSPTYQTVPDFQ NOV11i ------------------------------------- TMLSHIDEYISSSPTYQTVPDFQ NOV11a RVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVA NOV1lb RVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVA NOV11c RVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVA NOV11d RVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVA NOVlle RVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVA NOV11f RVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVA NOV11g RVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVA NOV11h RVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVA NOV11i RVQITGDYASGVTVEDFEIVCKGLYRALCIREKYMQKSFQRFPKTPSKYLRNIDGEAWVA NOV11a NESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPN NOV11b NESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPN NOV11c NESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPN NOV11d NESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPN NOV1le NESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPN NOV11f NESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPN NOV11g NESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPN NOV11h NESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPN NOV11i NESFYPVFTPPVKKGEDPFRTDNLPENLGYHLKMKDGVVYVYPNEAAVSKDEPKPLPYPN NOV11a LDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYN NOV11b LDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYN NOV11c LDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYN NOV11d LDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYN NOV11e LDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYN NOV11f LDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYN NOVllg LDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYN NOV1lh LDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYN NOV11i LDTFLDDMNFLLALIAQGPVKTYTHRRLKFLSSKFQVHQMLNEMDELKELKNNPHRDFYN NOV11a CRKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYSTKEKNLTLKELFAKLKMHPYDLT NOV11b CRKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVYSTKEKNLTLKELFAKLKMHPYDLT 211 WO 2004/056961 PCT/US2003/0341 14 NOVi ic CRKVDTHIHAAACMNQKHLLRFIKKSYQIDADRW~ySTKEQJLTLKELFAKLJ4HPYDLT NOVi hi CRKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVVySTKEKYNLTLKELFAKLKMHPYDLT NOV11 e CRKVDTHIHAACNQKHLLRFIKKSYQIDADRVVzYSTKEKNLTLKELFAKLKM~HPYDLT NOV11 f CRKVDTHIHAAACMNQKHLLRFIKKSYQIDADRVxySTxEKN'LTLKELFAKLKMHjPYDLT NOV11ig CRKVDTHII-AAACMNQKHLLRFIKKSYQT DADRW~ySTKEKNLTLKELFAKLQ4HPYDLT NOVi lh CRKVDTHINAAACMNQKHLLRFIKKSYQIDADRVVYSTKEKNLTLKELFAKLCJVHPYDLT NOVi ii CRKVDTHIHAAACMtUQKHLLRFIKKSYQIDADRVVYSTKEIQJLTLKELFAKLKMHPYDLT NOVi la VDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATI IKEVGADLVE Novi lb VDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATI IKEVGADLVE NOVi ic VDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATI IKEVGADLVE NOVi id VDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEVGADLVE NOVi le VDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATI IKEVGADLVE NOVi if VDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATIIKEVGADLVE NOVi ig VDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATI IKEVGADLVE NOVi lb VDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATI IKEVGADLVE NOVi ii VDSLDVHAGRQTFQRFDKFNDKYNPVGASELRDLYLKTDNYINGEYFATI IKEVGADLVE NOVila AKYQHAEPRLSIYGRSPDEWSKLSSWFVCNRINCPNI4TWMIQVPRIYDVFRSKNFLPNFG NOVi lb AKYQHAEPRLSIYGRSPDEWSKLSSWFVCNRIHCPNMTWMIQVPRIYDVFRSKNFLPHFG NOVi ic AKYQHAEPRLSIYGRSPDEWSKLSSWFVCNRIHCPNNTWNIQVPRIYDVFRSKUFLPHFG NOVi id AKYQHAEPRLSIYGRSPDEWSKLSSWFVCNRIHCPN'TWMIQVPRIYDVFRSKNFLPHFG NOVi le AKYQHAEPRLSIYGRSFDEWSKLSSWFVCNRIHCPNI4TWMIQVPRIYDVFRSKNFLPHFG NOVi if AKYQHAEFRLSIYGRSPDEWSKLSSWFVCNRIHCPNMTWMIQVPRIYDVFRSKNFLPHFG NOVI ig AKYQHAEPRLSIYGRSPDEWSKLSSWFVCNRIHCPNNTWD4IQVPRIYDVFRSKNFLPHFG NOVi lb AKYQNAEPRLS IYGRSPDEWSKLSSWFVCNRIHCFNMTWMIQVPRIYDVFRSKNFLPHFG NOVi ii AKYQI-AEPRLSIYGRSPDEWSKLSSWFVCNRIHCPNIVTWMIQVPRIYDVFRSKNFLPHFG NOVi la KMLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESKHSGNMFSSKSPKPQEWTLE NOVi lb KMLENIFMFVFEATINPQADFELSVFLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLE NOVi ic KMLENIFMPVFEATINFQADFELSVFLKHITGFDSVDDESKHSG-MFSSKSPKPQEWTLE NOVi id KNLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLE NOVi le KMLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLE NOVi if KMLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESKHSGHMFSSKSPKPQEWTLE NOVi ig KMLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESK-SGHMFSSKSPKPQEWTLE NOVi lb KMLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESKNSGHMFSSKSPKPQEWTLE NOVi ii KMLENIFMPVFEATINPQADPELSVFLKHITGFDSVDDESK-SGHMFSSKSPKPQEWTLE NOVi la KNPSYTYYAYYMYANIMVLNSLRKERGMNTFLFRPHCGEAGALTHLMTAFMIADDI SHOL NOVi lb KPSYTYYAYYMYAIMVLNSLRKERGMTFLFRPHCGEAGALTHLMTAFMIADDI SHGL NOVi ic KNPSYTYYAYYMYANIMVLNSLRKERGMNTFLFRPHCGEAGALTHLMTAFMIADDI SHOL NOVi id KNPSYTYYAYYMYANIMVLNSLRKERGMNIFLFRPHCGEAGALTHLMTAFMIADDI SHGL NOVi le KNPSYTYYAYYMYANIMVLNSLRKERGMNTFLFRPHCGEAGALTHLMTAFMIADDI SHOL NOVi if KNPSYTYYAYYMYANIMVLNSLRKERGMNTFLFRPHCGEAGALTHLMTAFMIADDI SHOL NOVi ig KNPSYTYYAYYMYANIMVLNSLRKERGMNqTFLFRPHCGEAGALTHLMTAFMIADDI SHGL NoVi lb KNPSYTYYAYYNYANWMVLNSLRKERGDINTFLFRPHCGEAGALTHLMTAFMIADDISHGL NOVi ii KNPSYTYYAYYMYANIMVLNSLRKERGMNTFLFRPHCGEAGALTHLMTAFMIADDI SHGL NOVi la NLKKSPVLQYLFFLAQIPIAMSPLSNNSLFLEYAKNPFLDFLQKGLMISLSTDDPMQFHF NOVI lb NLKKSPVLQYLFFLAQIPIANSPLSNNSLFLEYAKNPFLDFLQKGLISLSTDDP4QFHF NOVi ic NLKKSPVLQYLFFLAQIPIAMSFLSNNSLFLEYAKNPFLDFLQKGLMISLSTDDP4QFHF NOVi id NLKKSFVLQYLFFLAQI PIAMSFLSNNSLFLEYAKNPFLDFLQKGLMISLSTDDPMQFHF NOVi le NLKKSPVLQYLFFLAQI PIA 4SPLSNNSLFLEYAKNPFLDFLQKGLMISLSTDDPMQFHF NOV11 f NLKKSPVLQYLFFLAQIPIANSPLSNNSLFLEYAKNPFLDFLQKGLMISLSTDDpMQFHF NOVi ig NLKKSPVLQYLFFLAQIPIAMSPLSNNSLFLEYAKNPFLDFLQKGLMISLSTDDPMQFHF NOVi lb NLKKSPVLQYLFFLAQIPIAI4SPLSNNSLFLEYAKNFFLDFLQKGLMISLSTDDPMQFHF NOVi ii NLKKSPVLQYLFFLAQIPIANSPLSNNSLFLEYAKNFFLDFLQKGLMISLSTDDPMQFHF NOVi la TKEPLMEEYAIAAQVFKLSTCDMCEVAENSVLQCGISHEEKVKFLGDNYLEEGPAGNDIR NOVi lb TKEPLMEEYAIAAQVFKLSTCDMCEVAHNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIR 212 WO 2004/056961 PCT/US2003/034114 NOV11c TKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIR NOV11d TKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIR NOV11e TKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIR NOV11f TKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIR NOV11g TKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIR NOV11h TKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIR NOV11i TKEPLMEEYAIAAQVFKLSTCDMCEVARNSVLQCGISHEEKVKFLGDNYLEEGPAGNDIR NOV11a RTNVAQIRMAYRYETWCYELNLIAEGLKSTE----- NOV11b RTNVAQIRMAYRYETWCYELNLIAEGLKSTE----- NOV11c RTNVAQIRMAYRYETWCYELNLIAEGLKSTE----- NOV11d RTNVAQIRMAYRYETWCYELNLIAEGLKSTE----- NOV11e RTNVAQIRMAYRYETWCYELNLIAEGLKSTE----- NOV11f RTNVAQIRMAYRYETWCYELNLIAEGLKSTEHHHHHH NOV11g RTNVAQIRMAYRYETWCYELNLIAEGLKSTE----- NOV11h RTNVAQIRMAYRYETWCYELNLIAEGLXSTE----- NOV11i RTNVAQIRMAYRYETWCYELNLIAEGLKSTEHHHHHH NOV11a (SEQ ID NO: 78) NOV11b (SEQ ID NO: 80) NOV11c (SEQ ID NO: 82) NOV11d (SEQ ID NO: 84) NOV11e (SEQ ID NO: 86) NOV11f (SEQ ID NO: 88) NOV11g (SEQ ID NO: 90) NOV11h (SEQ ID NO: 92) NOV11i (SEQ ID NO: 94) Further analysis of the NOV11 a protein yielded the following properties shown in Table E7. Table E7. Protein Sequence Properties NOVI Ia [SignalP analysis: INo Known Signal Sequence Predicted PSORT 11 analysis: PSG: a new signal peptide prediction method N-region: length 11; pos.chg 2; neg.chg 2 H-region: length 2; peak value -16.49 PSG score: -20.89 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -12.21 possible cleavage site: between 26 and 27 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM regionallocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 1.85 (at 601) ALOM score: 1.85 (number of TMSs: 0) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 4.55 Hyd Moment(95): 4.70 G content: 0 D/E content: 2 S/T content: 0 Score: -7.43 213 WO 2004/056961 PCT/US2003/034114 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: RRKK (5) at 71 pat4: RKKR (5) at 72 pat7: none bipartite: none content of basic residues: 12.0% NLS Score: 0.15 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: KKXX-like motif in the C-terminus: LKST SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 70.6 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 43.5 %: cytoplasmic 39.1 %: nuclear 13.0 %: mitochondrial 4.3 %: vesicles of secretory system 214 WO 2004/056961 PCT/US2003/034114 >> prediction for CG192154-01 is cyt (k=23) A search of the NOV11 a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table E8. Table E8. Geneseq Results for NOVI1 a NOVila identities/ Geneseq Protein/Organism/Length [Patent #, Residues/ Similarities for Expect Identifier Date] Match the Matched Value Residues Region ABG70650 Rabbit adenosine monophosphate 1..747 700/747 (93%) 0.0 deaminase (AMPDA) - Oryctolagus 1..747 720/747 (95%) cuniculus, 747 aa. [EP1215587-A2, 19 JUN-2002] ABG02232 Novel human diagnostic protein #2223 - 128..747 620/620 (100%) 0.0 Homo sapiens, 1813 aa. [W0200175067- 1194..1813 620/620 (100%) A2, 11-OCT-2001] ABB65426 Drosophila melanogaster polypeptide 114..739 337/636 (52%) 0.0 SEQ ID NO 23070 - Drosophila 9..643 449/636 (69%) melanogaster, 658 aa. [WO200171042 A2, 27-SEP-2001] AAB31955 Amino acid sequence of a wheat AMP 101..739 302/640 (47%) e-1 67 deaminase enzyme - Triticum aestivum, 60..668 415/640 (64%) 681 aa. [W0200109305-A2, 08-FEB 2001] AAB31954 Amino acid sequence of a soybean AMP 183..739 281/558 (50%) e-165 deaminase enzyme - Glycine max, 603 37..589 371/558 (66%) aa. [W0200109305-A2, 08-FEB-2001] In a BLAST search of public sequence databases, the NOVI1 a protein was found to have homology to the proteins shown in the BLASTP data in Table E9. Table E9. Public BLASTP Results for NOV11 a Protein NOVIa Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion P23109 AMP deaminase 1 (EC 3.5.4.6) 1.147 747/747(100%) 0.0 (Myoadenylate deaminase) (AMP 1..747 747/747 (100%) deaminase isoform M) - Homo sapiens (Human), 747 aa. P10759 AMP deaminase 1 (EC 3.5.4.6) 1.747 693/747 (92%) 0.0 (Myoadenylate deaminase) (AMP 1-747 718/747(95%) deaminase isoform M) - Rattus norvegicus (Rat), 747 aa. Q803X5 Similar to AMP deaminase 3 - 13..745 466/739 (63%) 0.0 Brachydanio rerio (Zebrafish) (Danio 33.771 584/739 (78%) rerio), 779 aa. Q8CFR4 AMP deaminase 3 - Mus musculus 13..747 458/750 (61%) 0.0 (Mouse), 766 aa. 13..760 575/750 (76%) 215 WO 2004/056961 PCT/US2003/034114 008739 AMP deaminase 3 (EC 3.5.4.6) (AMP 13..747 457/750 (60%) 0.0 deaminase isoform E) (AMP deaminase 13..760 573/750 (75%) H-type) (Heart-type AMPD) - Mus musculus (Mouse), 766 aa. PFam analysis predicts that the NOV11 a protein contains the domains shown in the Table El 0. Table El0. Domain Analysis of NOV11a identities/ Pfam Domain NOVIla Match Region Similarities Expect Value for the Matched Region A_deaminase 289..703 205/447 (46%) 9.6e-236 400/447 (89%) Example E5. Expression Profile of the Human AMPD1 Gene The protocol for quantitative expression analysis is disclosed in Example 09. Expression of gene CG1 92154-01 was assessed using the primer-probe set Ag7615, described in Table El 1. Results of the RTQ-PCR runs are shown in Tables El 2, El 3 and El 4. Table El 1. Probe Name Ag7615 Primers Sequences Length Start Position SEQ ID No[ Forward 5'-cttcttttctactgtgctatcctagaatc-3' 29 40 143 1 Probe TET-5'-caacaatgcctctgttcaaactccca-3'-TAMRA 26 80 144 [Reverse 5'-tgcatcatcaatttgtttctctt-3' 23 j 110 145 Table E12. Human Metabolic Column A - Rel. Exp.(%) Ag7615, Run 322942020 Tissue Name 62 A Tissue Name A 137857 psoas-AA.M.Diab.- 33.4 139523 pancreas-HI.M.Norm-hi- 2 0.0 135760 psoas-HMb-hi-1 o .0 f13950 6pa*ncreas-CC.M.Norm-hi-1 0 .0 F 134827 psoas-CMD-hi-1 16.2 1142744 pancreas- H. M. Norm-med- 1 0o.0 137834 psoas-CC.M.Diab.- 56.3 1 39 5 31 pancreas-AA.M.Norm-med-1 0.0 137828 psoas-CC.M.Diab.- 80.7 137871 pancreas-CC.M.Norm-med-1 0.0 [135763 psoas-HMD-med-1 43.5139541 pancreas-Hi.M.Norm-low-1 0 142740 psoas-AS.M.Diab-low- 0.0 139537 pancreas-CC.M.Norm-low-2 0.0 F0.0 134834.p--s- ---- -lo - t2..... ...... pancreas C M .'Nor'm-low-'1'_ 1.... . ....... 137850 psoas-AS.M.Norm.-hi- 96.6 137845 pancreas-AS.M.Norm-low-1 0.0 135769 psoas-HMND-hi-1 48.01143530 small intestine-AA.M.Diab-hi-1 0.0 135766 psoas-AAMND-hi-1 21.3 143529 small intestine-CC.M.Diab-hi-1 0.0 142746 psoas-AA.M.Norm- 0.0 143538 small intestine-HI.M.Diab-med-1 0.0 med-I__ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 142745 psoas-HI.M.Norm- 0.0 143531 small intestine-AA.M.Diab-med-1 00 216 WO 2004/056961 PCT/US2003/034114 med-1 137844 psoas-CC. M. Norm- 133 1 1385 sosAAMNom 12.1 143528 small intestine-CC.M.Diab-med-2 0.0 med-1 psoas-CC.M.Norm- 6.4 143537 small intestine-HI.M.Diab-low-1 0.0 14242____________._Norm 0.0 143535 small intestine-AS.M.Diab-low-1 0.0 low-2 11o37873 psoas-AS.M.Norm- 33 1143534 small intestine-AA.M.Diab-low-1 0.0 17853 psoastHIA.NA[m.

low-1 51.8143544 small intestine-AS.M.Norm-hi-1 0.0 1135775 psoas-CMND-low-1 3.6 1 43 5 4 3 small intestine-HI.M.Norm-hi-1 0.1 137858 diaphragm- 20.2 143542 small intestine-CC.M.Norm-hi-1 0.0 135772 diaphragm-AMD-hi-1 63.7 143539 small intestine-AA.M.Norm-hi-1 135761 diaphragm-HMD-hi-1 127.2143548 small intestine-AA.M.Norm-med-2 00 134828 diaphragm-CMD-hi-1 17.1143547 small intestine-AA.M.Norr-re-d-1 137835 diaphragm- 47.01143540 small intestine-CC.M.Norm-med-1 0.0 CC.M.Diab.-med-2 I 1 24.71143550 small intestine-CC.M.Norm-low-2 0.0 114835 diaphragm-AAMD-low- 3.7 143549 small intestine-CC.M.Norm-low-1 0.0 142738 diaphragm CC.M.Norm-hi-1 0.0 143546 small intestine-HI.M.Norm-low-1 0.0 AS.M.Norm-hi-1 26.6 143525 hypothalamus-HI.M.Diab-hi-1 0.0 137848 diaphragm-H1. M. Norrr dhi-1 N 63.7 143515 hypothalamus-CC.M.Diab-hi-1 0.0 137843 diaphragm- 54

.

7 143513 hypothalamus-AA.M.Diab-hi-1 0.0 AA.M.Norm-hi-1 I ______________________ 137879 diaphragm- 45 143507 AA.M.Norm-med-2 1 1 hypothalamus-AS.M.Diab-hi-1 137872 diaphragm- I CC. M.Norm-med-1 15.31143506 hypothalamus-CC. M.Diab-med-1 0.0 135773 diaphragm-HMND- 349143505 hypothalamus-HI.M.Diab-med-1 0.0 3 9542 diap hragmH I M.Norm low-1 19.3 143509 hypothalamus-AA.M.Diab-low-1 0.0 137877 diaphragm- I CC.M.Norm-low-1 7.9 143508 hypothalamus-CC. M.Diab-low-10.0 137874 diaphragm- 1 AS.M.Norm-low-1 0.4 143503 hypothalamus-AS. M.Diab-low- 0.0 141340 sub~adipose AA.M.Diab-hi-1 0.0 143522 hypothalamus-HI.M.Norm-hi-1 0.0 H.M.Diab-hi-1 . 1 hypothalamus-AS.M.Norm-hi-1_ 0.0 135736 subQadipose-AMD3516 135771 subQadipose-AMD-hi- 0.1 143511 hypothalamus-CC.M.Norm-hi-1 0.0 I A A .M .D i a b -m e d -i 0 0_ y o h l m u - A M N r - e 137862 subQadipose- 10.1 1143517 hypothalamus-AA M.Nrm-ed- 0.0 217 WO 2004/056961 PCT/US2003/0341 14 CC.M.Diab.-medi 1 med6-i u~aios-HD 0.0 143514 hypothalamus-HI. M.Norm-med- 1 0.0 141338 sub~adipose- 0.0 143521 hypothalamus-AS. M. Norm-low-i 0.0 13954 su1dioe 0.01412 hypothalamus-CC. MNt-w20. HI.M.Diab-low-1. 451om- I1c 155 sbdpoeCD 10.01145454 Patient-25pl (CC.Diab.no insulin) 0.0 ~134832 subQadipose-AA MD- 0.0l 10916 Patient-18pI . low-i I__________________________ 1432subQadipose- 0.01093Pte-8g0. 135767 subQadipose-CMND- 0.0 10911 Patient-17p 0O.0 f 1 3 5 7 6 5 subQadipose-AMND- 0.0j 10908 Patienit- 17go ~.0 1439sub~adipose- 0.0 100752 Ptet1s 0. 1 H.M.Norm-med- 1 Pa.t.e..t..... '11334 s**ub Qadipose- I--- CC.M. Norm-med-i 0.0 19782 Patient- 13p1 10.0 13 -. . ......- -1 .......- 'F*..... .954 sub~adipose- 10.0 160114 Patt t27t (CC. Diab.obese. insulin) 0.0 1AA.M.Norm-med-2aen 137875 subQadipose- 0.0 '160113 Patient 27-pt (CC. Diab.obese. insulin) 0.0 AA. M. Norm-med-i 143s ub.oapoe-1 100 1160112 Patient 27-sk (CC.Diab obese. insulin) 22.8 137878 subQadipose- 10.01160111 Patient 27-go (CC. Diab.obese. insulin) 0.0 IHI.M.Norm-low-1 L_____________________ 137876 subQadipose- I-________________________ ICC.M.Norm-low-1 0.0 145461 Patient-2Bsk (CC. Diab.obese. insulin) 18.2 137859 vis.adipose- 0.0 1145441 Patient-22sk (CC. Diab. insulin) 4. AA.M.Diab.-hi-1 I _____________________ 135770 vis adipose-AMD-hi-1 10.0 f145438 Patient-22p1 (CC. Diab. nsulin)0. 7159 vis.adipose-HDh1 0 .0145427 Patient-20pl (CC. Diab.overwt. insulin) 0~- T.0~ 143502 vis.adipose-0. I'CC..Diabmed-21 0.097503 Patient-12p . 139510 vis.adipose- 0.0 1145443 Patient-23p (CC.Non-diab.overwt)0. AA. M. Diab-med-1 137861 visadipose- f 0 211145435.Patient-21 I 'CC Ndb0.0 FcC.M.Diab.-med-1 p .o-a ve 137839 visadipose- 10.0110921 Patient-19p1 . HI.M.Diab.-med-1 K _____________________ 139546 vis.adipose-HI.M.Diab- 10.0 {110918 Patient-l9go 0.0 low-i I___________________ 137831 vis-adipose-00 Pte-Os8. CC.M.Diab.-low-1 0. 97481 Ptet0s . 139522 vis____________ 0.2197478 Patient-07p1 0.0 139516 vis adipose- 0.0 160117 Human Islets-male, obese. AS.M.Norm-hi- 1___________________ 1137846 vis.adipose-PA l(pnra 1 CC.M.Norm-hi-1 jIcrioa . 218 WO 2004/056961 PCT/US2003/034114 137841 vis.adipose- 0.0 154911 Capan2 (pancreas adenocarcinoma) 0.0 AA.M.Norm-hi-1 __ 139543 vis.adipose- 0.0 141190 SW579 (thyroid carcinoma) 0.0 AA.M.Norm-med-2 I______________________ ~139532 vis.adipose- 0.0 1145489 SK-N-MC (neuroblastoma) 1 0.0 IAA.M.Norm-med-1 1 ________________________ 139530 vis.adipose HI.M.Norm-med-1 KNM nuolsma10. 13953 1is~0.0 145495 SK-N-SH (neuroblastoma) 1 0.0 139539 vis.adipose- 1 0.0 145498 U87 MG (glioblastoma) 2 0.0 HI.M.Norm-low-1 2 139535-0.0 145484 HEp-2 (larynx carcinoma) 1 0.0 CC.M.Norm-low-2 __________________ 137852 vis.adipose- A4 I ~ oa 3782 vs aipoe-0.0 145479 A549 (lung carcinoma) 0.0 CC.M.Norm-low-1 ngcri 135768 vis.adipose-AMND- 0.0 145488 A427 (lung carcinoma) 2 0.0 1437liver-HI.M.Diab-hi-1 0..442~ 738Lu (orm~allung) 1 0.0 139514 liver-H.M.Di 1 0.0 141187 SKW6.4 (B lymphocytes) 0.0 139526 liver-CC.M.Diab-med-2 1 4 IM (immunoglobulin secreting lymphoblast) 0.0 139511 liver-AA.M.Diab-med- 0.0 m5 MOLT-4 (acute lymphoblastic leukemia derived 0.0 from peripheral blood) .I 137840 liver-HI.M.Diab.-med-1 154648 U-937(histiocystic lymphoma) 0.0 137827 liver-CC.M.Diab.-med- 0.0 1154647 Daudi (Burkitt's lymphoma) 0.0 137838 liver-HI.M.Diab.-low-1 0.0 145494 SK-MEL-2 (melanoma) 2 0.0 135758 liver-CMD-low-1 10.0 141176 A375 (melanoma) [0.0 139519 liver-CC.M.Norm-hi-1 0.0 154642 SW 1353 (humerus chondrosarcoma) 0.0 139518 liver-AA.M.Norm-hi-1 0.0 141179 HT-1080 (fibrosarcoma) 0.0 137849 liver-AS.M.Norm.-hi-1 145491 MG-63 osteosarcomaa) 1 0.0 137847 liver-HI.M.Norm -hi- 1 0.0 141186 MCF7 (breast carcinoma) 0.0 142741 iver-AA.M.Norm-med- 0.0 141193 T47D (breast carcinoma) 0.0 141341 liver-HI.M.Norm-med-1 0. 0154641 BT-20 (breast carcinoma) 0.0 141335 liver-CC.M.Norm-med- 0.0 141175 293 (kidney transformed with adenovirus 5 DNA) 0.0 1 2 139540 liver-HI.M.Norm-low-1 0.0 141182 HUH hepatoma 1 0.0 139534 liver-CC.M.Norm-low-1 0.0 141184 HUH7 hepatoma 1 0.0 1139521 liver-ASV.Nrm-low-1 0.0 1145478 HT1376 (bladder carcinoma) 0.0 141328 pancreas-CC.M.Diab- 0.0 145481 SCaBER (bladder carcinoma) 0.0 hi-i 139525 pancreas-AS.M.Diab- 0.0 141192 SW620 (lymph node metastatsis, colon 0.0 Ihi-1- .......... .... .. .... .. *- - carcinom 'a)- 2 --- *"*. .... 137856 pancreas-AA.M.Diab.- 0.0 141180 HT29 (colon carcinoma) 1 0.0 1hi-1 137837 pancreas-HI.M.Diab.- 0.0 141188 SW480 (colon carcinoma) 1 0.0 hi-1 141337 pancreas-CC.M.Diab- 0.0 154646 CAOV-3 (ovary adenocarcinoma) 0.0 med-2 j566(vradncrima0. 139527 pancreas-CC.M.Diab- 0.0 141194 HeLa (cervix carcinoma)- 2 0.0 med-1I 139515 pancreas-HI.M.Diab- 10.0 1145482 HeLa S3 (cervix carcinoma) 1 0.0 219 WO 2004/056961 PCT/US2003/034114 139512 pancreas-AA.M.Diab- 0.0 145486 DU145 (prostate carcinoma) 00 med-11446D15(rsaecrioa0. 14739 pancreas-AS.M.Diab- 0.0 154643 PC-3 (prostate adenocarcinoma) 0.0 1o39513 pancreas-CC.M.Diab- 0.0 154649 HCT-8 (ileocecal adenocarcinoma) 0.0 142743 pancreas-AA. M.Norm- 0.0 hi-1 Table E13. Panel 5 Islet Column A - Rel. Exp.(%) Ag7615, Run 311303511 Tissue Name A Tissue Name A 97457 Patient-02go adipose 1 0.0 194709 Donor 2 AM - A adipose 10.0 97476 Patient-07sk skeletal muscle 0.0 194710 Donor 2 AM - B adipose 0.0 197477 Patient-07ut uterus 0.0 94711 Donor 2 AM -C adipose 0.0 97478 Patient-07pl placenta 0.0 94712 Donor 2 AD - A adipose 0.0 99167 Bayer Patient 1 1 0 94713 Donor 2 AD - B adipose 0.0 97482 Patient-O8ut uterus 0.0 94714 Donor 2 AD - C adipose 10.0 197483 Patient-08pl placenta 0.0 C42 Donor 3 U - A Mesenchymal Stem 0 97486 Patient-09sk skeletal muscle 14.5 94743 Donor 3 U - B Mesenchyma Stem 0.0 Cells 97487 Patient-09ut uterus 0.0 94730 Donor 3 AM - A adipose 0.0 197488 Patient-09pl placenta I 0.0 194731 Donor 3 AM - B adipose 0.01 97492 Patient-1 Out uterus 0.0 194732 Donor 3 AM - C adipose 0.0 974.93 Patient-i 0 pi placenta 0.0 973 Donor 3 AD - A adipose 17 97495 Patient-11 go adipose 0.0 94734 Donor 3 AD -B adipose 00 97496 Patient-i 1 sk skeletal muscle 49.3 94735 Donor 3 AD -C adipose 00 97497 Patient-11 ut uterus 0.0 77138 Liver HepG2untreated 0.0 197498 Patient-11 pl placenta 0.0 73556 Heart Cardiac stromal cells (primary) 0.0 97500 Patient-i 2go adipose 0. 0681735 Small Intestine 0o.0 97501 Patient-1 2sk skeletal muscle 1100.0 72409 Kidney Proximal Convoluted Tubule 10.0 97502 Patient-12ut uterus __0.0 82685 Small intestine Duodenum 0.1 97503 Patient-1 2pl placenta 0.0 90650 Adrenal Adrenocortical adenoma 0.0 94721 Donor 2 U - A Mesenchymal Stem 0.0_72410 Kidney HRCE 0 0 94722 Donor 2 U -B Mesenchya Stem 0.0 72411 Kidney HRE 0.0 Cells I N_ 94723 Donor 2 U - C Mesenchymal Stem Cells Donor 2 U - C Mesenchymal Stem 0.0 73139 Uterus Uterine smooth muscle cells 0.0 Table E14. General-screening-panel-v1.7 Column A - Rel. Exp.(%) Ag7615, Run 318345844 Tissue Name A Tissue Name A fAdipose 1.8 Gastric ca. (liver met.) NCI-N87 0.0 HUVEC 0.0 Stomach 0.0 IMelanoma* Hs688(A).T 0.0 Colon ca. SW480 0.0 220 WO 2004/056961 PCT/US2003/034114 Melanoma* Hs688(B).T 0.0 Colon ca. (SW480 met) SW620 0.0 Melanoma (met) SK-MEL-5 0.0 Colon ca. HT29 0.0 Testis 0.0 Colon ca. HCT-116 0.0 VProstate ca. (bone met) PC-3 [0.0 [Colon cancer tissue 0.0 Prostate ca. DU145 [ 0.0 Colon ca. SW1116 0.0 Prostate pool 0.1 Colon ca. Colo-205 0.0 [Uterus pool [0 Colon ca. SW-48 00 Ovarian ca. OVCAR-3 0.0 Colon 0.0 Ovarian ca. (ascites) SK-OV-3 00 [Small Intestine 0.0 Ovarian ca. OVCAR-5 0Y [Heart 0.0 Ovarian ca. IGROV-1 [.0 Lymph Node pool 1 0.0 [Ovarian ca. OVCAR-8 0.0 Lymph Node pool 2 0.1 ry 0.0 Fetal Skeletal Muscle Ti6] [Breast ca. MCF-7 _______ I. [Seea Muscl poo -66 Breast ca. MDA-MB-231 0.0 [Skeletal Muscle 100.0 [Breast ca. BT-549 0.0 Spleen O.0 Breast ca. T47D 0.0 Thymus 0.0 Breast pool 0.0 CNS cancer (glio/astro) SF-268 0.0 [Trac'hea [ ---- .......... CNs cancer (glioiastro) T98G 0~[ .0 Lung 0.0 CNS cancer (neuro;met) SK-N-AS 0.0 Fetal Lung 0.0 CNS cancer (astro) SF-539 0.0 ILung ca.- N'Cl-N4"17 [ 0.......0 [NS cancer (astro) SNB-75 I0.0 [Lung ca. LX-1 0.0 CNS cancer (glio) SNB-19 0.0 [Lung ca. NCI-H146 0.0 CNS cancer (glio) SF-295 0.0 Lung ca. SHP-77 0.0 Brain (Amygdala) .0 [ung ca. NCI-H23 0.0 Brain (Cerebellum) O [Lung ca. NCI-H460 0.0 Brain (Fetal) 0.0 [Lung ca. HOP-62 0.0 Brain (Hippocampus) 0.0 Lung ca. NCI-H522 0.0 Cerebral Cortex pool 0.0 Lung ca. DMS-114 0.0 Brain (Substantia nigra) 0.0 Liver 0.0 Brain (Thalamus) 0.0 Kidney pool 0.0 Spinal Cord 0.0 stal Kidne 0 Adrenal Gland 0.0 IRenal ca. A498 0.0 [Salivary Gland 0.1 JRTlca. ACHN 0.0 [hyroid 0.9 lRenal ca. UO-31..0 Panreatic ca. PANC-i 0.0 Renal 1-ca" K.... 1:- [0 .....................------- 1 -0.0 [Pancreas pool 0.0 _Bladder 0.0 General Screening Panel v1.7 Summary: Ag7615 The highest expression of AMPD1 is detected in skeletal muscle (CT=22.95) that is supporting GeneCalling and literature data and emphasizing the key role of this enzyme in energy homeostasis in skeletal muscle. Moderate to low expression of this gene is also seen in adipose, trachea, salivary gland and thyroid. 221 WO 2004/056961 PCT/US2003/034114 Human Metabolic Summary: Ag7615 The highest expression of this gene was detected in a skeletal muscle sample (CT=22). This gene was expressed at high to moderate levels in muscle samples from psoas, diaphragm, and skeletal muscle. Panel 5 Islet Summary: Ag7615 Notably, AMPD1 is significantly up-regulated in diabetic skeletal muscle (patient 12, CT=27.3) compared to nondiabetic skeletal muscle (patient 11 and 9). Moderate expression of this gene was exclusively seen in skeletal muscle samples from obese non-diabetic, and from diabetic patients. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of diabetes and obesity. Example E6. Assays Screening for Modulators of AMPD1 As shown below Adenosine monophosphate deaminase 1 catalyzes the deamination of AMP to IMP in skeletal muscle and plays an important role in the purine nucleotide cycle. AMP + H 2 0 -> IMP + NH 3 Assays for screening for antibody therapeutics or small molecule drugs targeting human AMPD1 can be formulated utilizing the non-exhaustive list of cell lines that express the AMPD1 from the RTQ-PCR results shown above. To assay the enzymatic activity of AMPD1 the monitoring the amount of NH 3 generated in reaction might be used. Concentration of NH 3 might be measured by converting it into coloured compound indophenol. The indophenol concentration might be determined by spectrophotometry at 625 nm as described in Acta Physiol Pharmacol Bulg. 1978;4(2):61-7, PMID: 735835. Another enzymatic assay for determination of AMPD1 activity that includes measurement AMP and IMP concentration by HPLC, is described in Comp. Biochem. Physiol. B99:125 (1991). Not to be limited by a particular mechanism of action, the inventors nevertheless have discovered that inhibition of AMPD1 has beneficial effects for treating diabetes/obesity by acting in many metabolic tissues, including skeletal muscle. Our results indicate that a modulator of AMPD1 activity, such as an inhibitor, activator, antagonist, or agonist of AMPD1 may be useful for treatment of such disorders as obesity, diabetes, and insulin resistance, as well as for enhancement of insulin secretion. In a preferred embodiment, the modulator of AMPD1 activity is antagonist or inhibitor of AMPD1 activity. Protocols Following Examples describe procedures, protocols and technologies described in this application. Example 01. Mouse Diet-Induced Obesity (DIO) Study (BP24.02) Overview The predominant cause for obesity in clinical populations is excess caloric intake. This so called diet-induced obesity (DIO) is mimicked in animal models by feeding high fat diets of greater than 40% fat content. The DIO study was established to identify the gene expression changes contributing to the development and progression of diet-induced obesity. In addition, the study design sought to identify the factors that led to the ability of certain individuals to resist the effects of a high fat diet and thereby prevent obesity. 222 WO 2004/056961 PCT/US2003/034114 The sample groups for the study normally had body weights +1 S.D., + 4 S.D. and + 7 S.D. of the chow-fed controls. In addition, the biochemical profile of the + 7 S.D. mice normally revealed a further stratification of these animals into mice that retained a normal glycemic profile in spite of obesity and mice that demonstrated hyperglycemia. Tissues examined included hypothalamus, brainstem, liver, retroperitoneal white adipose tissue (WAT), epididymal WAT, brown adipose tissue (BAT), gastrocnemius muscle (fast twitch skeletal muscle) and soleus muscle (slow twitch skeletal muscle). The differential gene expression profiles for these tissues revealed genes and pathways that can be used as therapeutic targets for obesity and/or diabetes. Protocol 5 groups of mice were used with 3 mice per group. Occasionally, more than 3 mice were used in a single group in order to preserve correct parameters for the study. In such case only 3 mice would be sacrificed for tissues. The groups were grouped based on the following parameters: Group 1. Chow fed mice Group 2, Mice fed a high fat diet who were 1 standard deviation in weight above the chow fed mice. Group 3. Mice fed a high fat diet who were 4 standard deviations in weight above the chow fed mice. Group 4. Mice fed a high fat diet who were 7 standard deviations in weight above the chow fed mice and who had normal glucose levels. Group 5. Mice fed a high fat diet who were 7 standard deviation in weight above the chow fed mice and who were hyperglycemic. In each group of mice, there were 3 mice that were sacrificed and tissues harvested for the study. Example Q2. Rat Pancreatic Islet Study (BP24.03) Overview An important clinical goal in the early phases of Type If diabetes is to increase insulin secretion from the beta cells of the pancreas. Numerous agents have been identified that can modulate insulin secretion experimentally and in therapeutic situations. When applied to isolated rat pancreatic islets, the changes in gene expression can be correlated with insulin secretion. In this study, acute and chronic changes in gene expression were examined from islets treated with an agent after short (4 hour) and long-term (5 days) exposure, respectively, compared with the basal state (11 mM glucose). The agents included elevated (25 mM) glucose, glucose (11 mM) and exendin-4 (1 nM), glucose (11 mM) and glybenclamide (50 uM) and glucose (11 mM) and oleate (2 mM). Protocol All samples were isolated rat islets. They differed only in the treatment that they received. The following samples were in the 4 hour group: 1) 11 mM glucose 2) 25 mM glucose 3) 11 mM glucose & JTT 608 4) 11 mM glucose & Carbacol 223 WO 2004/056961 PCT/US2003/034114 5) 11 mM glucose & Exendin-4 Isolated rat islets were treated with either 11mM glucose (basal state) or 25mM glucose (elevated glucose.). Then there were 3 additional sets of rat islets that were treated with 11mM glucose and one of the 3 agents: JTT 608, Carbacol, or Exendin-4. The following samples were in the 5 day group: 1) 11 mM glucose 2) 25 mM glucose 3) 11 mM glucose &1 nM Exendin 4) 11 mM glucose & 50uM Glybenclamide 5) 11 mMglucose & 2mM Oleic Acid Isolated rat islets were treated with either 1 1mM glucose (basal state) or 25mM glucose (elevated glucose.). Then there were 3 additional sets of rat islets that were treated with 11mM glucose and one of the 3 agents: exendin, glybenclamide, or oleic acid. From all 10 samples, each was split into 2 replicates. The 2 replicates were run for differential gene expression analysis (GeneCalling@). Example Q3. Rat Insulin Sensitivity Study (BP24.05) Protocol ZDF rats or their lean littermates were treated with a variety of agents that are known to alter insulin sensitivity. Metformin, vanadate, and AICAR enhance tissue response to insulin, while the free fatty acids generated by Liposyn (intravenous lipid infusion) treatment reduces the response. A variety of tissues were harvested, including gastrocnemius and soleus muscles, liver, retroperitoneal and epididymal WAT, and IBAT. Only gastrocnemius and soleus muscles were processed for differential gene expression analysis (GeneCalling@). There were 5 groups of samples: 1) Metformin vehicle (vehicle M) 2) Metformin treated rats 3) AICAR and vanadate vehicle (vehicle AV) 4) AICAR treated rats 5) Vanadate treated rats Treatment was for 4 hours and glucose values before and after treatment were obtained. Each sample was done in triplicate (5 groups X 3 rats X 2 tissues). In the second part of the study rats were given an intravenous lipid infusion which should reduce tissue response to insulin in treated rats. In the intravenous lipid infusion part of the study 2 groups were used: 1) Rats treated with lipid infusion vehicle. 2) Rats treated with lipid infusion. In each group, there were 3 rats (done in triplicate) and soleus and gastrocnemius samples were processed for differential gene expression analysis (GeneCalling@) (2 groups X 3 samples X 2 tissues). 224 WO 2004/056961 PCT/US2003/034114 Example 04. Mouse TZD Response Study (BP24.07) Overview and Protocol The peroxisome proliferator-activated receptor gamma (PPARg) is the member of the nuclear hormone receptor subfamily of transcription factors that plays a major role in regulation of metabolism. The thiazolidinedione (TZD) drugs, including rosiglitazone, are synthetic agonists of PPARg receptors that can normalize elevated plasma glucose levels in obese, diabetic rodents and are often quite efficacious therapeutic agents for the treatment of noninsulin-dependent diabetes mellitus in humans. Diabetic animals demonstrate differential responses to TZD treatment. To understand the basis for this differential response we compared changes in gene expression between diabetic animals that responded favorably and that did not respond to TZD treatment. Female db/db mice were treated daily with 10mg per kilogram body weight rosiglitazone for 7 days. On day 8, the mice were bled for blood glucose. Treated mice were grouped into either a responder group that demonstrated a significant decrease of their hyperglycemia and a non-responder group that demonstrated no change in their blood glucose level. Gene expression in skeletal muscle and adipose tissues was compared between untreated diabetic mice and the two sub-groups of TZD treated mice. 3 tissues were collected for differential gene expression analysis (GeneCalling@): liver, thigh muscle, and uterine white adipose. 3 groups of samples were used: 1) Vehicle treated 2) Rosiglitazone responders 3) Rosiglitazone non-responders Each group had 3 mice in it. Total of 27 samples were processed for differential gene expression analysis (GeneCalling@). Example 05. Insulin Resistance Study (MB.01) The spontaneoulsy hypertensive rat (SHR) is a strain exhibiting features of the human Metabolic Syndrome X. The phenotypic features include obesity, hyperglycemia, hypertension, dyslipidemia and dysfibrinolysis. Tissues were removed from adult male rats and a control strain (Wistar - Kyoto) to identify the gene expression differences that underlie the pathologic state in the SHR and in animals treated with various anti-hyperglycemic agents such as troglitizone. Tissues included sub-cutaneous adipose, visceral adipose, brain, muscle, and liver. Each tissue was collected in triplicate for differential gene expression analysis (GeneCalling®). Example 06. Genetically Obese Mice vs Genetically Lean Mice Study (MB.04) Overview A number of genetic models of obesity have been studied, most prominently in mouse and rat, but only a few causative genes have been identified. In this study, a set of mouse genetic models were studied in order to identify by positional expression cloning the genes for obesity in mice, which genes may be relevant to human obesity. Protocol 7 strains of mice were used. Some exhibited a lean phenotype, some were normal weight mice, and some of the mice were genetically obese. 225 WO 2004/056961- PCT/US2003/034114 The following strains of mice used in the study: 1) CAST/El - lean phenotype 2) SM/J black - lean phenotype 3) SWR/J - normal phenotype 4) C57UJ - normal phenotype 5) C57BU6J - normal phenotype 6) AKR/J - obese phenotype 7) NZB/BINJ - obese phenotype' Various tissues were processed for differential gene expression analysis (GeneCalling@): brain, liver, muscle, and adipose. Samples were processed in triplicate (i.e. 3 brain samples from 3 CAST/El mice). Total of 7 strains X 4 tissues X 3 samples = 84 samples were used. Example 07. Method of Identifying the Differentially Expressed Gene and Gene Product (GeneCalling@) The GeneCalling@ technology 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). GeneCalling@ technology is also disclose in U.S. Pat. No. 5,871,697. cDNA was derived from various 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 three methods routinely used to confirm the identity of the gene fragment found to have altered expression in models of or patients with obesity and/or diabetes are described below. A). Direct Sequencing The differentially expressed gene fragment is isolated, cloned into a plasmid, and sequenced. Afterwards, the sequence information is used to design an oligonucleotide corresponding to either or both termini of the gene fragment. This oligonucleotide, when used in a competitive PCR reaction, will ablate the electropherographic band from which the sequence is derived. B). Competitive PCR 226 WO 2004/056961 PCT/US2003/034114 In competitive PCR, the electropherographic peaks corresponding to the gene fragment of the gene of interest are ablated when a gene-specific primer (designed from the sequenced band or available databases) competes with primers in the linker-adaptors during the PCR amplification. C). PCR with Perfect or Mismatched 3' Nucleotides (TraPping) This method utilizes a competitive PCR approach using a degenerate set of primers that extend one or two nucleotides into the gene-specific region of the fragment beyond the flanking restriction sites. As in the competitive PCR approach, primers that lead to the ablation of the electropherographic band add additional sequence information. In conjunction with the size of the gene fragment and the 12 nucleotides of sequence derived from the restriction sites, this additional sequence data can uniquely define the gene after database analysis. TraPping is disclosed in a published PCT application Pub. No. WO 01/49886. Example Q8. Identification of Human Sequences The laboratory cloning was performed using one or more of the methods summarized below: SeqCallingmTechnology: 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 Corporation's SeqCalling technology that is disclosed in full in U. S. Ser. Nos. 09/417,386 filed Oct. 13,1999 (also in PCT application Pub. No.: WO 00/40757), and 09/614,505 filed July 11, 2000, the disclosures of which are incorporated herein. 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 bioinformatics 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. 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 cDNA. 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 redundancy 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. 227 WO 2004/056961 PCT/US2003/034114 Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message. 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. Exon Linking: The cDNA coding for the CG101 190-01 sequence was cloned by the polymerase chain reaction (PCR) using the primers designed based on known cDNA sequences or in silico predictions of the full length or some portion (one or more exons) of the cDNA/protein sequence of the invention. These primers were used to amplify a cDNA from a pool containing expressed human sequences derived from the following tissues: 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 and uterus. Physical Clone: 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 09. Quantitative expression analysis (RTQ-PCR) of clones in various cells and tissues The quantitative expression of various NOV genes 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) performed on an Applied Biosystems (Foster City, CA) ABI PRISM@ 7700 or an ABI PRISM@ 7900 HT Sequence Detection System. RNA integrity of all samples was determined 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 (degradation products). Control samples to detect genomic DNA contamination included 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. RNA samples were normalized in reference to nucleic acids encoding constitutively expressed genes (i.e., p-actin and GAPDH). Alternatively, 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 pg of total RNA in a volume of 20 pl or were scaled up to contain 50 pg of total RNA in a volume of 100 pl and were incubated for 60 minutes at 42 0 C. sscDNA samples were then normalized in reference to nucleic acids as described above. Probes and primers were designed according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using 228 WO 2004/056961 PCT/US2003/034114 the target sequence as input. Default reaction condition settings and the following parameters were set before selecting primers: 250 nM primer concentration; 580-600 C primer melting temperature (Tm) range; 590 C primer optimal Tm; 2* C maximum primer difference (if probe does not have 5' G, probe Tm must be 100 C greater than primer Tm; and 75 bp to 100 bp amplicon size. The selected probes and primers were synthesized by Synthegen (Houston, TX). 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: 900 nM forward and reverse primers, and 200nM probe. Normalized RNA was spotted in individual wells of a 96 or 384-well PCR plate (Applied Biosystems, Foster City, CA). PCR cocktails included a single gene-specific probe and primers set or two multiplexed probe and primers sets. PCR reactions were done using TaqMan@ One-Step RT PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 480 C for 30 minutes followed by amplification/PCR cycles: 950 C 10 min, then 40 cycles at 950 C for 15 seconds, followed by 600 C for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) and plotted 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 was the reciprocal of the RNA difference multiplied by 100. CT values below 28 indicate high expression, between 28 and 32 indicate moderate expression, between 32 and 35 indicate low expression and above 35 reflect levels of expression that were too low to be measured reliably. Normalized sscDNA was analyzed by RTQ-PCR using 1X TaqMan@ Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification and analysis were done as described above. Panels 1, 1.1, 1.2, and 1.3D Panels 1, 1.1, 1.2 and 1.3D included 2 control wells (genomic DNA control and chemistry control) and 94 wells of cDNA samples from cultured cell lines and primary normal tissues. Cell lines were derived from carcinomas (ca) including: lung, small cell (s cell var), non small cell (non-s or non sm); breast; melanoma; colon; prostate; glioma (glio), astrocytoma (astro) and neuroblastoma (neuro); squamous cell (squam); ovarian; liver; renal; gastric and pancreatic from the American Type Culture Collection. Normal tissues were obtained from individual adults or fetuses and included: adult and fetal skeletal muscle, adult and fetal heart, adult and fetal kidney, adult and fetal liver, adult and fetal lung, brain, 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. The following abbreviations are used in reporting the results: metastasis (met); pleural effusion (pl. eff or pl effusion) and * indicates established from metastasis. Generalscreeningpanel_vl.4, v1.5, v1.6 and v1.7 Panels 1.4, 1.5, 1.6 and 1.7 were as described for Panels 1, 1.1, 1.2 and 1.3D, above except that normal tissue samples were pooled from 2 to 5 different adults or fetuses. Panels 2D, 2.2, 2.3 and 2.4 229 WO 2004/056961 PCT/US2003/034114 Panels 2D, 2.2, 2.3 and 2.4 included 2 control wells and 94 wells containing RNA or cDNA from human surgical specimens procured through the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative, Ardais or Clinomics BioSciences (Frederick, MD). Tissues included human malignancies and in some cases matched adjacent normal tissue (NAT). Information regarding histopathological assessment of tumor differentiation grade as well as the clinical stage of the patient from which samples were obtained was generally available. Normal tissue RNA and cDNA samples were purchased from various commercial sources such as Clontech, Research Genetics and Invitrogen. HASS Panel v 1.0 The HASS Panel v1.0 included 93 cDNA samples and two controls including: 81 samples of cultured human cancer cell lines subjected to serum starvation, acidosis and anoxia according to established procedures for various lengths of time; 3 human primary cells; 9 malignant brain cancers (4 medulloblastomas and 5 glioblastomas); and 2 controls. Cancer cell lines (ATCC) were cultured using recommended conditions and included: breast, prostate, bladder, pancreatic and CNS. Primary human cells were obtained from Clonetics (Walkersville, MD). Malignant brain samples were gifts from the Henry Ford Cancer Center. ARDAIS Panel v1.0 and v1.1 The ARDAIS Panel v1.0 and v1.1 included 2 controls and 22 test samples including: human lung adenocarcinomas, lung squamous cell carcinomas, and in some cases matched adjacent normal tissues (NAT) obtained from Ardais. Unmatched malignant and non-malignant RNA samples from lungs with gross histopathological assessment of tumor differentiation grade and stage and clinical state of the patient were obtained from Ardais. ARDAIS Prostate v1.0 ARDAIS Prostate v1.0 panel included 2 controls and 68 test samples of human prostate malignancies and in some cases matched adjacent normal tissues (NAT) obtained from Ardais. RNA from unmatched malignant and non-malignant prostate samples with gross histopathological assessment of tumor differentiation grade and stage and clinical state of the patient were also obtained from Ardais. ARDAIS Kidney v1.0 ARDAIS Kidney v1.0 panel included 2 control wells and 44 test samples of human renal cell carcinoma and in some cases matched adjacent normal tissue obtained from Ardais. RNA from unmatched renal cell carcinoma and normal tissue with gross histopathological assessment of tumor differentiation grade and stage and clinical state of the patient were also obtained from Ardais. ARDAIS Breast v1.0 ARDAIS Breast v1.0 panel included 2 control wells and 71 test samples of human breast malignancies and in some cases matched adjacent normal tissue obtained from Ardais. RNA from unmatched malignant and non-malignant breast samples with gross histopathological assessment of tumor differentiation grade and stage and clinical state of the patient were also obtained from Ardais. Panel 3D, 3.1 and 3.2 230 WO 2004/056961 PCT/US2003/034114 Panels 3D, 3.1, and 3.2 included two controls, 92 cDNA samples of cultured human cancer cell lines and 2 samples of human primary cerebellum. Cell lines (ATCC, National Cancer Institute, German tumor cell bank) were cultured as recommended and were derived from: squamous cell carcinoma of the tongue, melanoma, sarcoma, leukemia, lymphoma, and epidermoid, bladder, pancreas, kidney, breast, prostate, ovary, uterus, cervix, stomach, colon, lung and CNS carcinomas. Panels 4D, 4R, and 4.1 D Panels 4D, 4R, and 4.1 D included 2 control wells and 94 test samples of RNA (Panel 4R) or cDNA (Panels 4D and 4.1 D) from human cell lines or tissues related to inflammatory conditions. Controls included total RNA from normal tissues such as colon, lung (Stratagene, La Jolla, CA), thymus and kidney (Clontech). Total RNA from cirrhotic and lupus kidney was obtained from BioChain Institute, Inc., (Hayward, CA). Crohn's intestinal and ulcerative colitis samples were obtained from the National Disease Research Interchange (NDRI, Philadelphia, PA). Cells purchased from Clonetics included: 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, and human umbilical vein endothelial. These primary cell types were activated by incubating with various cytokines (IL-1 beta -1-5 ng/ml, TNF alpha -5-10 ng/ml, IFN gamma -20-50 ng/ml, IL-4 -5-10 ng/ml, IL-9 -5-10 ng/ml, IL-13 5-10 ng/ml) or combinations of cytokines as indicated. Starved endothelial cells were cultured in the basal media (Clonetics, Walkersville, MD) with 0.1% serum. Mononuclear cells were prepared from blood donations using Ficoll. LAK cells were cultured in culture media [DMEM, 5% FCS (Hyclone, Logan, UT), 100 mM non essential amino acids (Gibco/Life Technologies, Rockville, MD), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10~5 M (Gibco), and 10 mM Hepes (Gibco)] and interleukin 2 for 4-6 days. Cells were activated with 10-20 ng/ml PMA and 1-2 pg/ml ionomycin, 5-10 ng/ml IL-12, 20-50 ng/ml IFN gamma or 5-10 ng/ml IL-18 for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in culture media with -5 mg/mI PHA (phytohemagglutinin) or PWM (pokeweed mitogen; Sigma-Aldrich Corp., St. Louis, MO). 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 them 1:1 at a final concentration of -2x1 06 cells/mI in culture media. The MLR samples were taken at various time points from 1-7 days for RNA preparation. Monocytes were isolated from mononuclear cells using CD14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet (Miltenyi Biotec, Auburn, CA) according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culturing in culture media with 50 ng/ml GMCSF and 5 ng/ml IL-4 for 5-7 days. Macrophages were prepared by culturing monocytes for 5-7 days in culture media with -50 ng/ml 10% type AB Human Serum (Life technologies, Rockville, MD) or MCSF (Macrophage colony stimulating factor; R&D, Minneapolis, MN). Monocytes, macrophages and dendritic cells were stimulated for 6 or 12-14 hours with 100 ng/ml lipopolysaccharide (LPS). Dendritic cells were also stimulated with 10 pg/ml anti-CD40 monoclonal antibody (Pharmingen, San Diego, CA) for 6 or 12-14 hours. 231 WO 2004/056961,., PCT/US2003/034114 CD4+ lymphocytes, 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. CD45+RA and CD45+RO 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 Miltenyi beads were then used to separate the CD45+RO CD4+ lymphocytes from CD45+RA CD4+ lymphocytes. CD45+RA CD4+, CD45+RO CD4 +and CD8+ lymphocytes were cultured in culture media at 106 cells/mI in culture plates precoated overnight with 0.5 mg/ml anti-CD28 (Pharmingen) and 3 pg/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, isolated CD8+ lymphocytes were activated for 4 days on anti-CD28, anti-CD3 coated plates and then harvested and expanded in culture media with IL-2 (1 ng/ml). These CD8+ cells were activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as described above. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. Isolated NK cells were cultured in culture media with 1 ng/ml IL-2 for 4-6 days before RNA was prepared. B cells were prepared from minced and sieved tonsil tissue (NDRI). Tonsil cells were pelleted and resupended at 106 cells/ml in culture media. Cells were activated using 5 pg/mI PWM (Sigma Aldrich Corp) or -10 pg/ml anti-CD40 (Pharmingen) and 5-10 ng/ml IL-4. Cells were harvested for RNA preparation after 24, 48 and 72 hours. To prepare primary and secondary Thl/Th2 and Tr cells, umbilical cord blood CD4+ lymphocytes (Poietic Systems, German Town, MD) were cultured at 10-10 6 cells/ml in culture media with IL-2 (4 ng/ml) in 6-well Falcon plates (precoated overnight with 10 pg/mI anti-CD28 (Pharmingen) and 2 pg/mI anti-CD3 (OKT3; ATCC) then washed twice with PBS). To stimulate Th1 phenotype differentiation, IL-12 (5 ng/ml) and anti-IL4 (1 pg/ml) were used; for Th2 phenotype differentiation, IL-4 (5 ng/ml) and anti-IFN gamma (1 pg/ml) were used; and for Tr phenotype differentiation, IL-10 (5 ng/ml) was used. After 4-5 days, the activated Th1, Th2 and Tr lymphocytes were washed once with DMEM and expanded for 4-7 days in culture media with IL-2 (1 ng/ml). Activated Th1, Th2 and Tr lymphocytes were re-stimulated for 5 days with anti-CD28/CD3 and cytokines as described above with the addition of anti-CD95L (1 pg/ml) to prevent apoptosis. After 4-5 days, the Thi, Th2 and Tr lymphocytes were washed and expanded in culture media with IL-2 for 4-7 days. Activated Th1 and Th2 lymphocytes were maintained for a maximum of three cycles. RNA was prepared from primary and secondary Thi, Th2 and Tr 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. Leukocyte cells lines Ramos, EOL-1, KU-812 were obtained from the ATCC. EOL-1 cells were further differentiated by culturing in culture media at 5 x105 cells/mI with 0.1 mM dbcAMP for 8 days, changing the media every 3 days and adjusting the cell concentration to 5 x10 5 cells/ml. RNA was prepared from resting cells or cells activated with PMA (10 ng/ml) and ionomycin (1 pg/ml) for 6 and 14 hours. RNA was prepared from-resting CCD 1106 keratinocyte cell line (ATCC) or from cells activated with -5 ng/ml TNF alpha and 1 ng/ml IL-1 beta. RNA was prepared from resting NCI-H292, 232 WO 2004/056961 PCT/US2003/034114 airway epithelial tumor cell line (ATCC) or from cells activated for 6 and 14 hours in culture media with 5 ng/ml IL-4, 5 ng/ml IL-9, 5 ng/mI IL-13, and 25 ng/ml IFN gamma. RNA was prepared by lysing approximately 107 cells/mI using Trizol (Gibco BRL) then adding 1/10 volume of bromochloropropane (Molecular Research Corporation, Cincinnati, OH), vortexing, incubating for 10 minutes at room temperature and then spinning at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was placed in a 15 ml Falcon Tube and 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 and washed in 70% ethanol. The pellet was redissolved in 300 pl of RNAse-free water with 35 ml buffer (Promega, Madison, WI) 5 pl DTT, 7 pl RNAsin and 8 pl DNAse and incubated at 370 C for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re precipitated with 1/10 volume of 3 M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down, placed in RNAse free water and stored at -80* C. Alcomprehensive panel-v1.0 Autoimmunity (Al) comprehensive panel v1.0 included two controls and 89 cDNA test samples isolated from male (M) and female (F) surgical and postmortem human tissues that were obtained from the Backus Hospital and Clinomics. Tissue samples included : normal, adjacent (Adj); matched normal adjacent (match control); joint tissues (synovial (Syn) fluid, synovium, bone and cartilage, osteoarthritis (OA), rheumatoid arthritis (RA)); psoriatic; ulcerative colitis colon; Crohns disease colon; and emphysmatic, asthmatic, allergic and chronic obstructive pulmonary disease (COPD) lung. Pulmonary and General inflammation (PGI) panel v1.0 Pulmonary and General inflammation (PGI) panel v1.0 included two controls and 39 test samples isolated as surgical or postmortem samples. Tissue samples include: five normal lung samples obtained from Maryland Brain and Tissue Bank, University of Maryland (Baltimore, MD), International Bioresource systems, IBS (Tuscon, AZ), and Asterand (Detroit, MI), five normal adjacent intestine tissues from Ardais, ulcerative colitis samples (UC) from Ardais; Crohns disease colon from NDRI, National Disease Research Interchange (Philadelphia, PA); emphysematous tissue samples from Ardais and Genomic Collaborative Inc. (Cambridge, MA), asthmatic tissue from Maryland Brain and Tissue Bank, University of Maryland (Baltimore, MD) and Genomic Collaborative Inc and fibrotic tissue from Ardais and Genomic Collaborative. Cellular OAIRA Panel Cellular OA.RA panel includes 2 control wells and 35 test samples comprised of cDNA generated from total RNA isolated from human cell lines or primary cells representative of the human joint and its inflammatory condition. Cell types included normal human osteoblasts (Nhost) from Clonetics (Cambrex, East Rutherford, NJ), human chondrosarcoma SW1353 cells from ATCC (Manossas, VA)), human fibroblast-like synoviocytes from Cell Applications, Inc. (San Diego, CA) and MH7A cell line (a rheumatoid fibroblast-like synoviocytes transformed with SV40 T antigen) from Riken Cell bank (Tsukuba Science City, Japan). These cell types were activated by incubating with various cytokines (IL-1 beta -1 -10 ng/ml, TNF alpha -5-50 ng/ml, or prostaglandin E2 for Nhost cells) 233 WO 2004/056961 PCT/US2003/034114 for 1, 6, 18 or 24 h. All these cells were starved for at least 5 h and cultured in their corresponding basal medium with - 0.1 to 1 % FBS. Minitissue OA/RA Panel The OA/RA mini panel includes two control wells and 31 test samples comprised of cDNA generated from total RNA isolated from surgical and postmortem human tissues obtained from the University of Calgary (Alberta, Canada), NDRI (Philadelphia, PA), and Ardais Corporation. Joint tissue samples include synovium, bone and cartilage from osteoarthritic and rheumatoid arthritis patients undergoing reconstructive knee surgery, as well as, normal synovium samples (RNA and tissue). Visceral normal tissues were pooled from 2-5 different adults and included adrenal gland, heart, kidney, brain, colon, lung, stomach, small intestine, skeletal muscle, and ovary. AI.05 chondrosarcoma AI.05 chondrosarcoma plates included SW1353 cells (ATCC) subjected to serum starvation and treated for 6 and 18 h with cytokines that are known to induce MMP (1, 3 and 13) synthesis (e.g. ILibeta). These treatments included: IL-1beta (10 ng/ml), IL-1beta + TNF-alpha (50 ng/ml), IL-1beta + Oncostatin (50 ng/ml) and PMA (100 ng/ml). Supernatants were collected and analyzed for MMP 1, 3 and 13 production. RNA was prepared from these samples using standard procedures. Panels 5D and 51 Panel 5D and 51 included two controls and cDNAs isolated from human tissues, human pancreatic islets cells, cell lines, metabolic tissues obtained from patients enrolled in the Gestational Diabetes study (described below), and cells from different stages of adipocyte differentiation, including differentiated (AD), midway differentiated (AM), and undifferentiated (U; human mesenchymal stem cells). Gestational Diabetes study subjects were young (18 - 40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. Uterine wall smooth muscle (UT), visceral (Vis) adipose, skeletal muscle (SK), placenta (PI) greater omentum adipose (GO Adipose) and subcutaneous (SubQ) adipose samples (less than 1 cc) were collected, rinsed in sterile saline, blotted and flash frozen in liquid nitrogen. Patients included: Patient 2, an overweight diabetic Hispanic not on insulin; Patient 7-9, obese non-diabetic Caucasians with body mass index (BMI) greater than 30; Patient 10, an overweight diabetic Hispanic, on insulin; Patient 11, an overweight nondiabetic African American; and Patient 12, a diabetic Hispanic on insulin. Differentiated adipocytes were obtained from induced donor progenitor cells (Clonetics). Differentiated human mesenchymal stem cells (HuMSCs) were prepared as described in Science Apr 2 1999:143 147. mRNA was isolated and sscDNA was produced from Trizol lysates or frozen pellets. Human cell lines (ATCC, NCI or German tumor cell bank) included: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells and adrenal cortical adenoma cells. Cells were cultured, RNA extracted and sscDNA was produced using standard procedures. Panel 51 also contains pancreatic islets (Diabetes Research Institute at the University of Miami School of Medicine). Human Metabolic RTO-PCR Panel 234 WO 2004/056961, PCT/US2003/034114 Human Metabolic RTQ-PCR Panel included two controls (genomic DNA control and chemistry control) and 211 cDNAs isolated from human tissues and cell lines relevant to metabolic diseases. This panel identifies genes that play a role in the etiology and pathogenesis of obesity and/or diabetes. Metabolic tissues including placenta (PI), uterine wall smooth muscle (Ut), visceral adipose, skeletal muscle (Sk) and subcutaneous (SubQ) adipose were obtained from the Gestational Diabetes study (described above). Included in the panel are: Patients 7 and 8, obese non-diabetic Caucasians; Patient 12 a diabetic Caucasian with unknown BMI, on insulin (treated); Patient 13, an overweight diabetic Caucasian, not on insulin (untreated); Patient 15, an obese, untreated, diabetic Caucasian; Patient 17 and 25, untreated diabetic Caucasians of normal weight; Patient 18, an obese, untreated, diabetic Hispanic; Patient 19, a non-diabetic Caucasian of normal weight; Patient 20, an overweight, treated diabetic Caucasian; Patient 21 and 23, overweight non-diabetic Caucasians; Patient 22, a treated diabetic Caucasian of normal weight; Patient 23, an overweight non-diabetic Caucasian; and Patients 26 and 27, obese, treated, diabetic Caucasians. Total RNA was isolated from metabolic tissues including: hypothalamus, liver, pancreas, pancreatic islets, small intestine, psoas muscle, diaphragm muscle, visceral (Vis) adipose, subcutaneous (SubQ) adipose and greater omentum (Go) from 12 Type 11 diabetic (Diab) patients and 12 non diabetic (Norm) at autopsy. Control diabetic and non-diabetic subjects were matched where possible for: age; sex, male (M); female (F); ethnicity, Caucasian (CC); Hispanic (HI); African American (AA); Asian (AS); and BMI, 20-25 (Low BM), 26-30 (Med BM) or overweight (Overwt), BMI greater than 30 (Hi BMI) (obese). RNA was extracted and ss cDNA was produced from cell lines (ATCC) by standard methods. CNS Panels CNS Panels CNSD.01, CNS Neurodegeneration V1.0 and CNS Neurodegeneration V2.0 included two controls and 46 to 94 test cDNA samples isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains were removed from calvaria of donors between 4 and 24 hours after death, and frozen at -80* C in liquid nitrogen vapor. Panel CNSD.01 Panel CNSD.01 included two specimens each from: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supernuclear Palsy (PSP), Depression, and normal controls. Collected tissues included: cingulate gyrus (Cing Gyr), temporal pole (Temp Pole), globus palladus (Glob palladus), substantia nigra (Sub Nigra), primary motor strip (Brodman Area 4), parietal cortex (Brodman Area 7), prefrontal cortex (Brodman Area 9), and occipital cortex (Brodman area 17). Not all brain regions are represented in all cases. Panel CNS Neurodegeneration V1.0 The CNS Neurodegeneration V1.0 panel included: six Alzheimer's disease (AD) brains and eight normals which included no dementia and no Alzheimer's like pathology (control) or no dementia but evidence of severe Alzheimer's like pathology (Control Path), 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. Tissues collected included: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 235 WO 2004/056961 PCT/US2003/034114 7), occipital cortex (Brodman area 17) superior temporal cortex (Sup Temporal Ctx) and inferior temporal cortex (Inf Temproal Ctx). Gene expression was analyzed after normalization using a scaling factor calculated by subtracting the Well mean (CT average for the specific tissue) from the Grand mean (average CT value for all wells across all runs). The scaled CT value is the result of the raw CT value plus the scaling factor. Panel CNS Neurodegeneration V2.0 The CNS Neurodegeneration V2.0 panel included sixteen cases of Alzheimer's disease (AD) and twenty-nine normal controls (no evidence of dementia prior to death) including fourteen controls (Control) with no dementia and no Alzheimer's like pathology and fifteen controls with no dementia but evidence of severe Alzheimer's like pathology (AH3), 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. Tissues from the temporal cortex (Brodman Area 21) included the inferior and superior temporal cortex that was pooled from a given individual (Inf & Sup Temp Ctx Pool). Example Q10. PathCalling@ Technology The sequence of NOVX was 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, were 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 that follow. 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 236 WO 2004/056961 PCT/US2003/034114 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 Exampe Q11. Determination of Single Nucleotide Polymorphisms (SNPs) Variant sequences are 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 cDNA. 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, however, in the case that a codon including a SNP encodes the same amino acid as a result of the redundancy 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 for example, alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, stability of transcribed message. Method of novel SNP Identification: SNPs are identified by analyzing sequence assemblies using CuraGen's proprietary SNPTool algorithm. SNPTool identifies variation in assemblies with the following criteria: SNPs are not analyzed within 10 base pairs on both ends of an alignment; Window size (number of bases in a view) is 10; The allowed number of mismatches in a window is 2; Minimum SNP base quality (PHRED score) is 23; Minimum number of changes to score an SNP is 2/assembly position. SNPTool analyzes the assembly and displays SNP positions, associated individual variant sequences in the assembly, the depth of the assembly at that given position, the putative assembly allele frequency, and the SNP sequence variation. Sequence traces are then selected and brought into view for manual validation. The consensus assembly sequence is imported into CuraTools along with variant sequence changes to identify potential amino acid changes resulting from the SNP sequence variation. Comprehensive SNP data analysis is then exported into the SNPCalling database. Method of novel SNP Confirmation: SNPs are confirmed employing a validated method know as Pyrosequencing. Detailed protocols for Pyrosequencing can be found in Genome Research. 10:1249 (2000). In brief, Pyrosequencing is a real time primer extension process of genotyping. This protocol takes double-stranded, biotinylated PCR products from genomic DNA samples and binds them to streptavidin beads. These beads are then denatured producing single stranded bound DNA. SNPs are characterized utilizing a technique based on an indirect bioluminometric assay of pyrophosphate 237 WO 2004/056961 PCT/US2003/034114 (PPi) that is released from each dNTP upon DNA chain elongation. Following Klenow polymerase mediated base incorporation, PPi is released and used as a substrate, together with adenosine 5' phosphosulfate (APS), for ATP sulfurylase, which results in the formation of ATP. Subsequently, the ATP accomplishes the conversion of luciferin to its oxi-derivative by the action of luciferase. The ensuing light output becomes proportional to the number of added bases, up to about four bases. To allow processivity of the method dNTP excess is degraded by apyrase, which is also present in the starting reaction mixture, so that only dNTPs are added to the template during the sequencing. The process has been fully automated and adapted to a 96-well format, which allows rapid screening of large SNP panels. Thus while we have illustrated and described the preferred embodiment of our invention, it is to be understood that this invention is capable of variation and modification, and we therefore do not wish to be limited to the precise terms set forth, but desire to avail ourselves of such changes and alterations which may be made for adapting the invention to various usages and conditions. Thus, such variations and modifications are properly intended to be within the full range of equivalents, and therefore within the purview of the following claims. Having thus described our invention and the manner and a process of making and using it in such full, clear, concise and exact terms so as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, we claim: 238

Claims (33)

1. An isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 9 and between 11 and 47.

2. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 9 and between 11 and 47.

3. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 9 and between 11 and 47.

4. A method for identifying compounds that modulate target polypeptide activity comprising: (a) combining a test compound with a target polypeptide and a substrate of the target polypeptide; and (b) determining whether the test compound modulates the activity of the target polypeptide; wherein the target polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 47, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n.

5. The method of claim 4, wherein the target polypeptide comprises a heterotrimeric protein comprising of an alpha 2, a beta 2 and a gamma 3 subunits of AMP-activated protein kinase.

6. The method of claim 5, wherein the alpha 2 subunit amino acid sequence is selected from the group consisting of SEQ ID NO:48, the amino acid sequence that is at least 95% identical to SEQ ID NO:48, the amino acid sequence of at feast one domain of SEQ ID NO:48, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:48.

7. The method of claim 5, wherein the beta 2 subunit amino acid sequence is selected from the group consisting of SEQ ID NO:62, the amino acid sequence that is at least 95% identical to SEQ ID NO:62, the amino acid sequence of at least one domain of SEQ ID NO:62, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:62.

8. The method of claim 5, wherein the gamma 3 subunit amino acid sequence is selected from the group consisting of SEQ ID NO:74, the amino acid sequence that is at least 95% identical to SEQ ID NO:74, the amino acid sequence of at least one domain of SEQ ID NO:74, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:74. 239 W02004/056961 PCT/US2003/034114

9. The method of claim 4, further comprising a step of identifying the test compound that modulates the target polypeptide activity by inhibiting the target polypeptide activity as an inhibitor of the target polypeptide activity.

10. The method of claim 4, further comprising a step of identifying the test compound that modulates the target polypeptide activity by inhibiting the target polypeptide activity as an antagonist of the target polypeptide.

11. The method of claim 4, further comprising a step of identifying the test compound that modulates the target polypeptide activity by activating the target polypeptide activity as an activator of the target polypeptide activity.

12. The method of claim 4, further comprising a step of identifying the test compound that modulates the target polypeptide activity by activating the target polypeptide activity as an agonist of the target polypeptide.

13. The method of claim 4, further comprising a step of identifying the test compound that modulates the target polypeptide activity as an enhancer of insulin secretion.

14. The method of claim 4, further comprising a step of identifying the test compound that modulates the target polypeptide activity as a therapeutic for treatment of insulin resistance.

15. The method of claim 4, further comprising a step of identifying the test compound that modulates the target polypeptide activity as a therapeutic for treatment of obesity.

16. The method of claim 4, further comprising a step of identifying the test compound that modulates the target polypeptide activity as a therapeutic for treatment of diabetes.

17. The method of claim 4, wherein the target polypeptide is an isolated polypeptide.

18. The method of claim 4, wherein the target polypeptide is produced by a process comprising culturing a recombinant host cell, the recombinant host cell comprising a nucleic acid encoding the target polypeptide, under conditions promoting expression of the target polypeptide.

19. The method of claim 18, wherein the nucleic acid comprises a nucleotide sequence selected from the group consisting of: 240 WO 2004/056961 PCT/US2003/034114 (a) SEQ ID NO:2n-1, wherein n is an integer between 1 and 47; (b) nucleotides encoding an amino acid sequence of the at least one domain of SEQ ID NO:2n; and c) a nucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n.

20. The method of claim 4, wherein the target polypeptide is produced by expression of a recombinant vector comprising a nucleic acid, the nucleic acid encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 47, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n.

21. The method of claim 20, wherein the test compound is combined with the target polypeptide in a mammalian cell grown in culture.

22. The method of claim 20, wherein the test compound is combined with the target polypeptide in vitro.

23. The method of claim 20, wherein the nucleic acid comprises a nucleotide sequence selected from the group consisting of: (a) SEQ ID NO:2n-1, wherein n is an integer between 1 and 47; (b) nucleotides encoding an amino acid sequence of the at least one domain of SEQ ID NO:2n; and c) a nucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n.

24. The method of claim 4, wherein the target polypeptide is produced by expression of an endogenous nucleic acid, the endogenous nucleic acid encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 47, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n.

25. The method of claim 24, wherein the test compound is combined with the target polypeptide in a mammalian cell grown in culture. 241 WO 2004/056961 PCT/US2003/034114

26. The method of claim 24, wherein the test compound is combined with the target polypeptide in vitro.

27. The method of claim 24, wherein the endogenous nucleic acid comprises a nucleotide sequence selected from the group consisting of: (a) SEQ ID NO:2n-1, wherein n is an integer between 1 and 47; (b) nucleotides encoding an amino acid sequence of the at least one domain of SEQ ID NO:2n; and (c) a nucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO:2n, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n.

28. An antibody that immunospecifically binds to the target polypeptide, wherein the target polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 47, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n.

29. The antibody of claim 28, wherein the antibody is a monoclonal antibody.

30. The antibody of claim 28, wherein the antibody is a humanized antibody.

31. The antibody of claim 28, wherein the antibody is a human antibody.

32. 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 a target polypeptide, the method comprising: (a) providing a cell expressing the target polypeptide and having a property or function ascribable to the target polypeptide; (b) contacting the cell with a composition comprising a candidate test compound; and (c) determining whether the test compound alters the property or function ascribable to the target polypeptide; whereby, if an alteration observed in the presence of the test compound is not observed when the cell is contacted with the composition in the absence of the test compound, the test compound is identified as a potential therapeutic agent; and wherein the target polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 47, the amino acid sequence that is at least 242 WO 2004/056961 PCT/US2003/034114 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n.

33. A method for screening for a modulator of activity of or of latency or predisposition to a pathology associated with a target polypeptide, the method comprising: (a) administering a test compound to a test animal at an increased risk for a pathology associated with the target polypeptide, wherein the test animal recombinantly expresses the target polypeptide; (b) measuring the activity of the target polypeptide in the test animal after administering the test compound of step (a); and (c) comparing the activity of the target polypeptide in the test animal with the activity of the target polypeptide in a control animal not administered the test compound, wherein a change in the activity of the target polypeptide in the test animal relative to the control animal indicates that the test compound is a modulator of activity of or of latency or predisposition to, a pathology associated with the target polypeptide; wherein the target polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 47, the amino acid sequence that is at least 95% identical to SEQ ID NO:2n, the amino acid sequence of at least one domain of SEQ ID NO:2n, and the amino acid sequence that is at least 95% identical to the at least one domain of SEQ ID NO:2n. 243