CA2333917A1 - 71 human secreted proteins - Google Patents

Abstract

The present invention relates to novel human secreted proteins and isolated nucleic acids containing the coding regions of the genes encoding such proteins. Also provided are vectors, host cells, antibodies, and recombinant methods for producing human secreted proteins. The invention further relates to diagnostic and therapeutic methods useful for diagnosing and treating disorders related to these novel human secreted proteins.

Description

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71 lHuman secreted Protein Field of the Invention This invention relatc;s to newly identified polynucleotides and the polypeptides encoded by these polynuc;leotides, uses of such polynucleotides and polypeptides, and their production.
~'ackground of the Invention Unlike bacterium, which exist as a single compartment surrounded by a membrane, human cells and other eucaryotes are subdivided by membranes into many functionally distinct compartments. Each membrane-bounded compartment, or organelle, contains different proteins essential for the function of the organelle. The cell uses "sorting signals," which are amino acid motifs located within the protein, to target proteins to particular cellular organelles.
One type of sorting signal, called a signal sequence, a signal peptide, or a leader sequence, directs a class of proteins to an organelle called the endoplasmic reticulurn (ER). The ER separates the membrane-bounded proteins from all other types of proteins. Once localized to the ER, both groups of proteins can be further directed to another organelle called the Golgi apparatus. Here, the Golgi distributes the proteins to vesicles, including secretory vesicles, the cell membrane, iysosomes, and the other organelles.
Proteins targeted to the ER by a signal sequence can be released into the extraceilular space as a secreted protein. For example, vesicles containing secreted proteins can fuse with the cell membrane and release their contents into the extraceliular space - a process called exocytosis. Exocytosis can occur constitutively or after receipt of a triggering signal. In the latter case, the proteins are stared in secretory vesicles (or secrcaory granules) until exocytosis is triggered.
Similarly, proteins residing on the cell membrane can also be secreted into the extracellular space by proteolytic cleavage of a "linker" holding the protein to the membrane.
Despite the great progress made in recent years, only a small number of genes encoding human secreted proteins have been identified. These secreted proteins include the commercially valuable human insulin, interferon, Factor VIII, human growth hor~rrone, tissue pla~sminogen activator, and erythropoeitin. Thus, in light of the pervasive role of secreted proteins in human physiology, a need exists for identifying and characterizing novel human secreted proteins and the genes that encode them. This knowledge will allow one to detect, to treat, and to prevent medical disorders by using secreted proteins or the genes that encode them.
Summary of the Invention The present invention relates to novel polynucleotides and the encoded polypeptides. Moreover, the present invention relates to vectors, host cells, antibodies, and recombinant methods for producing the polypeptides and polynucleotides. Also provided are diiagnostic methods for detecting disorders related to the polypeptides, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying binding partners of the polypeptides.
Detailed Desea'iption Definitions The following definitions are provided to facilitate understanding of certain terms used throughout this specification.
In the present invention, "isolated" refers to material removed from its original environment (e.g., the natural environment if it is naturally occurnng}, and thus is altered "by the hand of man" from its natural state. For example, an isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be "isolated" because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide.
In the present invention, a "secreted" protein refers to those proteins capable of being directed to the E:R, secretory vesicles, or the extraceilulax space as a result of a signal sequence, as well as those proteins released into the extracellular space without necessarily containing a signal sequence. If the secreted protein is released into the extracellular space, the secreted protein can undergo extracellular processing to produce a "mature" protein. Release: into the extracellular space can occur by many mechanisms, including exocytosis and proteolytic cleavage.
In specific embodiments, the polynucleotides of the invention are less than 300 kb, 200 kb, 100 kb, 50 kb, IS kb, 10 kb, or 7.5 kb in length. In a further embodiment, poiynucleotides of the. invention comprise at least 15 contiguous nucleotides of the coding sequence, but do not comprise all or a portion of any intron.
In another embodiment, the nucleic acid comprising the coding sequence does not contain coding sequences of a genomiic flanking gene (i.e., 5° or 3' to the gene in the genome).
As used herein , a "polynucleoi;ide" refers to a molecule having a nucleic acid sequence contained in 5E~! ID NO:X or the cDNA contained within the clone deposited with the ATCC. For example, the polynucleatide can contain the nucleotide sequence of the full length cDNA sequence, including the 5' and 3' untranslated sequences, the: coding region, with or without the signal sequence, the secreted protein coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence. Moreover, as used herein, a "polypeptide" refers to a molecule having the translated amino acid sequence generated from the polynucleotide as broadly .defined.
In the present invention, the full length sequence identified as SEQ ID NO:X
was often generated by overlapping sequences contained in multiple clones (contig analysis). A representativE; clone containing all or mast of the sequence for SEQ ID
NO:X was deposited with the American Type Culture Collection ("ATCC"). As shown in Table I, each clone is identified by a cDNA Clone ID (Identifier) and the ATCC Deposit Number. 'Che ATCC is located at 10801 University Boulevard, Manassas, Virginia 2011(1-2209, USA. The ATCC deposit was made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for purposes of patent procedure.
A "polynucleotide" of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SIv:Q ID NO:X, the complement thereof, or the cDNA
within the clone deposited with tfne ATCC. "Stringent hybridization conditions"
refers to an overnight incubation at 42° C in a solution comprising 50% formamide, 5x SSC (750 mM NaCI, 75 mM sodium citrate), 50 mM sodium phosphate {pH 7.6), 5x Denhardt's solution, 10% dextran sulfate, and 20 p,g/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1x SSC at about 65°C.
Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions.
Changes in the stringency of hybridization and signal detection are primarily accomplished through the nnanipulation of formamide concentration (lower percentages of formamide result in lowered stringency); salt conditions, or temperature. For example" lower stringency conditions include an overnight incubation at 37°C in a solution comprising 6X SSPE (20X SSPE = 3M
NaCI; 0.2M
NaH~P04; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% form.amide, 100 ug/ml salmon sperm blocking DNA; followed by washes at 50°C with 1XSSPE, 0.1% SDS.
In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5X SSC).
Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.
Of course, a polynucleotide which hybridizes only to polyA+ sequences {such as any 3' terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of "polynucleotide," since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch or the complement thereof (e.g., practically any double-stranded cDNA clone).
The poiynucleotid.e of the present invention can be composed of any polyribonucleotide or polydeaxribonucieotide, which may be unmodified RNA or DNA or modified RNA or DNA. For example, polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA
that may be single-stranded or, more typically, double-stranded or a mixture of single-s and double-stranded regions. In addition, the polynucleotide can be composed of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A
polynucleotide may also contain one or more modified bases or DNA or RNA
backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made: to DNA and RNA; thus, "poIynucleotide" embraces chemically, enzymatically., or metabolically modified forms.
The polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids.
The polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Such mcxlifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.
Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched , for example, as a result of ubiquitination, and they rnay be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic; methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid ar liopid derivative, covalent attachment of phosphotidylinositoi, cross-linking, cyclization., disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation; proteolytic processing, phosphorylation, prenylation, racemization, selenoylation; sulfation, transfer-RNA
mediated addition of amino acids to proteins such as arginylation> and ubiquitination.
(See, for instance, PROTEINS - STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York ( 1993);
POSTTRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C.
Johnson, Ed., Academic Press, New York, pgs. 1-I2 (1983); Seifter et aL, Meth Enzymol 182:626-646 (1990); Rattan et al., Ann NY Acad Sci 663:48-62 (1992).) "SEQ 1D NO:X" refers to a polynucleotide sequence while "SEQ ID NO:Y"
refers to a polypeptide sequence, both sequences identified by an integer specified in Table 1.
"A polypeptide having biological activity" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate palypeptide will exhibit greater activity or not more than about 25-fold leas and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention.) Polynucleotides and Polyeptides of the Invention FEATURES OF PROTF;IN ENCODED BY GENE NO: 1 In another embodiment, poIypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
PFCSGFFPSLWIYLPFIhNVSDLWMGSLSGCALPFCLXVFFLTVSPSAVGLLXF
AGGPLQTLFAW VSPV1~AAEQQRLLPVLSSGSFV SEGTCQMPARALLYEVS VG

PYWEIPPSQDTRRSGT'Y'LRRQSDP (SEQ ID NO: 195) . Polynucieotides encoding these polypeptides are also provided.
This gene is expressed primarily in pancreas islet cell tumors.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues} or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the pancreas, including cancer and diabetes.
Similarly, palypeptides and antibodif;s directed t:a these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For IO a number of disorders of the above tissues or cells, particularly of the pancreas, expression of this gene at ,significantly higher or Iower levels is routinely detected in certain tissues or cell types {e.g., endocrine, cancerous, or wounded tissues) or bodily fluids (e.g., lymph, serum., plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the i5 standard gene expression llevel, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in tumors of pancreatic islet cells indicates that polynucieotides and polypeptades corresponding to this gene are useful for diagnosis, treatment and intervention of such tumors, in addition to other endocrine or 20 gastrointestinal tumors where expres sion has been indicated. Furthermore, the protein may also be used to determine biological activity, ~to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed again.;t the protein may show utility as a tumor marker andlor 25 immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:I 1 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically 30 excluded from the scope ~~f the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1099 of SEQ ID NO:11, b is an integer of 15 to 1113, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:11, and where b is greater than or equal to a +
14.
FEATURES OF PROTE1IN ENCODED BY GENE NO: 2 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically; polypeptides of the invention comprise the following amino acid sequence:
HEGSCRAPGFSAHKGRGCPSPRM'TLPSRALASLGVGVWGMLRLNQVTVSCG

PGGSPS (SEQ ID NO: 196) . Polynucleotides encoding these polypeptides are also provided.
This gene is expressed equally in in .
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune and hematopoietic disorders, particularly leukemia.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing irnmunological probes far differential identification of the tissue{s) or cell type(s). For a number of disorders of the above tissues or cells; particularly of the vascular and immune systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hemolymphoid, cancerous and wounded tissues) or bodily fluids {e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.

WO 00104140 PCT/il'599115849 Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 104 as residues: Gly-29 to Ser-35, Ser-63 to Cys-Polynucleotides encoding said polypeptides are also provided.
The tissue distribution in hemangiopericytoma, breast lymph node, and bone marrow indicates that polynucieotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of hematopoietie related disorders such as anemia, pancytopenia, leuk.openia, thrombocytopenia or leukemia since stromal cells are important in the production of ceps of hematopoietic lineages.
Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11> I3, I4, 16, 18, 19> 20, and 27, and elsewhere herein. The uses include bone marrow cell ex vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product rrray also be involved in lymphopoiesis, therefore, it can be used in immune disorders such as infection, inflammation, allergy, immunodeficiency etc. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation andlor proli:Feration of various cell types. Furthermore, the protein may also be used to determine tliological activity, to raise antibodies, as tissue markers, to isolate cognate Iigands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunatherapy targets far the above listed tissues.
Many polynucleoti~de sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:12 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucIeotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or -more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 969 of SEQ ID N0:12, b is an integer of 1 S to 983, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID 110:12, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 3 S The translation product of this gene shares sequence homology with the Drosophila melanogaster slit protein, a secreted protein that contains both an EGF
domain and Leucine Rich Rrepeat domains. Tt is thought to be important in the development of midline glia and commissural axon pathways (See e.g., Rothberg et al. Genes Dev. 4:2169-87 (1990); which is hereby incorporated by;reference herein).
10 This gene is expressed primarily in human hippocampus.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological, and developmental disorders. Similarly, polypeptides and 1S antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type{s). For a number of disorders of the above tissues or cells, particularly of the neurological system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neurological, cancerous, or wounded tissues) or bodily fluids (e.g., lymph, ;serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution within human hippocampus combined with the homology to the DrosophilLa slit protein, indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection, treatment andlor prevention of neurodegene,rative disease states, behavioral disorders, or inflammatory conditions. Representative uses are described in the "Regeneration" and "Hyperproliferative Disorders" sections below, in Example 11, 15, and 18, and elsewhere herein. Briefly, the uses include, but are not limited to the detection, treatment, andlor prevention of Alzheimer's Disease, Parkinson's Disease, WO 00/04140 PCT/US99115849 .

Huntington's Disease, Tourette Syndrome, meningitis, encephalitis;
demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, bahance, and preception. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system. In addition, elevated expression of this gene product ~n regions of the brain indicates it plays a role in normal neural function.
Potentially; this gene product is involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate Iigands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Sorne of these sequences are related to SEQ >D N0:13 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides corr~prising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 959 of SEQ ID N0:13, b is an integer of 15 to 973, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:13, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 4 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
IPLTLPGIFLLIRLFWRLGQSICGPGKLVLWPQFCCGCAVISGHCVPRGMPSSW
LPGCFVLLCLVAVGCQLREWGVGGVSAVGLLALPHLQVLGMRGRGLISGG
S (SEQ ID NO: 197) . Polynucleotides encoding these polypeptides are also provided.
The gene encoding; the disclosed cDNA is believed to reside on chromosome 16. Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis for chrorr~osome 16.
This gene is expressed in KMH2 cells, ~steoblasts, fetal spleen, Jurkat membrane bound polysornes, breast, and cerebellum.
Therefore, polynuc;leotides and poiypeptides of the invention are useful as reagents for differential id',entification of the tissues} or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cancer, immune, and skeletal disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell types}. For a number of disorders of the above tis:cues or cells, particularly of the immune system, expression of this gene at significantlly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, skeletal, cancerous, or wounded tissues) or bodily fluids (e.g., lymph, serum,, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression Level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in KM~H2 cells, osteoblasts, and fetal spleen indicates that polynucleotides and ~polypeptides corresponding to this gene are useful for the diagnosis and treatment crf a variety of immune system disorders.
Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, i4, 16, 118, 19, 20, and 27, and elsewhere herein. Expression of this gene product in fetal spleen and T-cells indicates a role in the regulation of the proliferation: survival; differentiation; and/or activation of potentially all hematopoietic cell lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulncsss in the treatment of cancer (e.g., by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also used as an agent for immunological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia> psoriasis, hypersensitivities, such as T-cell mediated cyt.otoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseasds, or autoirnmunity disorders, such as autoimmune infertility, Tense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, scleroderma and tissues. Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Furthermore, the protein may allso be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:14 and may have been publicly available prior to conception of the present invention. Preferably, such related poiynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1444 of SEQ ID N0:14, b is an l4 integer of 15 to 1458, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:14, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 5 The translation product of this gene shares sequence homology with phospholipase A2 which clieaves fatty acids from carbon 2 of glycerol (ref.
Prosite pattern documentation for PS2_HIS). Many snake venoms contain phospolipase A2, which prevents transmission of nerve impulses to muscles by blocking the release of acetylchotine from the neuron. Therefore, included in this invention as;preferred domains are Phospholipase: A2 histidine active site domains, which were identified using the ProSite analysis stool (Swiss Institute of Bioinformatics).
Phospholipase A2 is an enzyme which releasca fatty acids from the second carbon group of glycerol.
Structurally, PA2's are small and rigid proteins of 120 amino-acid residues that have four to seven disulfide bonds. PA2 binds a calcium ion which is required for activity.
I5 The side chains of two conserved residues, a histidine and an aspartic acid, participate in a'catalytic network'. Two different signature patterns for PA2's were developed.
The first is centered on the. active site histidine and contains three cysteines involved in disulfide bonds. The consensus pattern is as follows: C-C-x(2)-H-x(2)-C [H
is the active site residue).
Preferred polypeptides of the invention comprise a Phospholipase A2 histidine active site domain selected from the following amino acid sequences: CCNQHDRC
(SEQ ID NO: 199), SLTKCCNQHDRCYET (SEQ ID NO: 200) , and/or LTKCCNQHDRCYETCCs (SEQ ID NO: 201) . Polynucleotides encoding these polypeptides are also provided. Further preferred are polypeptides comprising the Phospholipase A2 histidine active site domain of the sequence listed in Table 1 for this gene, and at least 5, 10, 15, 20, 25, 30, 50, or 75 additional contiguous amino acid residues of this referenced sequence. The additional contiguous amino acid residues is N-terminal or C- terminal to the Phospholipase A2 histidine active site domain.
Alternatively, the additional contiguous amino acid residues is both N-terminal and C-terminal to the Phospholipase A2 histidine active site domain, wherein the total N-and C-terminal contiguous amino acid residues equal the specified number. The above preferred polypeptide domain is characteristic of a signature specific to Phospholipase A2 proteins. Based on the sequence similarity, the translation product of this gene is expected to share at least some biological activities with Phospholipase A2 proteins. Such activities, are known in the art, some of which are described 5 elsewhere herein, or see, for example, McIntosh, et al. J. Biol. Chem. 270 (8), 3518-3526 (1995), incorporated herein by reference.
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the 10 following amino acid sequE,nce:
GPAGKEAWIWSWLLPSPGPAPLPSASWGLCGDAPR
AAARGPVEPGAARMAI,LSRPALTLLLLLMAAV VRCQEQAQTTDWRATLKTI
RNGVHKIDTYLNAALDLLGGEDGLCQYKCSDGSKPFPRYGYKPSPPNGCGSP
LFGXHLNIGIPSLTKCCNQHDRCYETCGKSKNDCDEEFQYCLSKICRDVQKTL
15 GLTQHVQACETTVELLIFDSVIHLGCKPYLDSQRAACRCHYEEKTDL (SEQ m NO: 198) . Polynucleotides encoding these polypeptides are also provided.
The gene encoding the disclosed cDNA is believed to reside on chromosome 4. Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis for chrom-osome 4.
This gene is expressed in a variety of cell types with no single type predominating.
Therefore; polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological disorders, or metabolism disorders, specifically phospholipase AZ deficiencies. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the neuromuscular system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., pancreas, cancerous and wounded tissues) or bodily fluids (e.g., bile, lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the e~:pression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 107 as residues: Gln-23 to Asp-30, Lys-66 to Cys-$7.
Polynucleotides encoding said polypeptides are also provided.
The ubiquitous tissue distribution and homology to phospholipase A2 indicates that poiynucleotides and polype;ptides corresponding to this gene are useful for diagnosis and treatment of neuromuscular disorders. Alternatively, considering the activity of phospholipase A2 as a block for neuro- transmission may suggest that poiynucleotides and polypc;ptides corresponding to this gene are useful for the detection/treatment of neua~odegenerative disease states and behavioural disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette I5 . Syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, Teaming di:~abilities, ALS, psychoses, autism; and altered behaviors, including disorders in feeding, sleep patterns, balance, and preception. In addition, the gene or gene product may also play a role in the treatment andlor detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system. Alternatively, the homology to Phospholipase A2 proteins may indicate a potemtiai use for the protein product of this gene in diagnosis, treatment and/or prevention of metabolism disorders, specifically deficiencies in Phospholipase A2. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate Iigands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotiide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:15 and may have been publicly available prior to conception of WO 00!04140 PCTIUS99!15849 the present invention. Preferably, such related polynucleotides are specifically excluded from the scope oiF the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between i to 1991 of SEQ ID N0:15, b is an integer of 15 to 2005, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:15, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 6 In a specific enbodiment polypeptides of the invention comprise the following amino acid sequence:
GTSSARPRGALPGGSAI?SAPHGQLPGRAQPAPVSGPPPTSGLCHFDPAAPWPL
WPGPWQLPPHPQDWP,AHPDIPQI)WVSFLRSFGQLTLCPRNGTVTGKWRGSH
V VGLLTTLNFGDGPDR.NKTRTFQATVLGSQMGLKGSSAGQLVLITARVTTER
TAGTCLYFSAVPGTLPSSQPPISCSEEGAGNATLSPRMGEECVSVWSHEGLVLT
KLLTSEELALCGSRLLVLGSFLLLFCGLLCCVTAMCFHPRRESHWSRTRL
(SEQ ID NO: 202) . PoIynucleotides encoding these polypeptides are also provided.
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
ARAPPGPEGLSPEAQPI'LLPMGNCQAGHNLHLCLAHHPPLV CATLILLLLGLS
GLGLGSFLLTHRTGLR'T LTSPRTGSLF {SEQ ID NO: 203) . Polynucleotides encoding these polypepticles are also provided.
This gene is expressed in a wide variety of tissue types including testes, cerebellum, dendritic cells, breast cancer, umbilical vein endothelial cells, epididymus, corpus colosum, chronic synovitis, liver hepatame, normal breast, osteoblasts, melanocytes, B cell lymphomas, and to a lesser extent in other tissues.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, cancer, particularly of endothelial tissues. Similarly, polypeptides and antibodies directed to these; polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at :oignificantly higher or lower levels is routinely detected in certain tissues or cell type:c (e.g., endothelial, cancerous, or wounded tissues) or bodily fluids (e.g., lymph, seminal fluid, serum, plasma, urine, synovial fluid and spinal fluid) or another tis;~ue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 108 as residues: Thr-52 to Gly-57.
Polynucleotides encoding said polypeptides are also provided.
Expression within embryonic tissue and other cellular sources marked by proliferating cells indicates that the protein product of this gene may play a role in the regulation of cellular division and may show utility in the diagnosis, treatment, and/or prevention of developmental diseases and disorders, cancer, and other proliferative conditions. Representative; uses are described in the "Hyperproliferative Disorders"
and "Regeneration" sections below and elsewhere herein. Additionally, the expression in hematopoietic cells and tissues indicates that this protein may play a role in the proliferation, differentiation, and/or survival of hematopoietic cell lineages. In such an event, this gene is useful in the treatment of Iymphoproliferative disorders, and in the maintenance and differentiation of various hematopoietic lineages from early hematopoietic stem and committed progenitor cells. Similarly, embryonic development also reties on decisions involving cel! differentiation andlor apoptosis in pattern formation.
Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proiifer;ation and differentiation, this gene product may have !9 applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polypeptides of the present invention are useful in treating, detecting, andlor preventing; said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new ZO insight into the regulation of cellular growth and proliferation.
Furthermore, the protein may also be used to~ determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to iits use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or 15 immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:16 a,nd may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically 20 excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides cornvprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 929 of SEQ ID N0:16, b is an integer of 15 to 943, where; both a and. b correspond to the positions of nucleotide 25 residues shown in SEQ ID N0:16, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 7 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by 30 the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:

RFLSVXPQXEVPFLLHPCVCFXGGHPSLLPDPCRAVGGGWEAPRCCLHEALC
QSLGCKAEEIVSVSESSSAQRCWYLLRGRKAGGRGPASPVLFALMRLESLCH
LCLACLFFRLPATRTVYCMNEAEIVDVALGILIESRKQXKACEQPALAGADNP
EHSPPCSVSPHTSSGSSSEEEDSGKQALXPGLSPSQRPGGSSSACSRSPEEEE
S EEDVLKYVREIFFS (SEC) ID NO: 204) . Polynucleotides encoding these polypeptides are also provided. Polynucleotides of the invention do not consist of the nucleic acid sequences shown as GeneSeq Accession Nos: VS9S9S and VS9744, which are hereby incorporated herein by reference.
This gene is expressed primarily in a variety of immune cell types, including 10 stromal cells, dendritic cells, leukocytes, activated T-cells, macrophages, monoctyes, neutrophils and to a lesser extent in a variety of other adult and fetal tissues.
Therefore, polynuclleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are 1S not limited to, cancer and other proliferative disorders. Similarly, polypeptides and antibodies directed to these; polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain 20 tissues or cell types (e.g., i:mmune, cancerous, or wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cetl sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
2S The tissue distribution in immune cells indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders. Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16, 18, 19, 20, and 27, and. elsewhere herein. Expression of this gene product in fetal tissue and various hematopoietic cancers indicates a role in the regulation of the proliferation; survival; dif~Ferentiation; andlor activation of potentially all hematopoietic cell lineages"including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g., by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in irnmnne functions. Therefore it is also used as an agent for immunological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulomatou's Disease, inflammatory - bowel disease, sepsis, acne., neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimmune infertility, tense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, scleroderma and tissues. Moreover, the protein may represent a secreted factor that influences the diifferentiation or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury. In addition, this gene product may have commercial utility in the e;cpansion of stem cells anal committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Furthermore, the protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate Iigands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:17 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1489 of SEQ ID N0:17, b is an integer of 1 S to 1503, where both a and b con espond to the positions of nucleotide residues shown in SEQ ID N0:17, and where b is greater than or equal to a +
14.
FEATURES OF PROTETN ENCODED BY GENE NO: 8 When tested against Jurkat T-cell lines, supernatants removed from cells containing this gene activated the NF-kB (Nuclear Factor kB) pathway. Thus, it is likely that this gene activates T-cells tlhrough the NF-kB signal transductioni pathway.
NF-kB is a transcription factor activated by a wide variety of agents, leading to cell activation, differentiation, or apoptosis. Reporter constructs utilizing the NF-kB
promoter element are used to screen supernatants for such activity. Preferred polypeptides of the invention comprise the following amino acid sequence:VPGWPRACSPCQADSPRAHPPKLRGILRWAPVPLXCAALCPPLDSG
MSMAACPEAPEPSFLRIEVPSSPASTQWHRPCNFRQVEANPRKEPKNLVWRD
VSLGQXSRTPRGSGLEL.VRVCGGGMQRDKTVVEERVGEERERERERESLGG
1S AGKHGEMRCVYVRES'VGAPGRAGGGGNGVNSVGCVRTVHSGSXPPPSAGV
S (SEQ ID NO: 20S) . Polynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in pans of the brain such as cerebellum and frontal lobe.
Therefore, polynuc:leotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurodegenerative disorders. Similarly, polypeptides and antibodies directed to these polypeptiides are useful in providing immunological probes for differential identification of the tissues) or cell types}. For a number of disorders of 2S the above tissues or cells, particularly of the central nervous system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, cancerous, or wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synoviaI fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.

The tissue distribution in cerebellum and frontal lobe indicates that polynucleotides and polypE:ptides corresponding to this gene are useful for the detection, prevention and/or treatment of neurodegenerative disease states and behavioural disorders, or inflammatory conditions. Representative uses are described in the "Regeneration" and "'Hyperproliferative Disorders" sections below, in Example 1 l, I5, and 18, and elsewhere herein. :E3riefly, the uses include, but are not limited to the detection, treatment, and/or prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital IO malformations, spinal cordl injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic. disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, eIe:vated expression of this gene product in regions of the 15 brain indicates it plays a role in normal neural function.
Potentially, this gene product is involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to 20 identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequience databases. Some of these sequences are 25 related to SEQ ID N0:18 and may have been publicly available prior to conception of the present invention. PreiFerably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general 30 formula of a-b, where a is any integer between 1 to 1498 of SEQ ID N0:18, b is an integer of 15 to 1512, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID :NO:18, and where b is greater than or equal to a +
I4.
FEATURES OF PROTEIN ENCODED BY GENE NO: 9 In a specific embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. S~aecifically, polypeptides of the invention comprise the following amino acid sequence:
TRPGKELNLVFGLQLS11~IARIGSTVNMNLMGWLYSKIEALLGSAGHTTLGITL
MIGGITCILSLICALALAYLDQRAERILHKEQGKTGEVIKLTDVKDFSLPLWLIF
IICVCYYVAVFPFIGLGF~VFFfEKFGFSSQAASAINS V VYVISAPMSPVFGLLV
DKTGKNIIWVLCA (SEQ ID NO: 206} . Polynucleotides encoding these polypeptides are also provided.
The gene encoding the disclosed cDNA is believed to reside on chromosome 3. Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis for chromosome 3.
This gene is expressed primarily in fetal tissue, and to a lesser extent in a variety of adult human tissues.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, fetal abnorrnalities, particularly developmental disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the reproductive system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., developing, or cancerous and wounded tissues) or bodily fluids {e:.g., amniotic fluid, lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.

Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID :(VO: 111 as residues: Lys-30 to Thr-35.
Poiynucleotides encoding said polypeptides are also provided.
The tissue distribution in fetal tissue indicates that polynucleotides and polypeptides corresponding; to this gene are useful for the diagnosis and treatment of cancer and other proliferative disorders. Representative uses are described in the "Hyperproliferative Disorders" and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation and/or apoptosis in pattern formation.
10 Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the deveaopment of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Expression within embryonic tissue and other cellular sources marked by proliferating cells 15 indicates that this protein may play a role in the regulation of cellular division.
Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polypeptides of the present invention are useful in treating, 20 detecting, andlor preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in 25 proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation.
Additionally, the expression in hematopoietic cells and tissues indicates that thus protein may play a role in the proliferation, differentiation, and/or survival of hematopoietic cell lineages.
In such an event, this gene is useful in the treatment of lymphoproliferative disorders, and in the maintenance and differentiation of various hematopoietic lineages from early hematopoietic stem and committed progenitor cells. Furthermore> the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate Iigands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against vthe protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotid~e sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:19 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucieotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1641 of SEQ ID N0:19, b is an integer of 15 to 1655, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:19, and where b is greater than or equal to a +
I4.
FEATURES OF PROTEItN ENCODED BY GENE NO: 10 The translation product of this gene shares sequence homology with human histiocyte-secreted factor (:EiSF) which is a novel cytokine that shows in viva antitumour activity without the cytotoxicity associated with tumour necrosis factor.
Furthermore, The translation product of this gene also shares sequence homology with the human endogenous virus S71 gag poiyprotein, the sequence of which is believed to represent a transformation locus for several cancers (See Genebank Accession No. pir~A46312~A46312; all references available through this accession are hereby incorporated by reference herein}. Similarly, The translation product of this gene also shares homology with B219, a sequence that is expressed in at least four isoforms in very primitive hematopoietic cell populations which may represent a novel hemapoietin receptor (See, e.g., Cioffi, et al. Nat. Med. 2:585-589 (1996), which is hereby incorporated by reference herein). In a preferred embodiment polypeptides of the invention comprise the following amino acid sequence:

CKDLCSRVYLLTLSPLL;iYDPATSHSPRNTQ (SEQ ID NO: 207) . Also preferred are the polynucleotides encoding these polypeptides.
This gene is expressed primarily in tonsil, and colon, and to a lesser extent in a wide variety of human tissues.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types}
present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune, hernatopoietic, and gastrointestinal disorders, particularly tumors of the colon and tonsil. Similarly; polypeptides and antibodies directed to 1~ these polypeptides are useful in providing immunological probes for differential identification of the tissue(;>) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hematopoietic, digestive and immune systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hematopoietic; gastrointestinal, or cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid} or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in heallthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 112 as residues: Met-1 to Cys-6. PoIynucleotides encoding said potypeptide:> are also provided.
The tissue distribution in tonsil and colon, combined with the homology to human histiocyte growth factor, the human endogenous viral protein, and B219 strongly indicate that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis, treatment andlor prevention, of a variety of hernatopoietic and immune system disorders such as anemia, pancytopenia, leukopenia, thrombocytopenia or leukf;mia. Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16>
18, 19>
24, and 27, and elsewhere herein. Expression of this gene product in tonsils indicates a role in the regulation of 'the proliferation; survival; differentiation;
and/or activation of potentially all hematopoietic cell lineages, including blood stem cells.
This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes that may al',so suggest a usefulness in the treatment of cancer (e.g., by boosting immune responses) Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in imrrmne functions. Therefore it is also used as an agent for immunologicaI disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia; rheumatoid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis; acne;, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autormmunrty disorders, such as autoimnaune infertility, lense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, scleroderma and tissues. Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hematopoietic cel'~ls to sites of injury. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Furthermore, the protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:20 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides cornprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2511 of SEQ ID N0:20, b is an integer of 15 to 2525, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:20, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: I I
The gene encoding the disclosed cDNA is believed to reside on chromasoine 7. Accordingly, polynucieotides related to this invention are useful as a marker in linkage analysis for chromosome 7.
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequience:
LICECWEEECQSCRLKI'TQPREICRMDFLVLFLFYLASVLMGLVLICVCSKTHS
LKGLARGGAQIFSCIIPI~CLQRAXHGLLHYLFHTRNHTFIVLHLVLQGMVYTE
YTWEVFGYCQEL,ELSL.HYLLLPYLLLGVNLFFFTLTCGTNPGITTKANELLFLH
VYEFDEVMFPKNVRC;iTCDLRKPARSKHCSVCNWCVHRFDHHCVWVNNCI
GAWNIRYFLIYVLTLT,~SAATVA.IVSTTFLVHLVVMSDLYQETYIDDLGHLHV
MDTVFLIQYLFLTFPRIVFMLGFVVVLSFLLGGYLLFVLYLAATNQTTNEWYR
GDWAWCQRCPLVAWPPSAEPQVHRNIHSHGLRSNLQEIFLPAFPCHERKKQE
{SEQ ID NO: 208) . Polynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in colon and brain and to some extent in all tissues.
Therefore, polynucleotides and poiypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological and digestive disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nervous system and digestive system, expression of this gene at significantly higher or lower levels is routinely detected in cert;~in tissues or cell types (e.g., neurological, gastrointestinal, or cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
5 The tissue distribution in brain indicates polynucleotides and polypeptides corresponding to this gene are useful for the detection, treatment, and/or prevention of neurodegenerative disease states, behavioral disorders, or inflammatory conditions.
Representative uses axe described in the "Regeneration" and "Hyperproliferative Disorders" sections below, in Example I I, I5, and I8, anø elsewhere herein.
Briefly, 10 the uses include, but are novt limited to the detection, treatment, andlor prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive I5 compulsive disorder, depression, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders an feeding, sleep patterns, balance, and perception. In addition, elevated expression of this gene product in regions of the brain indicates it plays a role in normal neural function.
Potentially, this gene product is involved in synapse formation, 20 neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Alternatively, expression of this gene in colon may indicate a role in the detection, prevention and/or treatment of colon diorders such as colon cancer, Crohn's Disease, ulcers, and digestive tract disorders in general. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to 25 isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly 30 available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:21 and may have been publicly available prior to conception of the present invention.1?referably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucieotides comprising a nucleotide sequence described by the general S formula of a-b, where a is any integer between 1 to 1382 of SEQ ID N0:21, b is an integer of 15 to 1396, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID :N0:21, and. where b is greater than or equal to a +
14.
FEATURES OF PROTEIfN ENCODED BY GENE NO: 12 When tested againsvt Reh cell lines, supernatants removed from cells containing this gene activai:ed the GAS (gamma activation site) pathway. Thus, it is likely that this gene activates B-cells through the Jaks-STAT signal transduction pathway. GAS isa promoter element found upstream in many genes which are involved in the Jaks-STAT pathway. The Jaks-STAT pathway is a large, signal transduction pathway involfved in the differentiation and proliferation of cells.
Therefore, activation of the; Jaks-STATs pathway, reflected by the binding of the GAS element, can be used to indicate proteins involved in the proliferation and differentiation of cells. This gene maps to chromosome 7, and therefore, is used as a marker in linkage analysis for chromosome 7.
This gene is expressed primarily in brain, and in the developing embryo.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological, behavioral, immune, and developmental disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous and deveiopment;al systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, developing, immune, or cancerous and wounded tissues) or bodily fluids (e.g., lymph, amniotic fluid, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue ar bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 114 as residues: Lys-60 to Asn-67.
Polynucleotides encoding said polypeptide~~ are also provided.
The tissue distribution in brain indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection, treatment, and/or prevention of neurodegenerative disease states, behavioral disorders, or inflammatory conditions.
Representative uses are described in the "Regeneration" and "Hyperproliferative Disorders" sections below" in Example 11, 15, and 1&, and elsewhere herein.
Briefly, the uses include, but are not limited to the detection, treatment, andlor prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, I5 trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, the tissue distribution in developing embryo indicates that the gene or gene product may also play a role in the treatment andlor detection of developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system.
Alternatively, the biological activity within B-cells indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders. Activation of genes witin B-cells indicates a role for this protein in the regulation of the proliferation; survival; differentiation;
and/or activation of potentially all hematopoietic cell lineages, including blood stem cells.
This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g., by boosting immune responses).

Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also used as an agent for immunoiogical disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. Furthermore, the protein may also be used to determine biological activity, to raise antibodies., as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions; in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:22 .and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is 1S cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleatides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1055 of SEQ ID N0:22, b is an integer of 15 to 1069, where both a and b correspond to the positions of nucleotide residues shown in SEQ IL) N0:22, arid where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: I3 The gene encoding the disclosed cDNA is believed to reside on chromosome 6. Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis for chromosome 6.
In another embodiiment, poiypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. SpE:cifically, poiypeptides of the invention comprise the following amino acid sequence:
LLSFKIRGLRTEDAGVNAQSSSGGLCVRGDAFWMPSSSSGLGSPSRPPSSFLCL

GCWARSTEQGAVGVATGTVLDI SLPASCLSLWPPGPSGGI (SEQ ID NO: 209) . Polynucleotides encoding these polypeptides are also provided.
In a specific embodi3ment polypeptides of the invention comprise the following amino acid sequence:
QLGLCLTSASLPPASRCCiHQAPLGASDLSAHHSAPGFSDSYFTMSCQSSLSRA
EILQCPLVPSVSPPTHLPQGRANKSSRASLPLLPQTHWCLFPSARGWRRGIQSG
LPPGGSCTSPRSPPQTLHQHITLVNHNTSYWQSPST (SEQ ID NO: 2I0) , HQPPCLLPLAVATRPLWGHI.TCLPIILHLVSVTLTSPCLANQAFQGQRSYNAL
WCPLFLLLPTSPKGEQTP~1HPEPACPCFPKLTGVFSLQHV VGAEEFSQVFLLVD
PVPVLDHI.LKLFTSTSHI.LIIIPHIGKAPAPDSLL EELSLSLATHCKVAVARFT
{SEQ ID NO: 211) . Also preferred axe the polynucleotides encoding these polypeptides. Polynucleotides of the invention do not consist mf the nucleic acid sequence shown as GeneSe~q Accession No. X043??, which is hereby incorporated herein by reference.
This gene is expressed primarily in brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, behavioral and neurological disorders. Similarly, polypeptides and antibodies directed to these: polypeptides are useful in providing imrnunological probes for differential identification of the tissue{s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nervous system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types. (e.g., neural, or cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogemc epitopes shown in SEQ ID NO: 115 as residues: Pro-2 to Gly-?, Ser-10 to Ser-16, Pro-52 to VaI-62, Arg-64 to Ser-?3. Polynucleotides encoding said potypeptides are also provided.
The tissue distribution in brain indicates that polynucleotides and poLypeptides corresponding to this gene are useful for the detection, treatment, and/or prevention of 5 neurodegenerative disease states, behavioral disorders, or inflammatory conditions.
Representative uses are described in the "Regeneration" and "Hyperproliferative Disorders" sections below, in Example 11, 15, and 18, and elsewhere herein.
Briefly, the uses include, but are not limited to the detection, treatment, and/or prevention of Alzheimer's Disease, Parkinson's Disease, Huntingtan's Disease, Tourette Syndrome, 10 meningitis, encephalitis, demyeiinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep 15 patterns, balance, and perception. In addition, elevated expression of this gene product in regions of the brain indicates it plays a role in normal neural function.
Potentially, this gene product is involved in synapse formation, neurotransmission, iearninl;, cognition, homeostasis, or neuronal differentiation or survival. Furthermore, the protein may also be used to determine biological activity, 20 to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly 25 available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:23 amd may have been publicly available prior to conception of the present invention. Prefc:rabiy, such related polynucleotides are specifically excluded from the scope oiF the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or 30 more polynucieotides comprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 1644 of SEQ ID N0:23, b is an integer of 15 to 1658, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID IV0:23, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 1~#
The translation product of this gene was shown to have homology to the lysosomal mannosidase alpha-B protein (See Genebank Accession~No. P34098) which is thought to be important in protein metabolism. One embodiment of this gene comprises polypeptides of the following amino acid sequence:
MAAEGSRFSSQSPGLVDRQGPKCDPSRLVSPWGRHGLRILQIGHHHGRDGQH
EATHHLLRVLRAPRVGhADEGAVDSDPSTPLQLKHEAAHAEDHAQQVHVVR
RRV VQGRVTFARRGLV PQHFVRPPW VRHIVSGHSESKARSRLFRCRNRSFRR
AS (SEQ ID NO: 212) , and/or RLVSPWGRHGLRILQIGE~IHGRDGQHEATHHI.L RVLRA (SEQ ID NO: 213) .
An additional embodiment is the polynucleotides encoding these polypeptides.
This gene maps to chromosome 19, and therefore, is used as a marker in linkage analysis for chromosome 19.
This gene is expressed primarily in brain, placenta, fetal liver; and to a lesser extent in most tissues.
Therefore, polynucieotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological, reproductive, and hepatic disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, hepatic, or cancerous and wounded tissues) or bodily fluids (e.g., bile, ;amniotic fluid, serum, plasma, urine, synovial fluid and spinal fluid} or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.

Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 116 as residues: Asn-34 to Lys-42, Leu-60 to Trp-70.
Polynucleotides encoding said polypeptides are also provided.
The tissue distribution predominantly in brain indicates a role in the detection/treatment of neun~odegenerative disease states and behavioural disorders such as Alzheimer°s Disease, Parkinsan's Disease, Huntinton's Disease, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder and panic.disorder.
Alternatively, the tissue distribution in liver indicates that polynucleotides and polypeptides -corresponding to this genre are useful for the detection arad treatment of liver disorders and cancers (e.g., hepatoblastoma, jaundice, hepatitis, liver metabolic diseases and conditions that are attributable to the differentiation of hepatocyte progenitor cells). In addition the expression in fetus would suggest a useful role for the protein product in devE;lopmental abnormalities, fetal deficiencies, pre-natal disorders and various would-healing models andlor tissue trauma.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Sorne of these sequences are related to SEQ ID N0:24 .and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucIeotides corruprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1063 of SEQ ID N0:24, b is an integer of 15 to 1077, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:24, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 15 This gene is expressed primarily in spinal cord, Merlcel cells, and adipose tissues.
Therefore, polynuc:leotides arid polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the nervous and immune systems, particularly those disorders relating to the CrdS involving lipid metabolism disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the nervous and immune systems and adipose tissue, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, immune, or cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distributiion in spinal cord, Merkel cells and adipose tissue indicates that polynucleotides and polypeptides corresponding to this gene are useful for the IS treatment and/or diagnosis of diseases the nervous systems, such as spinal cord injury, neurodegenerative diseases,, muscular dystrophy or obesity. Protein, as well as;
antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ m NO:25 a.nd may have been publicly available prior to conception of the present invention. Pref~:rably, such. related polynucIeotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly., preferably excluded from the present invention are one or more polynucleotides comparising a nucleotide sequence described by the general formula of a-b, where a is any integer between i to 1191 of SEQ ID N0:25, b is an integer of 15 to 1205, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:25, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 1~

The translation pro,Juct of this gene shares sequence homology with the human uncoupling protein-~2 which is thought to be important in energy metabolism, obesity, and the predisposivtion of hyperinsulinemia (See Genebank Accesion No.
gi~ 1857278). Recently, another group published on this gene, designating it brain mitochondria) carrier protein-1 (BCMP1) (J Biol Chem 1998 Dec 18;273(51):34b11-5). One embodiment of this gene comprises polypeptides of the following amino acid sequence: PTDVLKIRMQAQ (SEQ ID NO: 214) , andlor TYEQLKR (SEQ ID NO:
215) . An additional embodiment is the polynucleotides encoding these polypeptides.
This gene maps to the X chiromosome, and therefore, is used as a marker in linkage analysis for the X chromosome.
This gene is expres~~ed primarily in manic depression brain tissue, epileptic frontal cortex, human erythroleukemia cell line, T-helper cells, and to a lesser extent in endothelial and amygdala cells.
Therefore, polynucileotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the central nervous system or hematopoietic/immune disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immurnological prabes for differential identification of the tissues) or cell type(s). Fo:r a number of disorders of the above tissues or cells, particularly of the central nervous system or hematopoietic/immune systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types {e.g., neural, hemolymphoid, or cancerous and wounded tissues) or bodily fluids (e.;g., lymph, serum; plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 118 as residues: Ser-34 to Thr-39, Gln-198 to Leu-205. Polynucleatides encoding said polypeptides are also provided.

The tissue distribution in neural tissues combined with the homology to the human uncoupling protein indicates that polynucleotides and poiypeptides corresponding to this gene are useful for the detection andlor treatment of neurodegenerative disease states and behavioural disorders such as Alzheimer's 5 Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses , autism; and altered bahaviors, including disorders in feeding, sleep patterns, balance, and preception. In addition, the gene or gene product may .also play a role in the treatment and/or detection of 10 developmental disorders associated with the developing embryo, sexually-linked disorders, or disorders of the cardiovascular system. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and%or immunotherapy targets for the above listed tissues.
Alternatively, given the homology to uncoupling proteins, the gene and/or its 15 translation product may also be used in the diagnosis, treatment, and/or prevention of thermogenesis disorders such as obesity, cachexia, and hyperinsulinemia.
Uncoupling proteins dissipate the proton gradient created from the oxidation of fuels by the electron transport chain, thus releasing stored energy as heat. Dysfunction of thermogenesis can induce .disorders such as obesity and cachexia. It is thought that 20 obesity may result from decreased thermogenesis in humans. Alternatively, cachexia is a metabolic state in which energy expenditure exceeds food intake, for example in anorexia nervosa. Uncoupling proteins is useful for the treatment andlor prevention of diseases andlor disorders involved with aberrant metabolic and thermogenic pathways. The following method provides for the determination of respiration 25 uncoupling activity of the polypeptides of the present invention, including fragments and variants of the full length proteins.
Briefly, yeast are transfected with an expression vector expressing polypeptide of the present invention as previously described by Bouillaud et al., EMBO J.;
13:1990 (1994) (incorpora.ted by reference herein in its entirety). Rates of growth in 30 liquid medium of transformed yeast are measured in the presence of galactose, which induces expression, as described in International Publication No. WO 98/31396 (incorporated by reference herein in its entirety). Instameous generation times are compared between the pol~~peptide of the present invention and appropriate controls.
An in vivo decrease of membrane potential associated with uncoupling of respiration is analyzed by flow cytomEary of yeast labeled with the potential sensitive probe DiOC6 (3) (3,3'-dihexylox;acarbocyanine iodine, Molecular Probes, Eugene, OR).
The ability of a polypeptide of tithe present invention to influence mitochondria) activity and uncouple respiration is thus determined.
Many polynucleoti~ie sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:26 amd may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly., preferably excluded from the present invention are one or more polynucieotides comoprising a nucleotide sequence described by the general formula of a-b, where a is ;any integer between 1 to 1660 of SEQ LD N0:26, b is an integer of 15 to 1674, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:26, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 17 The translation product of this gene shares sequence homology with 55 kD
deglycosylated zona pellucida protein which is known to be important in egg fertilization (See Genebanl'c Accession No.R39356). Preferred polypeptides of the invention comprise the fol',lowing amino acid sequence:
RPRPSASSLARSASLLP~AAHGXGVGGAGGGSSXLRSRYQQLQNEEESGEPEQ
AAGDAPPPYSSISAESAHXFDYKDESGFPKPPSYNVATTLPSYDEAERTKAEA
TIPLVPGRDEDFVGRDI>FDDADQLRIGNDGIF (SEQ ID NO: 2I6) , RYQQLQNEEESGEPEQ.AAGD (SEQ ID NO: 217) , and/or PGRDEDFVGRDDFDDP~DQLRIG (SEQ ID NO: 218) . Polynucleotides encoding these polypeptides are also provided.

Preferred polypeptide fragments of the invention comprise the following amino acid sequence: MLT~FMAFLFNWIGFFT.SFCLTTSAAGRYG
AISGFGLSLIKWILIVRF;iTYFPGYFDGQY
WLWWVFLVLGFLLFLR.GFINYAKVRKMPET FSNLPRTRVLFIY (SEQ ID NO:
219). Polynucleotides encoding these polypeptides are also provided.
Preferred polypeptide varients of the invention comprise the following amino acid sequence:
MKKSLENLNRLQVMLL.HLTAAFLQRAQHXFDYKDESGFPKPPSYNVATTLPS
YDEAERTKAEATIPLVPGRDEDFVGRDDFDDADQLRIGNDGIFMLTFFM~AFLF
NWIGFFLSFCLTTSAAGRYGAISGFGLSLIKWILIVRFSTYFPGYFDGQYWLW
WVFLVLGFLLFLRGFINYAKVR KMPETFSNLPRTRVLFIY (SEQ ID NO: 220), MLLHLTAAFLQRAQFS'f YFPGYFDGQYWLW W V FLVLGFLLFLRGFINYAKV
RKMPETFSN LPRTRVLhIY (SEQ ID NO: 221), MLTFFMAFLFNWIGFFLSFCLT
TSAAGRYGAISGFGLSLIKWILIVRFSTYFPAFMNSLSRSKRTPAGSESRCRTQ
RNNHLL (SEQ ID NO: 222), and/or MKKSL,ENLNRLQVMLLHLTAAFLQRAHXIL TTRMSLGFQSPHLTM (SEQ ID
NO: 223) . Polynucleotides encoding these poiypeptides are also provided.
When tested against U937 cell lines, supernatants removed from cells containing this gene activavted the GAS (gamma activating sequence) promoter element. Thus, it is likely that this gene activates myeloid cells, and to a lesser extent, other immune and hematol>oietic cells and JAK-STAT signal transduction pathway.
GAS is a promoter elemen~ found upstream of many genes which are involved in the Jak-STAT pathway. The Jak-STAT pathway is a large, signal transduction pathway involved in the differentiation and proliferation of cells. Therefore, activation of the Jak-STAT pathway, reflected by the binding of the GAS element, can be used to indicate proteins involved :in the proliferation and differentiation of cells.
This gene is expressed primarily in adult kidney, colon adenocarcinoma, and fetal brain, and to a lesser extent, ubiquitously expression in many tissues.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues} or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of kidney, colon cancers, and central nervous system.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological ;probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the renal and neural systems, and cancers, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e:g., renal, neural, urogenital, or cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a.disorder, relative to the standard gene expression level, i.e., the expression l~wel in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ 1D~ NO: 119 as residues: Cys-15 to Gly-36.
Polynucleotides encoding said polypeptides are also provided.
The tissue distribution adult kidney, colon adenocarcinoma, and fetal brain indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of kidney diseases, colon cancers, and disorders of the central nervous system. Additionally, the homology to the zona pellucida protein indicates that the gene product is used for male contraceptive development, and infertility diagnosis etc. Protein> as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:27 .and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or mare polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1951 of SEQ 1D N0:27, b is an integer of 15 to 1965, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:27, and where b is greater than or equal to a +
14.
FEATURES OF PROTEiIN ENCODED BY GENE NO: i8 The translation product of this gene shares sequence homology with the chicken transferrin receptor in addition to a human prostate-specific protein homolog (See Genebank Accession t~os.pir~JH0570~JH0570 and gi~2565338 (AF026380), respectively). This gene also shares significant homology with both the murine and the rat hematopoietic lineage switch 2 proteins (See Genbank Accession Nos.
g3I69729 and g3851632, respectively), which are induced during an erythroid to myeloid lineage switch.
A preferred polypeptide fragment of the invention comprises the following amino acid sequence: MTVMDPKQMNVAAAVWAVVSYVVADMEEML PRS
(SEQ ID NO: 224). Polynucleotides emcoding these polypeptides are also provided.
This gene is expressed primarily in fetal tissues, such as Iiver/spleen and brain.
Therefore, polynuc',leotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, pre-natal disorders, anomalies, deficiencies. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunoIogical probes fox differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the developing fetus, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., dleveloping, cancerous and wounded tissues) or bodily fluids (e.g., amniotic fluid, serums, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 120 as residues: Arg-31 to Lys-37, Lys-58 to GIu-65, d5 Asp-157 to Gty-168, IIe-2:19 to Gly-225, AIa-260 to Ser-268, Thr-276 to Glu-282.
Polynucleotides encoding said polypeptides are also provided.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of pre-natal disorders, anomalies and deficiencies. The homology to the hematopoietic lineage switch 2 proteins indicates that The translation product of this gene is useful for the detection and/or treatment of immune system disorders. In addition, the homology to the transferrin receptor indicates that the translation product of the present invention may have utility in the regulation of iron metabolism as well as the numerous genes under the stringent control of physiologic iron levels.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:28 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope oir the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comvprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 1849 of SEQ ID N0:28, b is an integer of 15 to 1863, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:28, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 19 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame up;>tream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
PRVRSREPVAGAPGCG'TAGPPAMATLWGGLLRLGSLLSLSCLALSVLLLAHC
QTPPSDCLHVVEPMPVRGPDVEAYCLRCECKYEERSSVTIKVTIIIYLSILGLLL
LYMVYLTLVEPILKRRLFGHAQLIQSDDDIGDHQPFANAHDVLARSRSRANV

LNKVEYAQQRWKLQVQEQRKSVFDRHVVLS (SEQ ID NO: 225):
Polynucleotides encoding these polypeptides are also provided.
The polypeptide of this gene has been determined to have a transmembrane domain at about amino acid position 72 - 88 of the amino acid sequence referenced in Table 1 for this gene. Moreover, a cytoplasmic tail encompassing amino acids 89 to i67 of this protein has also. been determined. Based upon these characteristics, it is believed that the protein product of thiis gene shares structural features to type Ia membrane proteins.
' A preferred polypeiptide varient of the invention comprise the following amino acid sequence:
MATLWGGLLRLGSLLSLSCLALSVLLLAHCQTPPRISRMSDVNVSALPIKKNS
GHIYNKNISQKDCDCLHV VEPMPVRGPD VEAYCLRCECKYEERSS VTIKVTIII
YLSILGLLLLYMVYLTL,VEPILKRRLFGHAQLIQSDDDIGDHQPFANAHDVLA
RSRSRA.NVLNKVEYGTAALEASSPRAAKSLSLTGMLSSANWGIEFKVTRKKQ
ADNWKGTDWVLLGFILIPC (SEQ ID NO: 22fi). Polynucleatides encoding these polypeptides are also provided.
This gene is expressed primarily in infant brain tissue, and to a lesser extent in other cell types and tissues.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, developmental and neurodegenerative diseases of the brain and nervous system, such as depression, schizophrenia, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, mania., dementia, paranoia, addictive behavior, sleep disorders, epilepsy, transmissible spongiform encephalopathy {TSE), Creutzfeldt-Jakob disease (CJD). Similarly, polypeptides and antibodies directed to these polypeptides are useful in sproviding immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the brawn, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, developmental, or cancerous and wounded tissues) or bodily fluids (e.g., amniotic fluid, lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 121 a5 residues: Gln-110 to Pro-120, Val-152 to Val-159. Palynucleotides encoding said palypeptides are also provided.
The tissue distribution in infant brain tissue indicates that polynucleotides and palypeptides corresponding to this gene are useful for the treatment and/or diagnosis of developmental, degenerative and behavioral conditions of the brain and nervous system. Representative usea are described in the "Regeneration" and "Hyperproliferative Disorders" sections below, in Example 1 I, 15, and 18, and elsewhere herein. Briefly, 'the uses include, but are not limited to the detection, treatment, and/or prevention of schizophrenia, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Taurette Syndrome, transmissible spongiform encephalopathy (TSE), Crc:utzfeldt-Jakob disease (CJD), mania, depression, dementia, paranoia, addictive behavior, obsessive-compulsisve disorder and sleep disorders. Furthermore, the: protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate Iigands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplenrient. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immu:notherapy targets for the above listed tissues.
Many polynucleati~de sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:29 and may have been publicly available prior to conception of the present invention. Prefi~rably, such related poiynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 1612 of SEQ ID N0:29, b is an WO 00!04140 PCT/US99/15$49 integer of i5 to 1626, where both a and b correspond to the positions of nucleotide residues shown in 5EQ ID N0:29, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 20 S The translation product of this gene shares sequence homology with a recently published gene Dysferlin, which is thought to be a-skeletal muscle gene that is mutated in Miyoshi myopathy and limb girdle muscular dystrophy (See Genbank Accession No. g3600028, and Nat. Genet. 20 (1), 31-36 (1998)):
This gene is expressed primarily in fetal liver, fetal heart tissue, and T-cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immunodeficiency, tumor necrosis, lymphomas, auto-immunities, cancer, inflammation, anemias (leukemia) and liver disorders, vascular disorders, and cancers (e.g., hepatobiastoma, hepatitis, liver metabolic diseases and conditions that are attributable to the differentiation of hepatocyte progenitor cells).
Similarly, polypeptides and antibodies directed co these polypeptides are useful in providing immunological probes for differential identification of the tissues} or cell type(s). For a number of disorders of the above tissues or cells, particularly of the liver and immune system, expression of this gene at significantly higher or lower levels is routinely detected in certaiin tissues or cell types (e.g., hepatic, developmental, vascular, or cancerous and. wounded tissues) or bodily fluids (e.g., amniotic fluid, bile, lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene: are useful for the diagnosis and treatment of immune disorders including: leuke~nias, lymphomas, auto-immunities, immunodeficiencies (e.g., AIDS), immuno-supressive conditions (transplantation} and hematopoeitic disorders. In addition this gene product is applicable in conditions of general microbial infection, inflammation or cancer. Expression in liver may suggest a role for this gene product in the: treatment and detection of liver disorders and cancers (e.g., hepatoblastoma, jaundice, hepatitis, liver metabolic diseases and conditions that are attributable to the differentiation of hepatocyte progenitor cells).
Alternatively, the tissue distribution in fetal heart tissue .indicates that the protein product of this gene is useful for the diagnosis and treatment of conditions and pathologies of the cardiovascular system, such as heart disease, restenosis, atherosclerosis, stoke, angina, thrombosis, and wound healing. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunatherapy targets for the above listed tissues. Additionally, the homology to the dysferIin gene indicates that polynucleotides and polypeptides corresponding to this gene are useful for diseases related to degenerative myopathies that are characterized by the weakness and atrophy of muscles without neural degradation; such as Duchenne and Becker's muscular dystropies. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or irnmunotherapy targets for the above listed tissues Many polynucleotide sequences, such as EST sequences, are publicly available arid accessible through sequence databases. Some of these sequences are related to SEQ ID N0:30 ;end may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 59I of SEQ ID N0:30, b is an integer of 15 to 605, where both a and b correspond to the positions of nucleotide residues shown in SEQ IDS N0:30, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 21 This gene is expre:>sed primarily in haemopoietic cells and tumor cells, such as pancreatic tumor tissue, and to a lesser extent in bladder cells.

Therefore, polynuclleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diiagnosis of diseases and conditions which include, but are not limited to, haemopoietic disorders, diseases of the renal and pancreatic systems, 5 and cancer. Similarly, polypeptides and antibodies directed to these poiypeptides are useful in providing irnmunalogical probes for differential identification of the tissues) or cell type(s). Four a number of disorders of the above tissues or cells, particularly of the haemopaietic, pancreatic, and renal systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or 10 cell types (e.g., pancreas, renal, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the e;rpression level in healthy tissue or bodily fluid from an individual not having the disorder.
15 The tissue distribution indicates that polynucleatides and polypeptides corresponding to this gene are useful for the treatment and/or diagnosis of disorders of the renal, pancreatic and' haemopoietic systems, and cancers thereof.
Protein, as well as, antibodies directedl against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
20 Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:31 and may have been publicly available prior to conception of the present invention. Prefc;rably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is 25 cumbersome. Accordingly., preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is ~~ny integer between 1 to 917 of SEQ ID NO:31, b is an integer of 15 to 931, where: both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:31, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 22 5i This gene is expressed primarily in liver tissue, cancer cells and fetal lung tissue, and to a lesser extent in dendritic cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample arid for diagnosis of diseases and conditions which include;
but are not limited to, metabolic disorders, diseases of developing systems and cancers.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing irnmunological 'probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the fetus, metabolic systems and cancers, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., developing, metabolic, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression i5 level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the 'present invention comprise immunogenic epitopes shown in SEQ II) NO: 124 as residues: His-44 to GIy-49.
Polynucleotides encoding said polypeptide;s are also provided.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene; are useful for the treatment and/or diagnosis of disorders of the fetus, metabolic sy:ctems and cancers. The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection and treatment o!F liver disorders and cancers (e.g. hepatoblastoma, jaundice, hepatitis, liver metabolic .diseases and conditions that are attributable to the differentiation of hepatocyte progenitor cells). In addition the expression in fetus would suggest a useful role for the protein product in developmental abnormalities, fetal deficiencies, pre-natal disorders and various would-healing models andlor tissue trauma. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or im~munotherapy targets for the above listed tissues.

Many polynucleot;ide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:32 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope crf the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1393 of SEQ ID N0:32, b is an integer of ~1S to 1407, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:32, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 23 This gene is expressed primarily in central nervous system tissues and cancers, such as endometrial tumors, and to a lesser extent in other tissues and organs.
Therefore, polynuc:leotides and poiypeptides of the invention are useful as reagents for differential idientification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the CNS and cancers. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing imrnunoiogical probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nervous system and cancerous tissues, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, cancerous and wounded tissues) or bodily fluids (e;.g., lymph, serum, plasma, urine, synoviaI fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fl~~uid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 125 as residues: Tyr-16 to Ser-22, Asp-209 to Leu-215. Polynucleotides encoding said polypeptides are also provided.

The tissue distribution in central nervous system tissues indicates that poIynucleotides and polypeptides corresponding to this gene are useful for the treatment and/or diagnosis. of diseases of the central nervous system, as well as cancers of tissues where expression of this gene has been observed, such as in endometrial tumors. The tissue distribution in central nervous system tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatmemt of neurodegenerative disease states and behavioural disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, schiz~~phrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, or sexually-linked disorders. Protein, as well as, antibodies directed against the protein ZS may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:33 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides connprising a nucleotide sequence described by the general formula of a-b, where a is. any integer between I to 1512 of SEQ ID N0:33, b is an integer of 15 to 1526, where both a and b correspond to the positions of nucleotide residues shown in SEQ II) N0:33, and where b is greater than or equal to a +
14.
FEATURES OF PROTIEIN ENCODED BY GENE NO: 24 The translation product of this gene shares sequence homology with low-density lipoprotein receptor (See Genbank Accession No. >dbj~BAA24580.1), which is thought to be important in the pathogenesis of atherosclerosis and other disorders.

The translation product of this gene also shares sequence homology with a rat homolog of the human CD~94 (See Genbank Accession No. gb~AAC10220.1).
This gene is expressed primarily in macrophages, eosinophils, neutrophil and other cells of the haemopoietic and immune system.
Therefore, polynucleotides and polypeptides of the.invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the immune and haemopoietic systems and diseases of the endothelial and vascular system. Similarly, polypeptides and antibodies directed to these polypeptides are useiFul in providing immunological probes for differential identification of the tissuel;s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune, haemopoietic and vascular system, expression of this gene at ;>ignificantly higher or lower levels is routinely detected in certain tissues or cell type:; (e.g., immune, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptiides of the present invention comprise immunogenic epitopes shown in SEQ ID~ NO: 126 as residues: Lys-9 to Ala-17, Met-55 to Leu-61, Tyr-105 to Cys-127, Asp-:132 to Lys-141, Ser-165 to Tyr-172, Pro-178 to Met-186, His-222 to Gln-227. Polynucleotides encoding said polypeptides are also provided.
The tissue distribution and homology to LDL receptor and rat CD94 homolog indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and/or diagnosis of disorders of the immune, haemopoietic and vascular systems. The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and/or treatment of hematopoietic disorders. This gene product is primarily expressed in hematopoietic cells and tissues, suggesting that it plays a role in the survival, proliferation, and/or differentiation of hematopoieitic lineages. Expression of this gene product in eosinophils and macropha;;e also strongly indicates a role for this protein in immune function and immune surveillance. Protein, as well as, antibodies directed against the protein may show utility as, a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly 5 available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:34 amd may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope otF the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or 10 more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1723 of SEQ ID N0:34, b is an integer of 15 to 1737, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:34, and where b is greater than or equal to a +
14.
15 FEATURES OF PROTEIN ENCODED BY GENE NO: 2S
A preferred polype.ptide fragrraent of the invention comprises the following amino acid sequence:
MAAAGRLPSSWALFSF'LLAGLA.LLGVGPVPARALHNVTAELFGAEAWGTLA
AFGDLNSDKQTDLFVL.RERNDLI VFLA.DQNAPYFKPKVKVSFKNHSALITSV V
20 PGDYDGDSQMDVLLT'YLPKNYA.KSELGAVIFWGQNQTLDPNNMTILNRTFQ
DEPLIMDFNGDLIPDIFGITNESNQPQILLGGNLSWHPALTTTSKMRIPHSHAFI
DLTEDFTADLFLTTLNATTSTFQFEIWENLDGNFSVSTILEKPQNMMV VGQSA
FADFDGDGHMDHLLPGCEDKNCQKSTIYLVRSGMKQWVPVLQDFSNKGTL
WGFVPFVDEQQPTEIPI(PITLHIGDYNMDGYPDALVILKNTSGSNQQAFLLENV
25 PCNNASCEEARRMFKVYWELTDLNQIKDA.MVATFFDIYEDGILDIVVLSKGY
TKNDFAIHTLKNNFEADAYFVKVIVLSGLCS NDCPRR (SEQ ID NO: 227).
Polynucleotides encoding these polypeptides are also provided.
When tested against U937 cell lines, supernatants removed from cells containing this gene activated the GAS (gamma activating sequence) promoter 3Q element. Thus, it is likely that this gene activates myeloid cells, and to a lesser extent, other immune and hematopoietic cells and tissue cell types, through the JAK-STAT

signal transduction pathwaEy. GAS is a promoter element found upstream of many genes which are involved in the Jak-STAT pathway. The Jak-STAT pathway is a large, signal transduction pathway involved in the differentiation and proliferation of cells. Therefore, activation of the Jak-STAT pathway, reflected by the binding of the GAS element, can be used to indicate proteins involved in the proliferation and differentiation of cells.
This gene is expressed primarily in infant brain and placental tissues, and to a lesser extent in several other tissues including cancers.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential idc;ntification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, brain disorders and diseases of developing systems and cancers.
Similarly, polypeptides and antibodie s directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nervous system and fetal systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, developing, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression lf;vel in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 127 as residues: Leu-56 to Thr-62, Gln-80 to Pro-87, GIy-106 to GIn-113, Pro-122 to Lys-127, Gln-138 to Asn-14b. Palynucleotides encoding said polypeptides are also provided.
The tissue distribution in neural tissues and developing tissues indicates that polynucleotides and polypnptides corresponding to this gene are useful for the treatment and/or diagnosis of disorders of the central nervous system, disorders of developing systems, and cancers. The tissue distribution in infant brain tissue indicates that polynucleotides and polypeptides corresponding to this gene are useful WO 00/04140 PCTlE1S99/15849 for the detectionltreatment of neurodegenerative disease states and behavioural disorders such as Alzheimc;r's Disease, Parkinson's Disease, I-Iuntington's Disease, Tourette Syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, the gene or gene product may also play a role in the treatment and/or detection of developmental disorders associated with the developing embryo, or sexually-linked disorders.
The tissue distribution indicates that polynucleotid~s and polypeptides corresponding to this gene are useful for the diagnosis and/or treatment of disorders of the placenta. Specific expression within the placenta indicates that this gene product may play a role in the proper establishment and maintenance of placenta!
function. Alternately, this gene product is produced by the placenta and then transported to the embryo, where it may play a crucial role in the development and/or survival of the developing embryo or fetus. Expression of this gene product in a vascular-rich tissue such as the placenta also indicates that this gene product is produced more generally in endothelial cells or within the circulation. In such instances, it may play more generalized roles in vascular function, such as in angiogenesis. It may also be produced in the vasculature and have effects on other cells within the circulation, such as hematopoietic cells. It may serve to promote the proliferation, survival, activation, and/or differentiation of hematopoietic cells, as well as other cells throughout the body. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotiide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:35 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2228 of SEQ ID N0:35, b is an integer of 15 to 2242, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:35, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 26 Preferred polypeptiides of the invention comprise the following amino acid sequence:
MTKREDGGYTFTATPE',DFPKKHI~APVIDIGIANTGKFIMTASSDTTVLIWSLK
GQVLSTINTNQMNNTHiAAVSPCGRFVASCGFTPDVKVWEVCFGKKGEFQEV
VRAFELKGHSAAVHSFAFSNDSRRMASVSKDGTWKLWDTXVEYKKKQDPY
LLKTGRFEEAAGAXPCRLALSPNAQVLALASGSSIHLYNTRRGEKEECFERVH
GECIANLSFDITGRFLA;SCGDRAVRLFHNTPGHRAMVEEMQGHLKRASNEST
RQRLQQQLTQAQETLB:SLGALKK (SEQ ID NO: 228). Polynucleotides encoding such polypeptides are also provided.
The gene encoding the disclosed cDNA is thought to reside on chromosome 7.
Accordingly, polynucleoti~des related to this invention are useful as a marker in linkage analysis for chromosome 7.
When tested against U937 Myeloid cell lines, supernatants removed from cells containing this gene activated the GAS assay. Thus, it is likely that this gene activates myeloid cells through the ,Tak-STAT signal transduction pathway. The gamma activating sequence (GAS) is a promoter element found upstream of many genes which are involved in the ,lak-STAT pathway. The Jak-STAT pathway is a large, signal transduction pathway involved in the differentiation and proliferation of cells.
Therefore, activation of the Jak-STAT pathway, reflected by the binding of the GAS
element, can be used to indicate proteins involved in the proliferation and differentiation of cells. Recently, another group published this gene, naming it WS
beta-transducin repeats protein (See Human Genetics 103 (5), 590-599 (1998);
which is hereby incorporated herein by reference), in which it was suggested that the protein is involved in William's Disease.
The polypeptide of this gene has been determined to have a transrnembrane domain at about amino aciid position i2 - 28 of the amino acid sequence referenced in Table 1 for this gene. Based upon these characteristics, it is believed that the protein product of this gene shares structural features to type Ib membrane proteins.
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
VIRHEGSTNMELSQMS:~I,MGLSVLLGLLALMATAAVXRGWLRAGEERSGRP
ACQKANGFPPDKSSGSI~KQKQYQRIRKEKPQQHIVFTHRLLAAALKSHSGNIS
CMDFSSNGKYLATCADDRTIRIWSTKDFLQREHRSMRANVELDHATLVRFSP
DCRAFIVWLANGDTLRVFKMTKREDGGYTFTATPEDFPKKHKAPVIDIGIAN
TGK
FIMTASSDTTVLIWSLKGQVLSTINTNQMNNTHAAVSPCGRFVASCGFTPDVK
VWEVCFGKKGEFQEVVRAFELKGHSAAVHSFAFSNDSRRMASVSKDGTWK
LWDTXVEYKKKQDPY:LLKTGRFEEAAGAXPCRLALSPNAQVLALASGSSIHL
YNTRRGEKEECFERVHGECIANLSFDITGRFLASCGDRAVRLFHNTPGHRAM
VEEMQGHLKRASNES'I'RQRLQQQLTQAQETLKSLGALKK {SEQ ID NO: 229).
Polynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in testes, synovial sarcoma and fetal tissues, and to a lesser extent in several other tissues.
Therefore, polynuc:leotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the reproductive and developing systems and cancers.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of dlisorders of the above tissues or cells, particularly of the reproductive and developing systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., reproductive, testicular, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, seminal fluid, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an indiividual having such a disorder, relative to the standard gene WO 00/04140 1'CTIUS99/15849 expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the dlisorder.
The tissue distribution in testes tissue, synovial sarcoma, and fetal tissues, indicates that polynucleoti~des and polypeptides corresponding to this gene are useful 5 for the treatment and/or di;~gnosis of dlisorders of the reproductive and developing systems, and cancers. The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of conditions concerning proper testicular function (e.g: endocrine function, sperm maturation), as well as cancer. Therefore, this gene product is useful in the treatment 10 of male infertility and/or impotence. This gene product is also useful in assays designed to identify binding agents, a;> such agents (antagonists) are useful as male contraceptive agents. Similarly, the protein is believed to be useful in the treatment andlor diagnosis of testicular cancer. The testes are also a: site of active gene expression of transcripts that is expressed, particularly at low levels, in other tissues 15 of the body. Therefore, this gene product is expressed in other specific tissues or organs where it may play t~elated functional roles in other processes, such as hematopoiesis, inflammation, bone formation, and kidney function, to name a few possible target indications.
Furthermore, the tissue distribution indicates that polynuclevtides and 20 polypeptides corresponding to this gene are useful for the diagnosis and treatment of cancer and other proliferative disorders. Expression within embryonic tissue and other cellular sources marked by proliferating cells indicates that this protein may play a role in the regulation of cellular division. Additionally, the expression in hematopoietic cells and tissues indicates that this protein may play a role in the 25 proliferation, differentiation, and/or survival of hematopoietic cell lineages. In such an event, this gene is useful in the treatment of lymphaproliferative disorders, and in the maintenance and differentiation oiF various hematopvietic lineages from early hematopoietic stem and committed progenitor cells. Similarly, embryonic development also involves. decisions involving cell differentiation and/or apoptosis in 30 pattern formation. Thus this protein may also be involved in apoptosis or tissue differentiation and could again be useful in cancer therapy. This protein is useful for the treatment, detection, amd/or prevention of William's Disease. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to iits use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:36 and may have been publicly available prior to conception of the present invention. Prefc;rably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly" preferably exciuded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is ;any integer between 1 to 2221 of SEQ ID N0:36, b is an integer of 15 to 2235, where both a and h correspond to the positions of nucleotide residues shown in SEQ ID N0:36, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 27 Preferred polypepti.des of the invention comprise the following amino acid sequence positions 1-363, 2-363, 4-363, 5-363, 30-363, 31-363, 32-363, 75-363, 363 and 82-363 of the following amino acid sequence:
MSVMVVRKKVTRKWI:KLPGRN':CFCCDGRVMMARQKGIFYLTLFLILGTCTL
FFAFECRYLAVQLSPAIPVFAAMLFLFSMATLLRTSFSDPGVIPRALPDEAAFIE
MEIEATNGAVPQGQRP'PPRIKNFQINNQIVKLKYCYTCKiFRPPRASHCSICDN
CVERFDHHCPWVGNC'VGKRNYRYFYLFILSLSLLTIYVFAFNIVYVALKSLKI
GFLETLKETPGTVLEVLICFFTLW S V V GLTGFHTFLV ALNQTTNEDIKGS WTG
KNRVQNPYSHGNIVKNCCEVLCGPLPPSVLDRRGILPLEESGSRPPSTQETSSS
LLPQSPAPTEL NSNEMPEDSSTPEEMPPPEPPEPPQEAAEAEK (SEQ ID NO:
230). Polynucleotides enc~~ding such polypeptides are also provided.
A preferred polype;ptide varient of the invention comprises the following amino acid sequence: MLELFSMAT:LLRTSFSDPGVIPRALPDEAA

FIEMEIEATNGAVPQGQRPPPRIKNFQINNQIVKLKYCYTCKIFRPPRASHCSIC
DNCVE RFDHHCPWVCiNCVGKR:NYRYFYLFILSLSLLTIYVFAFNIVYVALK
SLKIGFLETLKGNS WNCSRSPHL:LLYTLVRRGTDWISYFPRGSQ PDNQ (SEQ
ID NO: 231). Polynucleotides encoding these poiypeptides are also provided.
This gene is expressed primarily in ovarian and endometrial tumors, fetal liver, spleen and brain tissues, and to a lesser extent in several other tissues and organs.
Therefore, polynuc;leotides and polypeptides of the invention axe useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the developing systems, and cancers of the female reproductive system. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). Far a number of disorders of the above tissues or cells, particularly of the developing, female reproductive and fetal systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., reproductive, developing, cancerous and wounded tissues) or bodily fluids (e-.g., lymph, serum, plasma, urine, synovial fluid arid spinal fluid) or another tissue or cell sample; taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: I29 as residues: Pro-4.4 to Lys-54, Cys-88 to His-95, Val-103 to Tyr-108, Gln-181 to Ser-:190, Thr-192 to Ile-206, Glu-233 to Ser-245, Ser-252 to Ala-286. Polynuclc;otides encoding said polypeptides are also provided.
The tissue distribution in developing systems indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment andlar diagnosis of disorders of developing and fetal systems, and cancers.
Furthermore, the tissue distribution in ovarian and endometrial tumor tissues indicates that the translation product of this. gene is useful for the detection, diagnosis, andlor treatment of cancers of the female reproductive system. Accordingly, preferred are antibodies which specifically bind a p~artion of The translation product of this gene.
Also provided is a kit for detecting these tumors. Such a kit comprises in one embodiment an antibody specific for The translation product of this gene bound to a solid support. Also provided is a method of detecting these tumors in an individual which comprises a step of contacting an antibody specific for The translation product of this gene to a bodily fluid from the individual, preferably serum, and ascertaining whether antibody binds to an antigen found in the bodily fluid. Preferably the antibody is bound to a solid support and the bodily fluid is serum. The above embodiments, as well as other treatments and diagnostic tests (kits and methods), are more particularly described elsewhere herein.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:37 a.nd may have been publicly available prior to conception of the present invention. Prefc;rably, such related polynucleotides are specifically i5 excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly.,, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2957 of SEQ ID N0:37, b is an integer of 15 to 2971, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:37; and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 28 This gene is expressed primarily in normal and cancerous colon tissue, macrophages, endothelial cells and placental tissue, and to a lesser extent in several other tissues and organs.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, colon cancer and gastrointestinal disorders, immune disorders, vascular diseases and disorders of developing systems. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification oi-' the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune , vascular and developing systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues c~r cell types (e.g., immune, gastrointestinal, developmental, vascular, cancerous and wounded tissues) or bodily fluids (e.g., lymph; serum, plasma, urine, synoviai fluid and spinal fluid) or another tissue or cell sample taken .
from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 130 as residues: Thr-27 to Ser-33.
Polynucleotides encoding said polypeptides, are also provided.
The tissue distribution in macrophage, endothelial and placental tissues, and normal and cancerous colon tissues, indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment andlor diagnosis of immune, gastrointestinal and vascular disorders and diseases. Expression of this gene product in colon tissue indicates involvement in digestion, processing, and elimination of food, as well as a potential role far this gene as a diagnostic marker or causative agent in the development of colon cancer, and cancer in general. Accordingly, preferred are antibodies which specifically bind a portion of the translation product of this gene.
Also provided is a kit for detecting colon cancer. Such a kit comprises in one embodiment an antibody specific for 'The translation product of this gene bound to a solid support. Also provided is a method of detecting colon cancer in an individual which comprises a step of contacting an antibody specific for The translation product of this gene to a bodily fluid from the individual, preferably serum, and ascertaining whether antibody binds to an antigen found in the bodily fluid.
Preferably the antibody is bound to a solid support and the bodily fluid is serum. The above embodiments, as well as other treatments and diagnostic tests (kits and methods), are more particularly described elsewhere herein. Alternatively, the tissue distribution in placental tissue indicates that polynucleotides and polypeptides corresponding to this gene: are useful for the diagnosis and/or treatment of disorders of the placenta. Specific expression within the placenta indicates that this gene product may playa role in the proper establishment and maintenance of placental function. Alternateiy, this gene product is produced by the placenta and then transported to the embryo, 'where it many play a crucial role in the development andlor survival of the developing embryo or fetus. Expression of this gene product in a vascular-rich tissue such as the placenta and endothelial cells also indicates that this gene product is produced more generally in endothelial cells or within the circulation.
In such instances, it may play more generalized roles in vascular function, such as in angiogenesis. It may also be produced in the vasculature and have effects on other 10 cells within the circulation, such as hematopaietic cells. It may serve to promote the proliferation, survival, activation, andfor differentiation of hematopoietic cells, as well as other cells throughout the body. Additionally, expression of this gene product in macrophage also strongly indicates a role for this protein in immune function and immune surveillance. This gene product is involved in the regulation of cytokine 15 production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g, by boasting immune responses).
Since the gene is e~:pressed in cells of lymphoid origin, the gene or protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy tarl;ets for the above listed tissues. Therefore it is also used as 20 an agent for imrnunoiagica~l disorders including arthritis, asthma, immune deficiency diseases such as ADDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stern cc;lis and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Protein, as well as, 25 antibodies directed against the protein may show utility as a tumor marker and/or irnmunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, axe pubiiciy available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:38 :end may have been publicly available prior to conception of 30 the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to I 149 of SEQ ID N0:38, b is an integer of 15 to 1163, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:38, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 29 The translation product of this gene shares homology with HNK-sulfatransferase, which directs glycan synthesis (see Genbank Accession no.
AF033827).
This gene is expressed primarily in activated T cells, osteoclastoma, and glioblastoma, and to a lesser extent in various other normal and transformed cell types.
Therefore, polynuc:leotides and poiypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for .diagnosis of diseases and conditions which include, but are not limited to, inflammation, immune defects, cancer. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune and hemopoietic systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ II) NO: I31 as residues: Pro-32 to Gly-48, Gln-63 to Thr-69, Pro-77 to Trp-84, Val-88 to Leu-94. Polynucleotides encoding said polypeptides are also provided.

The tissue distribution in T-cells and various types of neoplasms indicates that polynucleotides and polypE:ptides corresponding to this gene are useful for the detection, study and/or treatment of inflammatory and general immune defects, and various types of neoplasm.;. Expression of this gene product in T cells strongly indicates a role for this protein in immune function and immune surveillance.
This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid.origin, the gene or protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy tarl;ets for the above listed tissues. Therefore it is also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product may have commercial utility in the expansion of stern cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Alternatively, the tissue distribution in various cancerous tissues indicates that the translation product of the gene is useful for the detection, diagnosis, andlor treatment of these cancers, as well as cancers of other tissues where expression has been observed. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ iD N0:39 .and may have been publicly available prior to conception of the present invention. Preferably, such related poIynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comiprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1918 of SEQ ID N0:39, b is an integer of 15 to 1932, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:39, and where b is greater than or equal to a +
14.

FEATURES OF PROTEAN ENCODED BY GENE NO: 30 Preferred polypepti~des of the invention comprise the following amino acid sequence:
LHECLPGSISYLHPRTPWLCLPPQHLSFSTFSPPWQPAMSPVPGTGGPPCGL
(SEQ ID NO: 232), and/or MLPLLIICLLPAIEGKNCLRCWPELSALIDYDLQILW VTPGPPTELSQSIHSLFLE
DNNFLKPWYLDRDHLE~ETAKFFTQVHQAIKTLRDDKTVLLEEIYTHKNLFT
ERLNK~SDGLKEKGAPPLHECLPGSISYLHPRTPWLCLPPQHLSFSTFSPPWQP
AMSPVPGTGGPPCGL (~~EQ ID NO: 233). PolynucIeotides encoding these polypeptides are also provided.
This gene is expressed primarily in infant brain, testes and activated T
cells, and to a lesser extent in various other normal and transformed cell types.
Therefore, polynucl':eotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological, reproductive and inflammatory conditions.
Similarly, poIypeptides and antibodies directed to these polypeptides are useful in providing irzlmunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the neural, immune and male reproductive systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, innmune, reproductive, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluiid and spinal fluid) or another tissue or cell sample taken from an individual having ;such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 132 as residues: Gly-41 to Leu-46, Asp-67 to Thr-?5, IIe-114 to AIa-123. Poiynucleotides encoding said polypeptides are also provided.

The tissue distribution in infant brain tissue, testes tissue, and activated T-cells, indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study, diagnosis, andlor treatment of neurological, reproductive and immune system disorders. Expression of this gene product in T-cells indicates a role in the regulation of the proliferation; survival; differentiation; andlor activation of potentially ail hematopoietic cell lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is e;~pressed in cells of lymphoid origin, the gene or protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy ta~rl;ets for the above listed tissues. Therefore it is also used as an agent for immunological disorders including arthritis, asthma, immune deficiency diseases such as AIDS, lee:Gkemia, rheumatoid arthritis, inflammatory bowel disease, sepsis, acne, and psoriasis. In addition, this gene product rnay have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell type.
Alternatively, the tissue distribution in testes. tissue indicates that polynucleotides and poIypeptides corresponding to this gene are useful for the treatment and diagnosis of conditions concerning proper testicular function (e.g. endocrine function, sperm maturation), as well as cancer. Therefore, this gene product is useful in the treatment of male infertility andlor impotence. This gene product is also useful in assays designed to identify binding agents, as such agents (antagonists) are useful as male contaraceptive agents. Similarly, the prot~:in is believed to be useful in the treatment and/or diagnosis of testicular cancer. The testes are also a site of active gene expression of transcripts that is expressed, particularly at low levels, in other tissues of the body.
Therefore, this gene product is expressed in other specific tissues or organs where it may play related functional roles in other processes, such as hematopoiesis, inflammation, bone formation, and kidney function> to name a few possible target indications.
Furthermore, the tissue distribution in infant brain tissue indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioural disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, A>rS, psychoses, autism, and altered behaviors, 5 including disorders in feeding, sleep patterns, balance, and perception. In addition, the gene or gene product may also play a role in the treatment andlor detection of developmental disorders associated with the developing embryo, or sexually-linked disorders. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
IO Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:40 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present: invention. To list every related sequence is 1S cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 867 of SEQ ID N0:40, b is an integer of 15 to 881, where; both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:40, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 31 The translation product of this gene shares sequence homology with some human and rodent melanoma and ieukacyte specific antigens (see, for example, Genbank accession nos: gi~189384, gi~205898 and gi~180926). In addition, The translation product of this ;gene shares sequence homology with Tetraspan protein (see, for example, Genbank accession number: GI 3152703). Therefore, it is likely that the polypeptide of this. gene shares some biological functions, such as cell-to-cell signaling, adhesion, proliferation, and differentiation with Tetraspan.
The polypeptide of this gene has been determined to have two transmembrane domains at about amino acid position 52-68 and 197 - 213 of the amino acid sequence referenced in Table 1 for this gene. Based upon these characteristics, it is believed that the protein product of this gene shares structural features to type IIIa membrane proteins.
The transmembrane 4 superfamily (TM4SF) or tetraspan superfamily has at least 16 members (including CD9, CD:ZO, CD37, CD53, CD63, CD81, CD82, A15, CO-029, Sm23, RDS, Uro .'B, Uro A, SAS, Rom-1, PETA3, and YKKB), is the second biggest subfamily among C'.D antigen superfamily. and activation antigen of T-cells.
All TM4SF member contains four putative transmembrane domains, two extracellular loops, and two short cytopIasmic tails. They are variously expressed on Immature, early, mature, activated lymphocytes, monocytes, macrophages, granulocytes, platelets, eosinophils, basolphiIs, certain leukemic and lymphoma cells, and a variety of other cells and tissues. C'.D9 cell surface protein is expressed by both hematopoietic and neural cells, and may play a role for CD9 in intercellular signaling in the immune and nervous system. CD63 is a 53-Kd lysosomal membrane glycoprotein that has been identified as a platelet: activation molecule, which play important role in cell adhesion of platelets and endothelial cells. Increased mRNA for CD63 antigen was found in atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits, suggesting a potential role of CD63 in progression of atherosclerosis. CD63 is also a mast cell marker.
CD82 was originally identified. as the target of several mAbs inhibitory to syncytium formation induced by human T-cell leukemia virus type I (HTLV-I), the etiological agent of adult T'-cell leukemia. Therefore, this gene could be a target for the development of a drug for this leukemia. CD81 is the target of an antiproliferative antibody. A diverse group of human cell lines, including hematolymphoid, neuroectodermal, and mesenchymal cells, express the CD81 protein. Many of the lymphoid cell lines, in pari:icular those derived from large cell lymphomas, were susceptible to the antiproliferative effects of the antibody. CD81 may therefore play an important role in the rel;ulation of lymphoma cell growth. CD9, CD20, CD37, CD63, CD81 and CD82 have been implicated in the regulation of cell growth, adhesion, and signal transtiuction of B, T lymphocytes and some other non-lymphoid cells. They associate with CD2, CD21, CD4, CDB, MHC Class II molecules, integrins, function as co-re;ceptor for 7C, B and other lymphoid cells. Sorne TM4SF are leukocyte antil;ens, highly expressed in activated leukocytes, lymphocytes, are highly specific surface marker for iymphoblastic leukemia, lymphoma, melanoma, anal neuroblastoma. CD9 has been show to be involved in cell motility and tumor metastasis. These antigen could be a valuable immunogen or target to implement active and passive immunotherapy in patients with cancer.
Others have been shown to be involved in inhibition of prostate cancer metastasis.
This gene has close homology to C33. antigen (CD82). whic is a member of the transmembrane 4 superfamily (TMSF) and activation antigen of T- cells. C33 Ag (CD82 was originally identified as the target of several mAbs inhibitory to syncytium formation induced by human T-cell Ic:ukemia virus type I (HTLV-I), the etiological agent of adult T-cell leukemia. Therefore, this gene could be very important target for developing drug for leukemia. Other members of this family are Sm23, CO-029, R2, TAPA-1, CD9, CD37, CD53, and CD63. CD63 is a 53-Kd lysosomal membrane glycoprotein that has been identified as a platelet activation molecule.
There is strong evidence indicating that CD63 and Pltgp40, a platelet membrane glycoprotein aria the same molecule and that CD63/Pitgp40 is identical to the well-characterized, stale-specific melanoma-associated antigen ME491.
These antigen could be valuable iimmunogens or target to implement active and passive immunotherapy in patients. with cancer.
This gene is expressed primarily in fetal tissue (kidney, heart, liver, spleen, brain), macrophages, dendritic cells, retina and to a lesser extent in various other tissues, mostly of lymphoid origin or epithelial cell types. In addition This gene is expressed in cancerous tissues (e.g. breast).
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis o:f diseases and conditions which include, but are not limited to, immune and hematopoietic diseases andlor disorders and cancers in a variety of organs and cell hypes. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue!(s} or cell types}. For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower Levels is routinely detected in certain tissues or cell types {e.g., developmental, proliferating, immune, hematopoietic, integumentary, and cancerous and wounded tissues) or bodily fluids {e.g., lymph, serum, plasma, urine, synovial fluid, spinal fluid, or amniotic fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeprides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 133 as residues: Tyr-123 to Tyr-131, Cys-134 to Ser-145, Tyr-234 to Tyr-244. l?olynucleotides encoding said polypeptides are also provided.
The tissue distribution fetal cells and tissues and homology to tumor antigens indicates that polynucleotides and polypeptides corresponding to this gene are useful for study, treatment and diagnosis of lymphoid and epithelial disorders and neopiasms. Additionally, tissue distribution in immune cells and other tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatvment of disorders affecting hematopoesis, including cancers. Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16, 1$, 19, 20, and 27, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; differentiation; and/or activation of hematopoietic cell lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer {e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also useful as an agent for immunological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheurr~atoid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimmune infertility, lense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderma. Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury. Thus, this gene product is thought to be useful in the expansion of stem cells and committed progenitors-of various blood lineages, and in the differentiation a.nd/or proliferation of various cell types.
Moreover, the expression within embryonic tissue and other cellular sources marked by proliferating cells indicates this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment, and/or prevention of developmental diseases and disorders, including cancer, and other proliferative conditions. Representative; uses are described in the "Hyperpraliferative Disorders"
and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation andJor apoptosis in pattern formation.
Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (5MA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polypeptides of the present invention are useful in treating, detecting, and/or preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulations of cellular growth and proliferation.
Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein rnay show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
5 Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:41 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present: invention. To list every related sequence is 10 cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1918 of SEQ ID N0:41, b is an integer of IS to 1932, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:41, and where b is greater than or equal to a +
14.
IS
FEATURES OF PROTEIN ENCODED BY GENE NO: 32 The translation product of this gene shares limited sequence homology with VEGF which is thought to be important in regulation of endothelial cell growth.
Therefore, it is likely that t:he protein encoded by this gene would share some similar 20 biological functions.
When tested against U937 Myeloid cell lines, supernatants removed from cells containing this gene activated the GAS assay. Thus, it is likely that this gene activates myeloid cells, and to a lesser extent, other immune and hematopoietic cells and tissue cell types, through the Jak-STAT signal transduction pathway. The gamma activating 25 sequence (GAS) is a promoter element found upstream of many genes which are involved in the Jak-STAT pathway. The Jak-STAT pathway is a large, signal transduction pathway invcdved in the differentiation and proliferation of cells.
Therefore, activation of the Jak-STAT pathway, reflected by the binding of the GAS
element, can be used to indicate proteins involved in the proliferation and 30 differentiation of cells.
This gene is expressed in brain.

Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, nervous system disease and/or disorders. Similarly, polypeptides and antibodies directed to these poiypeptides are useful in providing immunologicai probes for differential identification of the. tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nervous system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypepti~des of the present invention comprise irnmunogenic I5 epitopes shown in SEQ ID NO: 134 as residues: Thr-25 to Pro-46.
Polynucleotides encoding said polypeptides are also provided.
The tissue distributiion in brain indicates polynucleotides and polypeptides corresponding to this gene are useful for the detection, treatment, andlor prevention of neurodegenerative disease states, behavioral disorders, or inflammatory conditions.
Representative uses are de:>cribed in the "Regeneration" and "Hyperproliferative Disorders" sections below, in Example 11, I5, and 18, and elsewhere herein.
Briefly, the uses include, but are not limited to the detection, treatment, and/or prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, de;myelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania; dementia, paranoia, obsessive compulsive disorder, depression, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, elevated expression of this gene product in regions of the brain indicates it plays a role in normal neural function.

Potentially, this gene product is involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to S identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotiide sequences, such as EST sequences, are publicly available and accessible tr~rough sequence databases. Some of these sequences are related to SEQ ID N0:42 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general 1S formula of a-b, where a is any integer between l to 1150 of SEQ ID N0:42, b is an integer of 1 S to 1164, where both a and b correspond to the positions of nucleotide residues shown in SEQ ILK N0:42, and where b is greater than or equal to a +
14.
FEATURES OF PROT)E:IN ENCODED BY GENE NO: ~3 The translation product of this gene shares sequence homology with human plSO which is thought to be important in signal transduction in neuronal cells.
Therefore, it is likely that the protein encoded by this polynucleotide would share some similar biological fuanctions with p150.
This gene is expressed primarily in whole embryo and cerebellum.
2S Therefore, polynucieatides and polypeptides of the invention are useful as reagents for differential idlentification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurological and growth defects/disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential idevntification of the tissues) or cell type(s). Fox a number of disorders of the above tissues or cells, particularly of the CNS, expression of this gene WO 00104140 PCT/US99l15849 at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, cancerous and wounded tissues) or bodily fluids {e.g., lymph, serum, plasma, urine; synowial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder. w The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful fox study and treatment of central nervous system, neurodevelopmenl:al, cognitive, and memory disorders. The tissue distribution also indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection, trf;atment, andlor prevention of neurodegenerative disease states, behavioral disorders, or inflammatory conditions. Representative uses are described in the "Regeneration" and "Hyperproliferative Disorders" sections below, in Example 11, 15, and 18, and elsewhere herein. Eriefly, the uses include, but are not limited to the detection, trf:atment, and/or prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic: disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, arid perception. In addition, elc;vated expression of this gene product in regions of the brain indicates it plays a role in normal neural function.
Potentially, this gene product is involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Furthermore, the protein rnay also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, tv identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Moreover, the expression within embryonic tissue and other cellular sources marked by proliferating cells indicsates this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment, and/or prevention of developmental diseases and disorders, including cancer, and other proliferative conditions. Representative uses are described in the "Hyperproliferative Disorders"
and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation and/or apoptosis in pattern formation.
Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as :spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polypeptides of the present invention are useful in treating, detecting, andlor preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this jprotein may modulate apoptosis or tissue differentiation and is useful in the detc~.ction, treatment, andlor prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and i;issues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate: ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:43 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 1091 of SEQ ID N0:43, b is an integer of 1S to 1105, whevre both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:43, and where b is greater than ar equal to a +
14.
FEATURES OF PROTEIN ENCOIDED BY GENE NO: 34 This gene is expressed primarr,ly in PMA stimulated HL-60 cells and to a 10 lesser extent in 6 week embryo.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders affecting cell differentiation, particulary hematopoietic 1S disorders and/or defects. Similarly, polypeptides and antibodies directed to these palypeptides are useful in providing immunological probes far differential identification of the tissues) or cell t;ype(s). For a number of disorders of the above tissues or cells, particularly of the metabolic system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types 20 (e.g., cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
2S Preferred polypeptides of the present invention comprise immunogenic epitapes shown in SEQ ID NO: 136 .as residues: Pro-bl to Asp-68.
Polynucleotides encoding said polypeptida~s are also provided.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for the study of cellular differentiation and for 30 the treatment and diagno~~is of hematopoietic related disorders such as anemia, pancytopenia, leukopenia., thrombocytopenia or leukemia. The tissue distribution also indicates polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders.
Representative uses are described in the "hmmune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation;
survival; differentiation; andlor activation of hematopoietic cell lineages, including blood stern cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses). Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury. Thus, this gene product is thought to be usa:ful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation andlor proliferation of various cell types Aditionally, the expression within embryonic tissue and other cellular sources marked by proliferating cells indicates this protein may play a role in the regulation of cellular diivision, and may show utility in the diagnosis, treatment, and/or prevention of devehapmental diseases and disorders, including cancer, and other proIiferative conditions. Representative uses are described in the "Hyperproliferative Disordlers" and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation and/or apoptosis in pattern formation.
Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to. control cell and tissue type specification.
Therefore, the polynucleotides and polypeptides of the present invention are useful in treating, detecting, and/or preventing said disorders and conditions, in addition to other types of degenerative conditions.. Thus this protein may modulate apoptosis or tissue WO 00/04140 PCTlUS99/15849 differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may aIso~be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to iits use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above ii~sted tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ iD N0:44 and may have been publicly available prior to conception of the present invention. Preferably, such related palynucleotides are specifically 1S excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly" preferably excluded from the present invention are one or more potynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1248 of SEQ 1D N0:44, b is an integer of 1S to 1262, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:44, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 35 This gene is expressed primarily in colon.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types}
present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders and/or defects of the digestive tract including but not limited to cancers of the gastrointestinal tract. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing irnmunological probes for differential identification of the tissues) or cell type(s). Far a number of disorders of the above tissues or cells, particularly of the digestive system, expression of this gene ai significantly higher or iowe;r levels is routinely detected in certain tissues or cell types (e.g., gastrointestinal, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the digestive system particulary disorders involving the colon. Further, expression of this IO gene product in colon tissue indicates involvement in digestion, processing, and elimination of food, as well as a potential role for this gene as a diagnostic marker or causative agent in the development of colon cancer, and cancer in general.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy tarl;ets for the colon and/or other gastrointestinal tissue 15 including, but not limited t:o, stomach, small intestine, large intestine, and rectum.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ >D N0:45 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically 20 excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more poiynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is -any integer between 1 to 503 of SEQ ID N0:45, b is an integer of 15 to 517, where both a and b correspond to the positions of nucleotide 25 residues shown in SEQ IDS N0:45, and where b is greater than or equal to a + 14.
FEATURES OF PROT>E;IN ENCODED BY GENE NO: 36 This gene is expre~>sed primarily in blood cells.
Therefore, polynuc:leotides and polypeptides of the invention are useful as 30 reagents for differential identification. of the tissue{s) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune and hematopoietic diseases. Similarly, polypeptides and antibodies directed to thesf; polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune and hematopoietic system, expression of this ;gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or IO bodily fluid from an individual not having the disorder.
Preferred polypeptiides of the present invention comprise immunogenic epitopes shown in SEQ ID~ NO: 138 as residues: Pro-19 to Cys-29, Thr-35 to Glu-44, Vai-72 to Lys-78. Polynuc.leotides encoding said polypeptides are also provided.
The tissue distribul:ion indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis andlor treatment of disorders of the immune and hematopoietic system. Representative uses are described in the "Immune Activity" .and "infectious disease" sections below, in Example 11, 13, 14, 16, 18, 19, 20, and 27, and eisewh~ere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival;
differentiation; and/or activation of hematopoietic cell lineal;es, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Many polynucleotiide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:46 and may have been publicly available prior to conception of the present invention. Preferably, such related poiynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 844 of SEQ ID N0:46, b is an WO 00/04140 PCT/US99/15$49 integer of 15 to 858, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:46, and where b is greater than or equal to a +
14.
FEATURES OF PROTEItN ENCODED BY GENE NO: 37 This gene is expressed in multiple tissue systems such as brain, immune cells, prostate, uterus, testes, placenta, and festal heart as well as in cancerous tissues such as ovarian tumors. .
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differeintial identification of the tissues) or cell types) present:in a 10 biological sample and for dliagnosis of diseases and conditions which include, but are not limited to, disorders of the immune, reproductive, urogenital, and central nervous system. Similarly, polypepvtides and antibodies directed to these poIypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). Fox a number of disorders of the above tissues or cells, 15 particularly of the central nervous sytem and immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, reproductive, urogenital, cancerous and wounded tissues) or bodily fluids (e.g., lymph, ;serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative 20 to the standard gene expre:~sion level, i.e:, the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 139 as residues: Tyr-33 to Lys-38.
Polynucleotides encoding said polypeptides are also provided.
25 The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the immune, urogenital, reproductive, andl central nervous systems. The tissue distribution in central nervous system tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and/or diagnosis 30 of diseases of the central nervous system, as well as cancers of tissues where expression of this gene ha:. been observed, such as in ovarian tumors. The tissue distribution in central nervous system tissues also indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioural disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, S schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses, autism, and altered.behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, the gene or gene product may also play a role in the treatment andlor detection of developmental disorders associated with the developing embryo. . Protein, as well as, antibodies directed against the protein 7may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Moreover, the expression within embryonic tissue and other cellular sources marked by proliferating cells indicates this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment, andlor prevention of developmental diseases and disorders, including cancer., and other proIiferative conditions.
Representative uses are described in the "Hyperprolliferative Disorders" and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation andlor apopt:osis in pattern formation.
Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acduired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucieotides and polype;ptides of the present invention are useful in treating, detecting, andlor preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation c~f cellular growth and proliferation.
Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to 'its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. The tissue distribution in uterus indicates that polynucleotides and polypeptides corresponding to this gene are useful for treating female infertilivty: The protein product is likely involved in preparation of IO the endometrium of implantation and could be administered either topically or orally.
Alternatively, this gene could be transfected in gene-replacement treatments into the cells of the endometrium and the protein products could be produced.
Similarly, these treatments could be performed during artificial insemination for the purpose of increasing the likelyhood of implantation and development of a healthy embryo.
In IS both cases this gene or its a;ene product could be administered at later stages of pregnancy to promote heathy development of the endometrium. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. The tissue distribution in testes indicates that polynucleotides and polypeptides corresponding to this gene are useful 20 for the treatment and diagnosis of conditions concerning proper testicular function (e.g. endocrine function, sperm maturation), as well as cancer. Therefore, this gene product is useful in the treatment of male infertility and/or impotence. This gene product is also useful in aa;says designed to identify binding agents, as such agents (antagonists) are useful as male contraceptive agents. Similarly, the protein is 25 believed to be useful in the treatment andlor diagnosis of testicular cancer. The testes are also a site of active gene expression of transcripts that is expressed, particularly at low levels, in other tissue, of the body. Therefore, this gene product is expressed in other specific tissues or organs where it may play related functional roles in other processes, such as hematopoiesis, inflammation, bone formation, and kidney function, 30 to name a few possible target indications. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:47 a.nd may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides compzising a nucleotide sequence desczibed by the general formula of a-b, where a is any integer between 1 to 6093 of SEQ ID N0:47, b is an integer of 15 to 6107, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:47, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 3S
IS This gene is expressed in a wide range of tissue systems such as brain, immune cells, fetal liver, kidney, testes, breast, and pancreas as well as cancerous tissue such as ovarian tumors.
Therefore, polynuc(eotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders of the central nervous systern, immune system, urogenital, and reproductive system. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing irnmunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune and central nervous system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, CNS, urogenital, reproductive, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.

WO 00!04140 PCTNS99/15$49 Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 140 as residues: Met-1 to Ser-7, Asp-32 to Pro-43, Ser-96 to Arg-102. Polynucleotides encoding said polypeptides are also provided.
The tissue distribution indicates that polynucieotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the immune, reproductive, urogenital and central nervous systems. The tissue distribution in central nervous system tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful for the treatment and/or diagnosis of diseases of the central nervous system, as well as cancers of tissues where expression of this gene has. been observed, such as in ovarian tumors. The tissue distribution in central nervous system tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful for the detection/treatment of neurodegenerative disease states and behavioural disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. The tissue distribution indicates polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders.
Representative uses are described in the "Immune Activity" and "infectious disease"
sections below, in ExamplE; 11, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein.
Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; differentiation; and/or activation of hematopoietic cell lineages, including blond stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is e~:pressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also useful as an agent for immunological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cyt~~toxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimmune infertility, Tense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's 5 Disease, and scleroderma. P~Ioreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury. Thus, this gene product is thought to be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation andlor proliferation of various cell types.
Furthermore, the 10 protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to iits use as a imtritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above lusted tissues. Moreover, the expression within 15 embryonic tissue and other cellular sources marked by proliferating cells indicates this protein may play a role: in the regulation of cellular division, and may show utility in the diagnosis, treatment, and/or prevention of developmental diseases and disorders, including cancer, and other proliferative conditions.
Representative uses are described in the "Hyperproliferative Disorders" and "Regeneration" sections below 20 and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation andlor apoptosis in pattern formation.
Dysregulation of apoptosis cam result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired imrnunodeficiency and certain 25 neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucle0tides and poiypeptides of the present invention are useful i:n treating, 30 detecting, andlor preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this ~arotein may modulate apoptosis or tissue WO 00!04140 PCT/US99115849 differentiation and is useful in the detection, treatment, andlor prevention of degenerative or proliferative conditions and diseases.
The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues.
The protein can also be used te~ gain new insight into the regulation of cellular growth and proliferation: Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunothe,rapy targets. for the above listed tissues.
Many polynucIeotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:48 .and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 689 of SEQ ID N0:48, b is an integer of 15 to 703, where both a and b correspond to the positions of nucleotide residues shown in SEQ IDS N0:48, and where b is greater than or equal to a +
14.
FEATURES OF PROT)E;IN ENCODED BY GENE NO: 39 This gene is expre:>sed primarily in macrophages and fetal cells and to a lesser extent in cancerous ovarian tissues.
Therefore, polynuc:Ieotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune diseases, disorders of developing tissues, and cancer.
Similarly, polypeptides an,d antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of tlhe above tissues or cells, particularly of the fetal and immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful fox treatment and diagnosis of developmental abnormalities and disorders of the immune systems. The tissue distribution cancerous ovaries indicates that poiynucleotides and palypeptides corresponding to this gene are useful for the diagnosis and intervention of these tumors. Protein, as well as, antibodies directed against the protein may show utility as a tissue-specific marker andlor immunotherapy target for the above listed tissues. Expression of this gene product in macrophage cellls strongly indicates a role for this protein in immune function and immune surveillance. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune responses).
This gene product may have clinical utility in the treatment of immune dysfunction; in the correction of autoimmunitv; in immune modulation; and in the control of inflammation.
The tissue distribution indicates polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders. Representative uses are described in the "immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; differentiation;
and/or activation of hematopoietic: ceil lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting, a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is a;cpressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also useful as an agent for immunological disorders including an:hritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granuiomatau's Disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity IO disorders, such as autoimmune infertility, tense tissue injury, demyelination, systemic lupus erythernatosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderma. Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury. Thus, this gene product is thought to be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Moreover, the expression within embryonic tissue and other cellular sources marked by proliferating cells indicates this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment, and/or prevention of developmental diseases and disorders, including cancer, and other proliferative conditions. Representative uses are described in the "Hyperproliferative Disorders"
and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions irmolving cell differentiation and/or apoptosis in pattern formation.
Dysregulation of a~poptosis can result in inappropriate suppression of cell death, as occurs in the development o:f some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to~ control cell and tissue type specification.
Therefore, the polynucleotides and polype;ptides of the present invention are useful in treating, detecting, andlor preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proIiferative conditions and diseases. The protein is useful in modulating the immune re:>ponse to aberrant polypeptides, as may exist in proliferating and cancerous; cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may also be used to determine biological activity, .ta raise antibodies, as tissue markers, to isolate cognate Iigands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlar immunotherapy targets for the above listed tissues. The tissue distribution also indicates that poIynucleotides and poiypeptides corresponding to this gene are useful for the treatment, diagnosis, andlor prevention of various skin disorders such as melanomas.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:49 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope oiF the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 625 of SEQ ID N0:49, b is an integer of 15 to 639, where; both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:49, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 40 This gene is expressed primarily in neutrophils, bone marrow, brain, and fetal cells.

Therefore, polynucl'.eotides and polypeptides of the invention are useful as reagents for differential identification oaf the tissues) or cell types) present in a biological sample and for dfiagnosis of diseases and conditions which include, but are not limited to, hematopoietic disorders, Limbic system disfunction/defects and 5 disorders of the immune system and developing systems. Similarly, poiypeptides and antibodies directed to these: polypeptides are useful in providing immunological probes for differential idenvtification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune, Limbic system and developing systems, expression of this gene at significantly higher or lower levels is i0 routinely detected in certain tissues or cell types (e.g., immune, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
15 Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 142 as residues: Ala-84 to Gln-93.
Polynucleotides encoding said polypeptides are also provided.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for treatment and diagnosis of disorders of the 20 immune, Limbic system, C'NS and developing systems. Expression of this gene product in bone marrow, eosinophils, and neutrophils strongly indicates a role for this pmtein in hematopoiesis and immune surveillance. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes that may also suggest a usefulness in the treatment of cancer (e.g. by boosting immune 25 responses). This gene product may have clinical utility in the treatment of immune dysfunction; in the correction of autoimmunity; in immune modulation; and in the control of inflammation. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues. The tissue distribu~.tion indicates polynucleotides and polypeptides 30 corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders. Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16, I8, 19, 20, and 27, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; differentiation;
andlor activation of hematopoietic cell lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting; a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also useful as an agent for immunological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheurr~atoid arthriitis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne, neutropemia, neutrophilia> psoriasis;
hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimrnune infertility, tense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderrna. Moreover, the protein may represent a secreted factor that influences the differentiatiion or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury.
Thus, this gene product is thought to be useful in the expansion of stem cells and committed progenitors of various blood Iineages, and in the differentiation and/or proliferation of various cell types. Furthermore, the protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to idc;ntify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues. Additionally, the expression within embryonic tissue and other cellular sources marked b;y proliferating cells indicates this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment, and/or prevention of developmental diseases and disorders, including cancer, and other proliferative conditions: Representative uses are described in the "Hyperproliferative Disorders" and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation and/or apoptosis in pattern formation.
Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy {SMA). Because of potential roles in proliferatiion and differentiation, this gene product may have applications in the adult foo tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polype;ptides of the present invention are useful in treating, detecting, and/or preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune re:cponse to aberrant polypeptides, as may exist in proliferating and cancerou:e cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor maxker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:50 a.nd may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 853 of SEQ ID N0:50, b is an integer of IS to 867, where; both wand b correspond to the positions of nucleotide residues shown in SEQ ID NO:SO, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 41 This gene is expressed primarily in ovary and to a lesser extent in fetal tissue, colon, and immune cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, ovarian cancer, gastrointestinal and immune system disorders.
Similarly, polypeptides arnd antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the female reproductive system, expression of this gene at significantly higher or lower 1S levels is routinely detectedi in certain tissues or cell types (e.g., reproductive, gastrointestinal, immune, cancerous arid wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovia:l fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise irnrnunogenic epitopes shown in SEQ IDS NO: 143 as residues: IIe-23 to Ala-29.
Polynucleotides encoding said polypeptides are also provided.
The tissue distribution indicates that palynucleotides and polypeptides 2S corresponding to this gene are useful for diagnosis and treatment of ovarian cancer and related metastases. The tissue distribution indicates that polynucleotides and poiypeptides corresponding to this gene are useful for treating female infertility. The tissue distribution in colon tissues indicates that polynucleotides and poiypeptides corresponding to this gene; are useful for the diagnosis and/or treatment of disorders involving the gastrointestinal tract. This may include diseases associated with digestion and food absorpation, as well as hematopoietic disorders involving the Peyer's patches of the small intestine, or other hematopoietic cells and tissues within the body. Similarly, expre:;sion of this gene product in colon tissue indicates again involvement in digestion, processing, and elimination of food, as well as a potential role for this gene as a diagnostic marker or causative agent in the development of colon cancer, and cancer in general. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues. Moreover, the expression within embryonic tissue and other cellular sources marked by proliferating cells indicates this protein may play a role in the regulation of cellular division; and. may show utility in the diagnosis, treatment, andlor prevention of developmental diseases and disorders, including cancer, and other proiiferative conditions. Representative uses are described in the "Hyperproliferative Disorders" and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation andlor apoptosis in pattern formation.
Dysregulation of alyoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the palynucleotides and polypeptides of the present invention are useful in treating, detecting, and/or preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, andlor prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate. ligands or receptors, to identify agents that modulate their ioo interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleoti~de sequenct;s, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:S1 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 1SSS of SEQ ID NO:S1, b is an integer of iS to 1569, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:S 1, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 42 The translation product of this gene shares sequence homology with retrovirus-related reverse transcriptase pseudogene. In addition, this gene shares homology with human interferon-beta (Genseq accession number T3SS24; all references available throu~;h this accession are hereby incorporated herein by reference), therefore, it is likely that this gene and the protein encoded by this gene shares some similar biological functions with this protein.
This gene is expressed primarily in frontal cortex.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a 2S biological sample and for diagnosis of diseases and conditions which include, but are not limited to, neurodegern~rative diseases and/or disorders. Similarly, polypeptides and antibodies directed to ' hese polypeptides are useful in providing immunological probes for differential identification of the tissue{s) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nervous system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell type:. (e.g., neural, cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual rat having the disorder.
The tissue distribution in frontal cortex and homology to retrovirus-related reverse transcriptase pseudlogene and human interferon=beta indicates that polynucleatides and polypeptides corresponding to this gene are useful for diagnosis and treatment of neurodegenerative diseases of the brain, particularly of the frontal cortex. The tissue distribution indicates palynucleotides and polypeptides corresponding to this gene are useful for the detection, treatment, and/or prevention of neurodegenerative disease states, behavioral disorders, or inflammatory conditions.
Representative uses are described in the "Regeneration" and "Hyperproliferative Disorders" sections below" in Example 11, 15, and 18, and elsewhere herein.
Briefly;
the uses include, but are not limited to the detection, treatment, and/or prevention of Alzheimer's Disease, Parkinson's Disease, multiple schlerosis, cystic fibrosis, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neaplasia, trauma, congenital malformations, spinal card injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic disorder, learning disabilities; ALS, psychoses, autism, and altered behaviors, including disorders in feeding, steep patterns, balance, and perception. bn addition, elevated expression of this gene product in regions of the brain indicates it plays a role in normal neural function.
Potentially, this gene product :is involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands ar receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein rriay show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.

WO 00/04140 PC1'/US99/15$49 t02 Many potynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:52 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope o~f the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between I to 1182 of SEQ ID N0:52, b is an integer of 15 to 1196, where both a and b correspond to the positipns of nucleotide residues shown in SEQ ID N0:52, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 43 This gene is expressed primarily in immune cells, brain, fetal tissue, and cancerous tissues (such as testes, stomach, lung, pancreas, ovaries) and to a lesser ~ extent in other numerous tiissues including, but not limited to, testes and kidney.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential idc,ntification of the tissues) or cell types) present in a biological sarnpie and for diagnosis of diseases and conditions which include, but are not limited to, neurodegenerative diseases. Similarly, polypeptides and antibodies directed to these polypepti~des are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nervous system and immune cells expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell type~c (e.g., cancerous and wounded tissues} or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptiides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 145 as residues: Lys-23 to Lys-35, Met-46 to Tyr-52.
Polynucleotides encoding said polypeptides are also provided.

The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosis and treatment of neurodegenerative disorders of the frontal cortex, as well as, cancer or a number of tissues including but not limited to testes, stomach, lung, pancreas, and ovaries. The tissue distribution indicates polynucleotides and poIypeptides corresponding to this gene are useful for the detection, treatment, and/or prevention of neurodegenerative disease states, behavioral disorders, or inflammatory conditions.
Representative uses are described in the "Regeneration" and "Hyperproliferative Disorders"
sections below, in Example 11, 1S, and 18, and elsewhere herein. Briefly, the uses include, but are not limited to the detection, treatment, and/or prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinatin;; diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic: disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, elevated expression of this gene product in regions of the brain indicates it plays a role in normal neural function.
Potentially, this gene product its involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker a.nd/or immunotherapy targets for the above listed tissues.
The tissue distribution indicates polynucleotides and polypeptides corresponding to this gene are useful for the. diagnosis and treatment of a variety of immune system disorders. Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, I4, 16, 18, 19, 20, and 2'7, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; difFerentiation; and/or activation of hematopoietic cell lineages, including blood stem cells. 'This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene S product is involved in immune functions. Therefore it is also useful as an agent for immunalogicaI disorders including arthritis, asthma, immunodeficiency diseases such as AB~S, leukemia, rheumatoid arthr7itis; granulomatou's Disease, inflammatory bowel disease, sepsis, acne; neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated c~~totoxicity; immune reactions to transplanted organs arid tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimrnune infertility, Tense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderma. Moreover, the protein may represent a secreted factor that influences the differentiatiion or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury. Thus, this gene product is thought to be useful in the expansion of stem c:eils and committed progenitors of various blood lineages, and in the differentiation andlor proliferation of various cell types.
Furthermore, the protein may also be used t:o determine biologic~i activity, raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. Moreover, the expression within embryonic tissue and other cellular sources marked by proliferating cells indicates this protein may play a roiie in the regulation of cellular division, and may show utility in the diagnosis, treatment, and/or prevention of developmental diseases and disorders, including cancer, and other proiiferative conditions.
Representative uses are described in the "Hypezproliferative Disorders" and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation andlor apolatosis in pattern formation.
Dysregulation of a.poptosis ca.n result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent WO 00/04140 PCT/US99/i5849 of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polypeptides of the present invention are useful in treating, detecting, and/or preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognatE; ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:53 .and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly', preferably excluded from the present invention are one or more polynucIeotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer' between 1 to 931 of SEQ ID NO:53, b is an integer of 15 to 945, where both a and b correspond to the positions of nucleotide residues shown in SEQ IDS N0:53, and where b is greater than or equal to a +
14.
FEATURES OF PROTI?:IN ENCODED BY GENE NO: 44 This gene is expressed primarilly.in epithelioid sarcoma and to a tenser extent in pancreatic carcinoma, aorta endothelial cells induced with TNF-alpha, and amniotic cells induced with TNF. This gene is also expressed, to a lesser extent, in cancerous lung and ovary tissue and festal tissue.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification ~of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to; epithelioid sarcoma and related cancers. Similarly, polypeptides and .' antibodies directed to these; polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., cancerous and wounded tissues) or bodily fluids (e.g., amniotic, lymph, serum, plasma, urine;, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypepti.des of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 146 as residues: Tyr-39 to Arg-51.
Polynucleotides encoding said polypeptide;~ are also provided.
The tissue distribution indicates that polynucleotides and polypeptides corresponding to this gene are useful iFor diagnosis and treatment of certain cancers, including epithelioid sarcoma and pancreatic carcinoma. The tissue distribution in tumors of lung, ovary, and pancreas origins indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and intervention of these tumors, in addition to other tumors where expression has been indicated.
Protein, as well as, antibodies directed against the protein may show utility as a tissue-specific marker and/or immunotherapy target for the above listed tissues.
Moreover, the expression within embryonic tissue and other cellular sources marked by proliferating cells indicates this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment, and/or prevention of developmental diseases and disorders, including cancer, and other praliferative conditions. Representative uses are described in the "Hyperproliferative Disorders"
and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell: differentiation and/or apoptosis in pattern formation.
Dysregulation of ap~optosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferatiion and differentiation, this gene product may have applications in the adult for° tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polype;ptides of the present invention are useful in treating, detecting, and/or preventing said disorders and conditions, in addition to other types of,degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate Iigands or :receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues. The tissue distribution indicates polynucleotides and polypc:ptides corresponding to this gene are useful for the diagnosis and treatment of a variety of immune system disorders.
Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation;
survival; differentiation; and/or activation of hematopoietic cell lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also useful as an agent for immunological disorders including artlhritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulornatou's Disease, inflammatory bowel disease, sepsis, acne, neutropen:ia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus,-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimmmne infertility, Tense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderma. Moreover, t:he protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits 1S hematopoietic cells to sites. of injury. Thus, this gene product is thought to be useful in the expansion of stem ce;Ils and committed progenitors of various blood lineages;
and in the differentiation a:nd/or proliferation of various cell types.
Furthermore, the protein may also be used to deternnine biological activity, raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleoti~de sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are 2S related to SEQ ID NO:S4 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucIeotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 474 of SEQ ID NO:S4, b is an integer of 15 to 488, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:54, and. where b is greater than or equal to a +
14.
FEATURES OF PROTEIfN ENCODED BY GENE NO: 45 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
PPVPPWISLPLTGSPPRP~GFVPVSPFCFSPMTNGHQVLLLLLLTSAVAAGPWPQ
VHAGQWGWMCLPPGLPSVQARSGLGGLPGGPQWVPGGARGY {SEQ ID NO:
234). Polynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in fetal and infant tissue, particularly infant brain and fetal Iiverlspleen libraries, and to a lesser extent in breast, ovary tumor, pharynx carcinoma, endometrial stromal cells, thymus, islet cell tumors, and adult cerebellum.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for d',iagnosis of diseases and conditions which include, but are not limited to, cancer and other proliferative disorders. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing irnmunological probes for differential identification of the tissue{s) or cell type(s). For a number of disorders of the above tissu~.es or cells, particularly of the brain and breast, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, developmental, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, amniotic fluid, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distributiion in developing cells and tissues indicates that polynucleotides and polype;ptides corresponding to this gene are useful far diagnosis WO 00104140 PCT/US99l15849 and treatment of cancer and other proliferative disorders. The expression within cellular sources marked by proliferating cells indicates this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment, andlor prevention of developmental diseases and disorders, including cancer, and other proliferative conditions. Representative uses are described in the "Hyperproliferative Disorders" and "R.egeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation and/or apoptosis in pattern formation.
Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed. to occur in acquired immunodeficiency arid certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucIeotides and polypc~ptides of the present invention are useful in treating, detecting, and/or preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutnitionai supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Same of these sequences are related to SEQ ID NO:55 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2846 of SEQ ID N0:55, b is an integer of I5 to 2860, where both a and b correspond to the positions of nucleotide residues shown in SEQ iD N0:55, amd where b is greater than or equal to a +
14.
FEATURES OF PROTE',IN ENCODED BY GENE NO: 46 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
IQQWGDSVLGRRCRDLLLQLYL~>RPELRVPVPEVLLHSEGAASSSVCKLDGLI
HRFITLLADTSDSRALENRGADASMACRKLAVAHPLLLLRHLPMIAALLHGR
THLNFQEFRQQNHLSC:FLHVLGLLELLQPHVFRSEHQGALWDCLLSFIRLLLN
YRKSSRHLAAFINKFV(ZFIHKYIT'YNAPAAISFLQKHADPLHDLSFDNSDLVM
LKSLLAGLSLPSRDDR7.'DRGLDEEGEEESSAGSLPLVS VSLFTPLTAAEMAPY
MKRLSRGQTVEDLLEVLSDIDEMSRRRPEILSFFSTNLQRLMSSAEECCRNLA
FSLALRSMQNSPSIAAA.FLPTFMY'CLGSQDFEVVQTALRNLPEYALLCQEHA
AVLLHRAFLVGMYGQMDPSAQISEALRILHMEAVM (SEQ ID NO: 235).
Polynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in breast cancer, and to a lesser extent in a variety of other cancers, including uterine cancer, synovial sarcoma, and pharynx carcinoma.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell types) present in a biological sample and for diagnosis oiF diseases and conditions which include, but are not limited to, breast cancer; proliferative diseases andlor disroders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the breast, expression of this gene at siignifacantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., reproductive, breast, proliferative, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, breast milk, urine, synovial fluid and spinal fluid) or anotiher tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual eat having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 148 as residues: Glu-35 to His-41, Ser-62 to Ala-67, Pro-I45 to Leu-155, Glu-I:57 to Ser-lfi3, Arg-190 to Val-197, Asp-208 to Pro-215, Ser-247 to Pro-252. Polynu~cleotides encoding said polypeptides are also provided.
The tissue distribution in breast cancer tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful far the diagnosis andlor treatment of cancer. Elevated expression of this gene product in cancers, such as breast cancer, suggest that lit is involved in the abnormal proliferation of cells, dedifferentiation, angiogenesis, and other processes that accompany the development of cancer. Thus, therapeutics targeted against this gene product is useful therapeutic products in and of themselves. Alternately, expression of this gene product at elevated levels in breast tissue is reflective of expression within breast lymph nodes, and may suggest a hematopoietic rolfe for this protein. Representative uses are described in the "Hyperproliferative Disorders" and "Regeneration" sections below arid elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation and/or apoptosis in pattern formation.
Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired imrnunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polype:ptides of the present invention are useful in treating;
detecting, and/or preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerou,~ cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may also be~ used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may shave utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:56 amd may have been publicly available prior to conception of the present invention. PrefE:rably, such related polynucIeotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly" preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is ;any integer between 1 to 1545 of SEQ ID N0:56, b is an integer of 15 to 1559, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:56, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 47 The translation product of this gene shares limited sequence homology with cytochrome-c oxidase. An alternative embodiment is the polypeptide comprising the following amino acid sequence:
MLLKHLQRMVSVPQVI~ASALKV VTLTANDKTS VSFSSLPGQGVIYNVIVWD
PFLNTSAAYIPAHTYAC'.SFEAGEGSCASLGRVSSKVFFTLFALLGFFICFFGHR
FWKTELFFIGFIIMGFFF'YILITRLTPIKYDVNLILTAVTGSVGGMFLVAVWWR

ll4 FGILSICMLCVGLVLGFLISSVTFFTPLGNLKIFHDDGVFWVTFSCIAILIPVVF
MGCLRILNILTCGVIGSYSVVLAIDSYWSTSLSYITLNVLKRALNKDFHRAFTN
VPFQTNDFIILA V WGNLLA V SGITLQIRRERGRPFFPPHPYKLWKQERERRVTNI
LDPSYHIPPLRERLYGRLTQIKGLFQKEQPAGERTPLLL (SEQ ID NO: 236).
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
WARLRGPGAHARTSPQPWRGPSPAQAAMGFLQLLV VXVLXSEHRVAGAAE .
VFGNSSEGLIEFSVGKFRYF
ELNRPFPEEAILHI~ISSNVTFLIFQIHSQYQNTTVSFSPRRRSPTM (SEQ ID NO:
237). Polynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in keratinocytes, brain, and spinal card and to a lesser extent in hematopoietic cells and tissues.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis oi" diseases and conditions which include, but are not limited to, neurodegenerative disorders; hematopoietic disorders;
integumentary disroders; immune dysfunction; learning disabilities. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing 'immunological probes for differential identification of the tissue{s) or cell type(s). For a number of disorders of the above tissues or cells" particularly of the immune and nervous systems, expression of thi~o gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., integumentary, neural, developmental, cancerous and wounded ti:>sues) or bodily fluids {e.g., lymph, serum, plasma, urine, synoviaI fluid and spinal fluid} or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in brain and spinal cord cells and tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of a variety of neurological and hematopoietic disorders. For example, elevated levels of expression of this gene product in brain and spinal cord indicates that it is involved in neurode:generative disorders. Representative uses are described in the "Regeneration" and "Hyperproliferative Disorders" sections below, in Example i 1, 15, and 18, and elsewhere herein. Briefly, the uses include, but are not limited to the detection, treatment, andlor prevention of Alzheimer's Disease, Parkinson's Disease, Huntiangton's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischernia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic: disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, elevated exprEasion of this gene product in regions of the brain indicates it plays a role in normal neural function.
Potentially, this gene product is involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Alternately, expression of this gene product in hematopoietic cells indicates that it is involved in the proliferation, differentiation, survival, and activation of all hematopoietic lineages, including stem and progenitor cells. Expression of this gene product in keratinocytes indicates that it is involved in normal skin function, and could be involved in sltin disorders, dermatitis, and fibrosis. The protein is useful in detecting, treating, andlor preventing congenital disorders (i.e. nevi, moles, freckles, Mongolian spots, hemangi.omas, port~~wine syndrome), integumentary tumors (i.e.
keratoses, Bowen's Disease, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Paget's Disease, mycosis fungoides, and Kaposi's sarcoma), injuries and inflammation of the skin (i.e.wounds, rashes, prickly heat disorder, psoriasis, dermatitis}, atherosclerosis, uticaria, eczema, photosensitivity, autoimmune disorders (i.e. lupus erythe;matosus, vitiligo, dermatomyositis, morphea, scleroderma, pemphigoid, and pemphigus), keloids, striae, erythema, petechiae, purpura, and xanthelasma. In addition, such disorders may predispose increased susceptibility to viral and bacterial infections of the skin (i.e. cold sores, warts, chickenpox, molluscum contagiosurn, herpes zoster, boils, cellulitis; erysipelas, impetigo, tinea, althletes foot, and ringworm). Moreover, the protein product of this gene may also be useful for the treatment or diagnosis of various connective tissue disorders (i.e., arthritis, trauma, tendoniti;>, chrondomalacia and inflammation, etc.), autoimmune disorders (i.e., rheumatoid arthritis, lupus, scleroderma, denmatomyositis, etc.), dwarfism, spinal deformation, joint abnormalities, amd chondrodysplasias (i.e.
spondyloepiphyseal dysplasia congeniita, familial osteoarthritis, Atelosteogenesis type II, metaphyseal chondrodysplasia type Schmid). Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors> to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleoride sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:57 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 2050 of SEQ ID N0:57, b is an integer of 15 to 2064, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:57, and where b is greater than or equal to a +
14.
FEATURES OF PROTE',IN ENCOIDED BY GENE NO: 48 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
PRVRPASPPVRSPARWGSMAGSPLLWGPRAGGVGLLVLLLLGLFRPPPALCA
RPVKEPRGLSAASPPLARLALLAASGGQCPEVRRRGRCRPGAGAGASAGAER

1i7 QERARAEAQRLRISRRASWRSCCASGAPPATLIRLWAWTTTPTRLQRSSLALC
SAPALTLPP (SEQ ID NO: 238). Pol;ynucleotides encoding these polypeptides axe also provided.
This gene is expressed primarily in human pituitary and to a lesser extent in pineal gland, and other areas of the brain.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential idc;ntification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, pituitary dysfunction; abnormal growth; neurological defects;
insufficient milk secretion:; abnormal smooth muscle contraction. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endocrine and nervous systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues ar cell types (e.g., endocrine, developmental, reproductive, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, amniotic fluid, breast milk, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expre;~sion level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypepti~,des of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 150 as residues: Pro-36 to GIy-42, Pro-64 to Ala-76, Gly-83 to Ala-90, Ser-100 to Cys-108, Thr-126 to Ser-135. Polynucleotides encoding said polypeptides are also provided.
The tissue distribution primarily in pituitary cells and tissues indicates that polynucleotides and polyp~eptides corresponding to this gene are useful for the diagnosis and/or treatment of a variety of disorders. Elevated expression of this gene product in the pituitary indicates that 'r.t is possibly a hormone-like substance that either controls pituitary development iitself, or various processes controlled by the pituitary. These include growth, milk secretion, smooth muscle contraction, diuresis, blood pressure, and homeostasis. Thus, this gene product may have numerous clinical applications. Expression oiF this gene product in other regions of the brain also indicates that it is involved! in normal neurological function, and is useful in the treatment of a variety of neurological disorders. Representative uses are described in the "Biological Activity", "Hyperproliferative Disorders", and "Binding Activity"
sections below, in Example 11, 17, 18, 19, 20 and 27, and elsewhere herein.
Briefly, the protein can be used for the detection, treatment, and/or prevention of Addison's Disease, Cushing's Syndrome, and disorders and/or cancers of the pancrease (e.g.
diabetes mellitus), adrenal cortex, ovaries, pituitary (e.g., hyper-, hypopituitarism), ' thyroid (e.g. hyper-, hypot4lyroidism), parathyroid (e.g. hyper-,hypoparathyroidism) , hypothallamus, and testes. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility Many polynucleoti~de sequencc;s, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:58 and may have been publicly available prior to conception of the present invention. Preferably, such related poiynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1036 of SEQ ID N0:58, b is an integer of 15 to 1050, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:58, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 49 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
PRVRLATPNIWDLSML:FAFISLLVMLPTWWIVSSWLVWGVILFVYLVIRALRL
PZ030PCT' WRTAKLQVTLKKYSVHI.EDMATNSRAFTNLVRKALRLIQETEVISRGFTLVS
AACPFNKAGQHPSQHLIGLRKA V YRTLRANFQAARLATLYMLKNYPLNSES
DNVTNYICVVPFKELGLGLSEEQISEEEAHNFTDGFSLPALKVLFQLWVAQSS
EFFRRLALLLSTANSPPtsPLLTPAL.LPHRILSD VTQGLPHAHSACLEELKRSYE
FYRYFETQHQSVPQCL;iKTQQKS12ELNNVHTAVRSLQLHLKALLNEVIILEDE
LEKLVCTKETQELVSEAYPILEQKLKLIQPHVQASNNCWEEAISQVDKLLRRN
TDKKGKPEIACENPHC7uVSTFEAA~YSTHCRQRSNPRGAGIRSLCR (SEQ ID
NO: 239). Polynucleotides encoding these polypeptides are also provided.
The polypeptide of this gene has been determined to have a transmembrane domain at about amino acid position 7 - 23 of the amino acid sequence referenced in Table 1 for this gene. Morc;over, a cytoplasmic tail encompassing amino acids 24 to 390 of this protein has also been determined. Based upon these characteristics, it is believed that the protein product of this gene shares structural features to type Ib membrane proteins.
The gene encoding the disclosed cDNA is believed to reside on chromosome 12. Accordingly, polynuclc;otides related to this invention are useful as a marker in linkage analysis for chromosome 12.
This gene is expressed primarily i:n prostate and placenta and to a lesser extent in pancreatic tumors and hematopoietic cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential idc;ntification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, hut are not limited to, prostate cancer; pancreatic cancer; prostate dysfunction;
hematopoietic disorders; reproductive diseases and/or disorders, and pancreatitis.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the endocrine and immune systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., reproductive, prostate, pancease, placental, vascular, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, seminal fluid, plasma, urine, synovial fluid and spinal fluid} or another tissue or cell sample: taken from an individual having such a disorder, relative to the standard gene expression Level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID 110: 151 as residues: Pro-85 to Ser-94, Pro-127 to Thr-136, Glu-154 to Glu-160, Phe-240 to Ser-250, Leu-255 to Leu-265, Leu-341 to Lys-351, Thr-372 to GIy-384. Polynucleotides encoding said poiypeptides are also provided.
The tissue distribution in prostate and placental ells and tissues; indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and/or treatment of a variety of reproductive disorders. Elevated expression of this gene product in the prostate indicates that it is involved in normal prostate function, and is a diagnostic: marker for prostate cancer. Alternately, expression of this gene product in placenta indicates that it may play a role in normal vascular I5 function, and is involved in such processes as angiogenesis and endothelial cell chemotaxis. Thus, this gene product is useful in the treatment of myocardial infarction, cancer, ischemia, and diabetic retinopathy. Expression of this gene product in placenta may also be indicative of fetal health and development.
Similarly, expression of this gene product in hematopoietic cells indicates that it is involved in the proliferation, differentiation, survival, or activation of all hematopoietic cell lineages,. Finally, expression of this gene product in pancreatic cancers indicates that it may play a roll; in cancer in general, or in pancreatic function.
The secreted protein can al:co be used to determine biological activity, to raise antibodies, as tissue marker's, to isolate cognate iigands or receptors, to identify agents that modulate their interactions, and as nutritional supplements. It may also have a very wide range of biological activities. Representative uses are described in the "Chemotaxis" and "Binding; Activity" sections below, in Examples 11, 12, 13, 14, 15, 16, 18, 19, and 20, and elsewhere hereiin. Briefly, the protein may possess the following activities: cytokine, cell proliferation/differentiation modulating activity or induction of other cytokines; immunostimulating/immunosuppressant activities (e.g.
for treating human immunodeficiency virus infection, cancer, autoimmune diseases WO 00/04140 PC1'/US99/15849 12t and allergy); regulation of hematopoiesis (e.g. for treating anemia or as adjunct to chemotherapy); stimulation or growth of bone, cartilage, tendons, ligaments and/or nerves (e.g. for treating wounds, stimulation of follicle stimulating hormone (for control of fertility); chernotactic and chemokinetic activities (e.g. for treating infections, tumors); hemostatic or thrombolytic activity {e.g. for treating hemophilia, cardiac infarction etc.); anti-inflammatory activity (e.g. for treating septic shock, Crohn's Disease); as antimicrobials; for treating psoriasis or other hyperproliferative diseases; for regulation of metabolism,, and behavior. Also contemplated is the use of the corresponding nucleic acid in gene therapy procedures. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleoti~de sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:59 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded froth the scope o:f the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 2519 of SEQ ID N0:59, b is an integer of 15 to 2533, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:59, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 50 When tested against Jurkat and K562 cell lines, supernatants removed from cells containing this gene activated the GAS (gamma activating sequence) and ISRE
(interferon-sensitive responsive element ) promoter elements, respectively.
Thus, it is likely that this gene activates myeloid, leukemia, and to a lesser extent, other immune or hematopoietic cells and tissue cell-types, through the JAK-STAT signal transduction pathway. GA;S is a promoter element found upstream of many genes which are involved in the Jak-STAT pathway. The 3ak-STAT pathway is a large, signal transduction pathway involved in the differentiation and proliferation of cells.
~r, ~~.m~... .r _____ - _.. . ~ M ~ .__ WO 00104140 PCTlfJS99/15849 Therefore, activation of the Jak-STA T pathway, reflected by the binding of the GAS
element, can be used to indicate proteins involved in the proliferation and differentiation of cells. IS1RE is also a promoter element found upstream in many genes which are involved in the Jak-STAT pathway. The Jak-STAT pathway is a Iarge, signal transduction pathway involved in the differentiation and proliferation of cells. Therefore, activation of the Jak-STAT pathway, reflected by the binding of the ISRE element, can be used to indicate proteins involved in the proliferation and differentiation of cells.
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
AAPHPPLLRPLCLWCP:LWPAWPi.RGRPRSAWKRWPPLPVGPAKLGCSMTTR
QPTAVSWPCWLMSSSLSTACLAWTLTGSLAREATRRARSLSPTWNCSARQV
PPSPPHSGLGRRGWAHiCHLT CLLVTQLFRVGRIHPILSLPLVT (SEQ ID NCB:
240). PoIynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in brain and placenta.
Therefore, polynucaeotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell type{s) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, vascular diseases; aberrant angiogenesis; neurological disorders;
learning disorders; placental insufficiency; and fetal distress. Similarly, polypeptides and antibodies directed to these poIypeptides are useful in providing imniunological probes for differential identification of the tissues) or cell type(s). For a number of 2S disorders of the above tissues or cells, particularly of the vascular and neurological systems (CNSIPNS), expression of thus gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, reproductive, vascular, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 152 as residues: Met-1 to Thr-7, Glu-36 to Ser-43, Pro-46 to Gly-63. Polynucleotides encoding said polypeptides are also provided.
The,tissue distribuvtion in brain and placental cells and tissues, combined with the detected GAS and ISRE biological activties, indicates that the protein products of this gene are useful for the; diagnosis and/or treatment of a variety of neural, reproductive, and vascular diseases and/or disorders. neurodegenerative disease states, behavioral disorders, or inflammatory conditions. Representative uses are described in the "Regener;ation" and "'Hyperproliferative Disorders" sections below, in Example 11, 15, and 18, and elsewhere herein. Briefly, the uses include, but are not limited to the detection, treatment, and/or prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Di:>ease, Tourette Syndrome, meningitis, encephalitis, deinyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic disorder, learning disabilities, ALS, psychoses, autism, arid altered behaviors, including disorders in feeding, sleep patterns, balance, arid perception. In addition, elevated expression of this gene product in regions of the brain indicates it plays a role in normal neural function.
Potentially, this gene product is involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Expression of this gene product in placenta indicates that it may play a role in blood vessel developm~;nt or function, as the placenta is a highly vascularized organ. Thus, this gene product is involved in such processes as angiogenesis, endothelial cell chemotax:is, and vascular cord formation. Thus, it is useful in the treatment of such conditicms as myocardial infarction; ischemia; and cancer.
Alternately, expression of this gene product in the brain indicates that it may play a role in the survival, proliferation, or function of neurons, and thus is useful in the diagnosis and treatment of such neurological disorders as ALS, schizophrenia, and Alzheimer's Disease. It many likewise be involved in learning disorders as well.
Furthermore, the protein rrlay also be used to determine biological activity, to raise antibodies, as tissue rnarke;rs, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:60 and may have been publicly available. prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope o:f the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more poIynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between i to 885 of SEQ ID N0:60, b is an integer of 15 to 899, where: both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:60, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: S1 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Spec:i~cally, polypeptides of the invention comprise the following amino acid sequence:
LQLASQSAGIKGMSHC.ARPTFLTLLLASCFVVAAAIPNRNVILSV5FRPLHMQ
FTLSILVFILRILILLRSFL (SEQ ID NO: 241). Polynucleotides encoding these polypeptides are also proviided.
The polypeptide of this gene has been determined to have a transmembrane domain at about amino acid position 4~0 - 56 of the amino acid sequence referenced in Table 1 for this gene. Moreover, a cytoplasmic tail encompassing amino acids 57 to 60 of this protein has also 'been determined. Based upon these characteristics, it is believed that the protein product of this gene shares structural features to type Ia membrane proteins.

This gene is expressed primarily in spleen derived from patients with chronic Iymphocytic leukemia.
Therefore, polynucleotides and. polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, chronic lymlahocytic leukemia; hematopoietic disorders;
impaired immune function; cancer. :iimiIarly, palypeptides and antibodies directed to these polypeptides are useful in I>roviding innmunological probes for differential identification of the tissues} or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard I5 gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in spleen cells and tissues indicates that polynucleotides and polypc:ptides corresponding to this gene are useful for the diagnosis andlor treatment of a variety of hematopoietic disorders.
Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example I 1, 13, 14, 16, i8, 19, 20, and 27, and elsewhere herein. Briefly, the uses include bone marrow cell E;x-vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lyrnphopoiesis, therefore, it can be used in immune disorders ouch as infection, inflammation, allergy, imrnunodeficiency etc. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation andlor proliferation of various cell types. Elevated expression of this protein in the spleens of patients with CLL indicates that it is a useful marker for this Disease. Alternately, it is associated with the development and/or progression of the disease, and is a useful tar;~et for therapeutic intervention. Additionally, this gene product may play more general roles in hematopoiesis, and may serve to control cellular decisions regarding proliferation, survival, activation, andlor differentiation of all hematopoietic cell lir~eages. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as. a tumor marker. and/or immunotherapy targets for the above listed tissues.
Many polynucieotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:6I a.nd may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly" preferably excluded from the present invention are one or more poIynucleotides comoprising a nucleotide sequence described by the general formula of a-b, where a is ;any integer between 1 to 1065 of SEQ ID N0:61, b is an integer of I5 to 1079, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:61, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 52 The translation product of this gene shares sequence homology with a putative tyrosine protein kinase from the Chilo iridescent virus. See, for example, Genbank accession no. gi~273845 i (AF003534). Based on the sequence similarity, the translation product of this gene is expected to share at least some biological activities with tyrosine kinase and signaling proteins. Such activities are known in the art, some of which are described elsewhere herein.
This gene is expressed in a variety of tissues, including microvascular endothelial cells, dendritic cells, and fetal tissues. as well as several tumors.
Therefore, palynuc:leotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for .diagnosis of diseases and conditions which include, but are not limited to, vascular, irr~mune, and developmental diseases and/or disorders, particularly cancer. Similarly, palypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above S tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., vascular, immune, dE;velopmental, proliferative, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, amniotic fluid, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having IO such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptiides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 1S4 as residues: Ala-21 to Lys-31, Arg-41 to Cys-S6, Thr-92 to Cys-102, Arg-132 to Val-I3?, Lys-152 to Ile-159, Pro-199 to Ser-205, Arg IS 210 to Asp-219, Ser-22S to Lys-230, 'ryr-236 to Ala-241, Lys-243 to Leu-249, Thr 37S to Asp-381. Polynucle;otides encoding said polypeptides are also provided.
The tissue distribution and homology to a tyrosine kinase indicates that polynucleotides and polyp~eptides corresponding to this gene are useful for diagnosis and treatment of cancer. Representative uses are described in the "Immune Activity"
20 and "infectious disease" sections below, in Example 1 i, 13, I4, 16, 18, 19, 20, and 2?, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; .differentiation; and/or activation of hematopoi,etic cell lineage~s, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes 2S suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses}.
Since the gene is e:Kpressed in cells of lymphoid origin, the natural gene product is involved in irnrrrune functions. Therefore it is also useful as an agent for immunological disorders including arthritis, asthma, immunodeficiency diseases such 30 as AIDS, leukemia, rheumatoid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cy:otoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases; or autoimmunity disorders, such as autoimmune infertility, tense tissue injury, dernyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderma. ;Moreover, the protein may represent a secreted factor that influences the differentiation or behaviior of other blood cells, or that recruits hernatopoietic cells to sites of injury. Thus, this gene product is thought to be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation andlor proliferation of various cell types.
Alternatively, the protein is useful in the detection, treatment, and/or prevention of vascular conditions, which include, but are not :limited to, rnicrovascular disease, vascular leak syndrome, aneurysm, stroke, atherosclerosis, arteriosclerosis, or embolism. For example, this gene product may represent a soluble factor produced by smooth muscle that regulates the innervation of organs or regulates the survival of neighboring neurons.
Likewise, it is involved in controlling the digestive process, and such actions as peristalsis. Similarly, it is involved in controlling the vasculature in areas where smooth muscle surrounds the endothelium of blood vessels. Furthermore, the protein may also be used to deterrrune biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucieotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Same of these sequences are related to SEQ ID N0:62 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucieotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1914 of SEQ ID NO:62, b is an integer of 15 to 1928, where both a and h correspond to the positions of nucleotide residues shown in SEQ ID N0:62, and where b is greater than or equal to a +
I4.
FEATURES OF PROTEIN ENCODED BY GENE NO: 53 The polypeptide of this gene has been determined to have a transmembrane domain at about amino acid position 2 - 18 of the amino acid sequence referenced in Table 1 for this gene. Based upon these characteristics, it is believed that the protein product of this gene shares structural features to type Ib membrane proteins.
This gene is expressed primarily in neutrophils.
Therefore, polynuclleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune and hematopoietic diseases andlor disorders, particularly cancer and immune suppression. Simillarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid} or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ iD NO: 155 a s residues: Gly-63 to Ser-72.
Polynucleotides encoding said polypeptide:c are also provided.
The tissue distribution in neutrophils indicates that polynucleotides and polypeptides corresponding to this gene are useful as a marker for neutrophil monitoring in cancer and/or immune suppressed patients and/or during chemotherapy or radiation therapy. Representative uses are described in the °'Immune Activity" and "infectious disease" sections below, in. Example 11, 13, 14, I6, 18, 19, 20, and 27, and WO 00!04140 PCTIUS99/15849 elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation:; survival; differentiation; andlor activation of hematopoietic cell lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in t:he treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also useful as an agent for immunological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulomatau's Disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cptotoxicity; immune reactions to transplanted organs and tissues, such as host-versu:~-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimrriune infertility, tense tissue injury, demyelination, systemic lupus erythematosis, drug induced hernolytic anemia, rheumatoid arthritis, Sjagren's Disease, and scleroderma. Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hematopoietic cells to site:. of injury. 'Thus, this gene product is thought to be useful in the expansion of stem cE:lls arid committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Furthermore, the protein may also be used to determine biological acrivity, raise antibodies, as tissue markers, to isolate cognate. ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against: the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:63 .and may have been publicly available prior to conception of the present invention. Preferably, such related palynucleotides are specifically excluded from the scope o~f the present invention. To List every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 767 of SEQ ID N0:63, b is an integer of 15 to 781, where: bath a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:63, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 54 This gene is expressed primarily in IL-1 and LPS induced neutrophils, and to a lesser extent, in fetal brain.
Therefore, polynucaeotides and polypeptides of the invention are useful as reagents for differential id~~ntificatian of the tissues) or cell types) present in a biological sample and for.diagnosis of diseases and conditions which include, but are not limited to, immune, hematopoietic, and neural diseases and/or disorders, particularly cancer and immune suppression. Similarly, polypeptides and antibodies directed to these polypeptides acre useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, 'particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hema~topoietic, neural, and cancerous and waunded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, amniotic fluid, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the 'present invention comprise immunogenic epitopes shown in SEQ IL> NO: 156 ass residues: Ile-28 to Trp-37, Ser-68 to Lys-81.
Polynucleotides encoding said polypeptides a;re also provided.
The tissue distribution in neutrophiis indicates that polynucleotides and polypeptides corresponding to this gene are useful as a marker in neutrophils to monitor patients who are immune suppressed or cancer patients during chemotherapy or radiation therapy. Representative uses are described in the "Immune Activity" and "infectious disease" secticms below, in Example 11, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; differentiation; and/or activation of hematopoietic cell lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in t:he treatment of cancer (e.g. by boosting immune responses}.
Since the gene is er:pressed in cells of lymphoid origin, the natural gene product is involved in immmne functions. Therefore it is also useful as an agent fox immunological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulornatou's Disease, inflammatory bowel disease, sepsis, acne., neutropenia, neutrophiiia> psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimmune infertillity, Iense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's IS Disease, and scleroderma. Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury. 'Thus, this gene product is thought to be useful in the expansion of stem cells and cornrnitted progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Alternatively, polynucleotides and polypeptides corresponding to this gene are useful for the detection, treatment, andlor prevention of neurodegenerative disease states, behavioral disorders, or inflammatory conditions. Furthermore, the protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identiEfy agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may slEOw utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:64 and may have been publicly available prior to conception of the present invention. Preferably, such related poiynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is a:ny integer between 1 to 1180 of SEQ ID N0:64, b is an integer of 15 to 1194, where; both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:64, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 55 This gene is expressed primanii;y in prostate.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissue{s) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, urogenital diseases andlor disorders, particularly prostate cancer.
Similarly, polypeptides and', antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). Fox a number of disorders of the above tissues or cells, particularly of the urogenital system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., urogenital, prostate, renal, and cancerous and wounded tissues) or bodily fluids {e.g., lymph, serum, plasma, urine, synoviai fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 157 as residues: Arg-30 to Gln-36.
Polynucieotides encoding said polypeptide:; are also provided.
The tissue distribution in prostate cancer cells indicates that polynucleotides and polypeptides corresponding to this gene are useful for study, treatment and diagnosis of prostate cancer and other urogenital disorders. Moreover, the expression within cellular sources marrked by proliferating cells indicates this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment, andlor prevention of developmental diseases and disorders, including cancer, and other proliferative conditions. Representative uses are described in the "Hyperproliferative Disorders" and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation andlor apoptosis in pattern formation.
Dysregulation of ap~optosis can result in inappropriate suppression of cell death, as occurs in the devE;loprnent of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain rieurodegenerative disorders, such as spinal muscular. atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult fo:r tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cellf and tissue type specification.
Therefore, the polynucieotides and poiypeptides of the present invention are useful in treating, detecting, andlor preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferati~re conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate; ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor imrnunotherapy targets for the above listed tissues.
Many polynucleoti.de sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:65 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1663 of SEQ ID N0:65, b is an integer of I5 to 1677, where: both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:65, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 56 A preferred polypeptide of the invention comprises the following amino acid sequence:
MVLVLRHPLCARERAFF;EPGRGLLTRTGQHDGAPAVTAVPGPLGAVAAAEG
RRSAWGAGGSSPPRKVLWGDMRGRRAGVDVLGPALSSEAAGAEARGWGM
PGMGVGVGASETRGAL:FLGREGVHGPCPMDGLGPWPWGPW (SEQ ID NO:
242). PoIynucleotides encoding these polypeptides are also provided.
This gene is expressed primarily in rejected kidney.
Therefore, polynucieotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, diseases ancL'or disorders affecting the kidney. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the urinary tract, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., urogenital, renal, kidney, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, :cerurn, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypepti~des of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 158 as residues: Ala-30 to Gly-36, Asp-45 to Trp-50, Lys-65 to Cys-71, Pro-80 t~o Cys-87. Polynucleotides encoding said poiypeptides are also provided.

WO 00/04140 PCTIUS99115$49 t36 The tissue distribution in kidney indicates the protein product of this gene could be used in the treatment andlor detection of kidney diseases including renal failure, nephrites, renal tubular acidosis, proteinuria, pyuria, edema, pyelonephritis, hydronephritis, nephrotic syndrome, crush syndrome, gIomerulonephritis, hematuria, renal colic and kidney stones, in addition to Wilm's Tumor Disease, and congenital kidney abnormalities such ;as horseshoe kidney, polycystic kidney, and Falconi's syndrome. The protein is uaeful for modulating the immune response to aberrant proteins, as may exist in proliferating cells and tissues. Such modulation of the immune response would also show utility in inhibiting the rejection of transplanted tissues, particularly of the renal system. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:66 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1223 of SEQ ID N0:66, b is an integer of 15 to 1237, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID~ N0:66, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 57 The translation product of this gene shares sequence homology with both human and mouse Fibulin-2 which is an extracellular matrix protein found in heart tissue (See Genbank Accession Nos. emb~CAA57876.1 and embf CAA53040.1, respectively; all references available through these accessions are hereby incorporated herein by reference; for example, J. Cell Biol. 123 (5), 1269-1277 (1993)).
Preferred polypeptides encoded by this gene comprise the following amino acid sequence:
MGPAVKMWTNAWKGI~DDCHYNQLCENTPGGHRCSCPRGYRMQGPSLPCL
DVNECLQLPKACAYQC'HNLQGSYRCLCPPGQTLLRDGKACTSLERNGQNVT
TVSHRGPLLPWLRPWASiPGTSYHAWVSLRPGPMALSSVGRAWCPPGFIRQN
-GVCTDLDECRVRNLCQHACRNTEGSYQCLCPAGYRLLPSGKNCQDINECEEE
SIECGPGQMCFNTRGS~C'QCVDTPCPATYRQGPSPGTCFRRCSQDCGTGGPSTL

GLGAVYTRRALTRAGL,YRLTVRAAAPRHQSVFVLLIAVSPYPY (SEQ ID NO:
243). Polynucleotides encoding these polypeptides are also provided.
A preferred polype~ptide fragment of the invention comprises the following amino acid sequence:
MRVL V VTIAPiYW ALAEZESGEAL1VGHSLTGGKFRQSHTW SLLQGAAHDDPV
ARGLDPDGLLLLDV VVNGV VPGRAWLTQIFKCRTLKKHYVQTRAWPAVRG
LHTALLPGRPPLVPTLQ!PQHPVQRGPGPPAPAGAAPAGLSYQLGL (SEQ ID
NO: 244). Polynucleotides encoding tlhese polypeptides are also provided.
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
HASGAFLV VRGEPQGSWGSMTGVINGRKFGVATLNTS VMQEAHSGVSSIHSS
IRHVPANVGPLMRVLVVTIAPIYVVALARESGEALNGHSLTGGKFRQESHVEF
ATGELLTMTQWPGVWIPMASCSSTWWSMALSPDSLADADLQVQDFEEHYV
QTGPGQLFVGSTQRFFQGGLPSFL.RCNHSIQYNAARGPQPQLVQHLRASAISS
AFDPEAEALRFQLATAC,QAEENEVGCPEGFELDSQGAFCVDVDECAWDAHL
CREGQRCVNLLGSYRC'.LPDCGPCTFRVADGAGCEDVDECLEGLDDCHYNQLC
ENTPGGHRCSCPRGYRMQGPSLPCLDVNECLQLPKACAYQCHNLQGSYRCL
CPPGQTLLRDGKACTS:LERNGQNVTTVSHRGPLLPWLRPWASIPGTSYHAWV
SLRPGPMALSSVGRAWCPPGFIRQNGVCTDLDECRVRNLCQHACRNTEGSY
QCLCPAGYRLLPSGKNCQDINECEEESIECGPGQMCFNTRGSYQCVDTPCPAT
YRQGPSPGTCFRRCSQIDCGTGGPSTLQYRLLPLPLGVRAHHDVARLTAFSEV

GVPANRTELSMLEPDPI(tSPFALRPLRAGLGAVYTRRALTRAGLYRLTVRAAA
PRHQSVFVLLIAVSPYP'Y (SEQ ID NO: 245). Polynucleotides encoding these polypeptides are also provided.
When tested again,~t U937 and Jurkat cell lines, supernatants removed from cells containing this gene repeatedly activated the GAS (gamma activating sequence) promoter element. Thus, it: is likely that this gene activates myeloid, T-cells, and to a lesser extent, other immune and hematopoietic cells and tissue cell types, through the JAK-STAT signal transduction pathway. GAS is a promoter element found upstream of many genes which are involved in the Jak-STAT pathway. The Jak-STAT pathway is a large, signal transduction pathway involved in the differentiation and proliferation of cells. Therefore, activation of the Jak-STAT pathway, reflected by the binding of the GAS element, can be used to indicate proteins involved in the proliferation and differentiation of cells.
This gene is expressed primarily in kidney.
Therefore, polynucleotides and palypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, diseases an,dlor disorders affecting the kidney and renal system.
Similarly, polypeptides and antibodies directed to these poiypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the urinary tract, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., renal, urogenitaI, kidney, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ fD NO: 159 as residues: Lys-32 to Ser-37, His-89 to Gly-94, Asn-124 to Gln-130, Ala-l63 to Val-168, Cys-196 to Arg-201, Gln-244 to Gln-264, His-288 to Tyr-294, Leu-314 to Gln-319, Ala-392 to Ser-399, Pro-412 to Asp-419, Ala-452 to Pro-460, Arg-465 to Thr-47:3. Poiynucleotides encoding said polypeptides are also provided.
The tissue distribution in rejected kidney, the homology to the conserved Fibulin-2 protein, in addition to the detected GAS biological activity, indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of dlisorders affecting kidneys, particularly proliferative disorders. Representative uses are described here and elsewhere herein. The protein product of this gene could be used in the treatment andlor detection of kidney diseases including renal failure, nephritus, renal tubular acidosis, proteinuria, pyuria, edema, pyelonephritis, hydronephritis, nephrotic syndrome, crush syndrome, glomerulonephritis, hematuria, renal colic and kidney stones, in addition to Wilm's TumorDisease, and congenital kidney abnormalities such as horseshoe kidney, polycystic kidney, and Falconi's syndrome. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptor<c, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor irnmunotherapy targets for the above listed tissues.
Many polynucieotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:67 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more poiynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1920 of SEQ ID N0:67, b is an integer of 15 to 1934, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:67, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIfN ENCODED BY GENE NO: 5g WO 00/04140 PCTNS99115$49 Preferred polypeptides of the invention comprise the following amino acid sequence:
MGEKFLLLAMKENHPECFCKILKILHCMDPGEWLPQTEHC V HLTPKEFLI WT
MDIASNERSEIQSVALRlLASKVISHI3MQTCVENRELIAAELKQWVQLVILSCE
DHLPTESRLAVVEVLTSTTPLFLTNPHPILELQDTLALWKCVLTLLQSEEQAV
RDAATETVTTAMSQENTCQSTEFAFCQVDASIALALALAVLCDLLQQWDQL
APGLPILLGWLLGESDDLVACVESMHQVEEDYLFEKAEVNFWAETLIFVKYL
CKHLFCLLSKSGWRPPSPEMLCHLQRMVSEQCHL.LSQFFRELPPAAEFVKTV
EFTRLRIQEERTLACLRLLAFLEGKEGEDTLVLSVWDSYAESRQLTLPRTEAA
C (SEQ ff3 NO: 246). Polynucleotides encoding such polypeptides are also provided.
A preferred polype~ptide fragment of the invention comprises the following amino acid sequence: MGEPNRHPSM
FLLLLVLERLYASPMD(.iTSSALSMGPFVPFIMRCGHSPVYHSREMAARALVP
FVMIDHIPNTIRTLLSTL, PSCTDQCFRAKPHSWGHFSRFFHLLQAYSDSKTRNEFRLPARAD (SEQ ID NO:
247). Polynucleotides encoding these polypeptides are also provided.
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
MTGREFFSRFPELYPFL,LKQLETVANTVDSDMGEPNRHPSMFLLLLVLERLY
ASPMDGTSSALSMGPFVPFIMRCGHSPVYHSREMAARALVPFVMIDHIPNTIR
TLLSTLPSCTDQCFRQI'dHIHGTLL,QVFHI..LQAYSD5KHGTNSDFQHELTDITV
CTKAKLWLAKRQNPCLVTRAVYIDILFLLTCCLNRSAKDNQPVLESLGFWEE
VRGIISGSELITGFPWAIFKVPGLPQYLQSLTRLAIAAVWAAAAKSGERETNVPI
SFSQLLESAFPEVRSLTLEALLEKFLAAASGLGEKGVPPLLCNMGEKFLLLAM
KENHPECFCKILKILHC:MDPGEWLPQTEHCVHLTPKEFLIWTMDIASNERSEIQ
S VALRLASKVISHHMQTCVENRELIAAELKQW VQLVILSCEDHLPTESRLAV V
EVLTSTTPLFLTNPHPIILELQDTLALWKCVLTLLQSEEQAVRDAATETVTTAM
SQENTCQSTEFAFCQVDASIALALALAVLCDLLQQWDQLAPGLPILLGWLLG
ESDDLVACVESMHQVEEDYLFEKAEVNFWAETLIFVKYLCKHLFCLLSKSG

WRPPSPEMLCHLQRMVSEQCHLLSQFFRELPPAAEFVKTVEFTRLRIQEERTL
ACLRLLAFLEGKEGED'TLVLSVWDSYAESRQLTLPRTEAAC {SEQ ID NO:
248). Polynucleotides encoding these polypeptides are also provided.
The polypeptide of this gene has been determined to have two transmembrane domains at about anuno acid position 144 - i60, and 462 - 478 of the amino acid sequence referenced in Table 1 for this gene. Based upon these characteristics, it is believed that the protein product of this gene shares structural features to type IIIa membrane proteins. Included in this invention as a preferred domain is the formate and nitrite transporters domain, which was identified using the ProSite analysis tool (Swiss Institute of Bioinforrnatics}. A number of bacterial and archaebacterial proteins involved in transporting formate or nitrite have been shown [i] to be related:
- focA and focB, from Escherichia coli, transporters involved in the bidirectional transport of formate. - fdhC, from Methanobacteriurn formicicum and thermoformicicum, a probable formate transporter. - nirC, from Escherichia coli and Salmonella typhimurium, a probable nitrite transporter. - Bacillus subtilis hypothetical protein yrhG. - Bacillus subtilis hypothetical protein ywcJ (ipa-48R).
These transporters are proteins of about 280 residues and seem to contain six transmembrane regions. A.s signature patterns, we selected two conserved regions.
The first one is located in what seems to be a cytoplasmic loop between the second and third transmembrane domains; the second is part of the fourth transmembrane region. The 70 Kd yeast hypothetical protein YHI.008c is highly similar, in its N-terminal section, to the prokaryotic members of this family. The concensus pattern is as follows: [LIVMA)-[LI'JMY]-x-G-~[GSTA]-[DES]-L-[FI]-[TN]-[GS].
Preferred polypeptides of the invention comprise the following amino acid sequence: IISGSELITG (;iEQ ID NO: 249). Polynucleotides encoding these polypeptides are also provided. Further preferred are poIypeptides comprising the formate and nitrite transporter domain of the sequence referenced in Table for this gene, and at least 5, 10, 1.'i, 20, 25, 3t), 50, or 75 additional contiguous amino acid residues of this referenced sequence. The additional contiguous amino acid residues is N-terminal or C- terminal to the formate and nitrite transporter domain.
Alternatively, the additional contiguous amino acid residues is both N-terminal and C-terminal to l42 the formate and nitrite transporter domain, wherein the total N- and C-terminal contiguous amino acid residues equal the specified number. The above preferred polypeptide domain is characteristic of a signature specific to formate and nitrite transporter proteins. Based on the sequence similarity, the translation product of this gene is expected to share at least some biological activities with formate and nitrite transporter proteins. Such activities are known in the art, some of which are described elsewhere herein. It is believed that this gene maps to chromosome 2.
Accordingly, polynucleotides derived from this gene are useful in linkage analysis as markers for chromosome 2.
This gene is expressed primarily in cells of the immune system, primarily T-cells and to a lesser extent in spleen, liver, thymus, tonsils, and testis.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential idc;ntification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, immune anct hematopoietic diseases and/or disorders, particularly disorders affecting hematopoesis. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of hematopoetic cells, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hematopoie;tic, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual leaving such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred poiypeptides of the present invention comprise immunogenic epitopes shown in SEQ IIr~ NO: 160 as residues: Gly-2 to Pro-8, Ser-82 to His-92, Tyr-107 to Asp-117, Arg-162 to Pro-169, Ser-224 to Thr-229, Leu-310 to His-315, Ser-333 to Glu-338, Glu-381 to Ser-388, Gln-428 to Ala-433, Met-446 to Thr-455, Ser-548 to Ser-554, Gly-613 to Asp-fil8, Ser-627 to Gln-633. Polynucleotides encoding said polypeptide;s are also provided.

The tissue distribution in immune cells and tissues indicates that polynucieotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of .disorders affecting hematopoesis, including cancers.
Representative uses are described in the "Immune Activity" and "infectious disease"
sections below, in Example. 11, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein.
Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; differentiation; and/or activation of hematopoietic cell lineages, including blood si:em cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in veils of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also useful as an agent for immunological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheum;~toid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cptotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimrnune infertility, tense tissue injury, demyeIination, systemic lupus erythematosis, drug induced hernoiytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderma. Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other biaod cells, or that recruits hematopoietic cells to sites. of injury. Thus, this gene product is thought to be useful in the expansion of stem ceals and committed progenitors of various blood lineages, and in the differentiation andlor proliferation of various cell types.
Furthernare, the protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate. ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the proteins may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:68 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more poIynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 3286 of SEQ -iD N0:68, b is an integer of 15 to 3300, where both a and b correspond to the positions of nucleotide residues shown in SEQ ILK N0:68, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: S9 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of tPne predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
VDGIDKLDTEFLQQFLETHSRGPRLHSPGHASQEATPGANMSSGTELLWPGAA
LLVLLGVAASLCVRCSRPGAKRSEKIYQQRSLREDQQSFTGSRTYSLVGQAW

YNWGRFSKPPEDDDANSYENVLICKQKTTETGAQQEGIGGLCRGDLSLSLAL
KTGPTSGLCPSASPEEI)EGI (SEQ ID NO: 250). Polynucleotides encoding these polypeptides are also provided.
The polypeptide of this gene has been determined to have a transmembrane domain at about amino acid position 10 - 26 of the amino acid sequence referenced in Table 1 for this gene. Based upon these characteristics, it is believed that the protein product of this gene sharers structural features to type Ib membrane proteins.
The gene encoding the disclosed cDNA is believed to reside on chromosome 7. Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis for chromosome 7.
This gene is exprf;ssed primarily in bone marrow, CD34 positive cells, and immune cells, including, neutrophils, T-cells, B-cells, macrophages, monocytes, and dendritic cells and to a lesser extent iin brain and tonsils.

Therefore, polynuc:leotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, disorders affecting the immune and hematopoietic systems, particularly hematopoesis. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing imrnunological probes for differential identification of the tissues) or cell type{s). For a number of disorders of the above tissues_or cells, particularly of the the immune system and hematopoeitic system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ IL) NO: 161 as residues: Ser-29 to Thr-57, Pro-74 to Lys-79, Pro-85 to Glu-i0?, Tyr-11'.8 to Tyr-136, Gln-144 to Gln-152, Ala-182 to Glu-188.
Polynucleotides encoding said polypeptides are also provided.
The tissue distribution in immune and hematopoietic cells and tissues indicates that polynucleotides and polypeptides corresponding to this gene are useful for the diagnosis and treatment of disorders affecting the immune system and hematopoesis. Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; differentiation; andlor activation of hematopoietic cell lineage;s, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also useful as an agent for WO 00104140 PCT/US99/i5849 immunoiogical disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimrrmne infertility, Tense tissue injury, demyelination, systemic lupus erythematosis, drug iinduced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderma. Moreover, the protein may represent a secreted factor that influences the differentiati~nn or behavior of other blood cells, or that recruits hematopoietic cells to site:. of injury. 'Thus, this gene product is thought to be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation andlor proliferation of various cell types.
polynucleotides and polypeptides correspovnding to this gene are useful for the treatment and diagnosis of hematopoietic related disorders such as anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. The uses include bone marrow cell ex-vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia. The secreted protein can also be used to determine biological activity, to raise: antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, and as nutritional supplements. It may also have a very wide range of biological activities.
Representative uses are described in the "Chemotaxis°' and "Binding Activity"
sections below, in Examplles 11, 12, 1:3, 14, 15, 16, 18, 19, and 20, and elsewhere herein. Briefly, the protein may possess the following activities: cytokine, cell 2S proliferationldifferentiation modulating activity or induction of other cytokines;
immunostimulatinglimmunosuppressant activities (e.g. for treating human immunodeficiency virus infection, cancer, autoimmune diseases and allergy);
regulation of hematopoies,is (e.g. for treating anemia or as adjunct to chemotherapy);
stimulation or growth of bone, cartilage, tendons, ligaments andlor nerves (e.g. for treating wounds, stimulation of follicle stimulating hormone (for control of fertility);
chemotactic and chemokivnetic activities (e.g. for treating infections, tumors);

hemostatic or thrombolytic activity (e.g. for treating hemophilia, cardiac infarction etc.); anti-inflammatory activity (e.g, for treating septic shock, Crohn's Disease); as antimicrobials; for treating psoriasis or other hypergroliferative diseases;
for regulation of metabolism, and behavior. Also contemplated is the use of the corresponding nucleic acid. in gene therapy procedures.
Based upon the the proteins immune cell specific message distribution, it may be involved in many aspects of the imnnune response, especially its initial stages, inflammation, allograft rejection, infectious disease response efc. The expression of this clone is frequently found in the hematopoietic cell cDNA libraries. Thus, this factor could be involved in the control of hematopoietic cell proliferation, differentiation, and function. Based on this one can postulate its use in the management of anemias, leukemias, neutropenia, thrombocytopenia, autoimrnune diseases, blood tissue engraftment, and poikilothromerythromatosis.
Furthermore, the protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognatE; ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotiide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:69 and may have been publicly available prior to conception of the present invention. PreiFerably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1783 of SEQ ID N0:69, b is an integer of 15 to 1797, where both a and b correspond to the positions of nucleotide residues shown in SEQ II) N0:69> and where b is greater than or equal to a +
14.
FEATURES OF PROTIEIN ENCODED BY GENE NO: 60 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, pokypeptides of the invention comprise the following amino acid sequence:
VLWREASALVLSNRLSSGLLHDLLLQPAIHSRLFPRRSRGLSEGEGSSVSLQRS
RVLSAMKHVLNLYLLC~VVLTLLSIFVRVMESLEGLLESPSPGTSWTTRSQLAN
TEPTKGLPDHPSRSM (S~EQ ID NO: 251). Polynucleotides encoding these polypeptides are also proviided.
This gene is expressed primarily in immune cells including activated T cells, macrophages, jurkat cells, bone marrow cells, and osteoblasts and to a lesser extent in kidney cortex, brain, placenta and lung.
Therefore, polynuc:leotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for .diagnosis of diseases and conditions which include, but are not limited to, immune and hematopoietic diseases and/or disorders, particularly inflammation and disease; rekated to inflammatory activity. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) ar cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hernatopoietic, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogensc epitopes shown in SEQ III NO: 162 as residues: Pro-34 to Met-63.
Polynucleotides encoding said polypeptidc;s are also provided.
The tissue distribution in immune cells and tissues indicates that polynucleotides and poky~~eptides corresponding to this gene are useful for treating or diagnosing disease related to the normal or abnormal activation of T cells.

Representative uses are described in the "Immune Activity" and "infectious disease"
sections below, in Example 11, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein.
Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; differentiation; and/or activation of hematopoietic cell Iineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation; or other processes suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in imrrmne functions. Therefore it is also useful as an agent for immunological disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne;, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimmune infertility, Tense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderma. Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hernatopoietic cells to sites of injury. Thus, this gene product is thought to be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation zmdlor proliferation of various cell types.
Furthermore, the protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to Identify agents that modulate their interactions, in addition to~ its use as a. nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor imrnunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:70 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is isa cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is a.ny integer between 1 to 1359 of SEQ ID N0:70, b is an integer of 15 to 1373, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:70, andl where b is greater than or equal to a +
I4.
FEATURES OF PROTEIN ENCODED BY GENE NO: 61 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequE:nce:
YTFHTQIFLDFPMIFLTVLPLAFLFGHSGFYHYISFSCLFSLSLALFFFLD VATFR
RPGQLFCERS VLFDMFHiFGFVSLFLHEWIQAKHFWAGLF
IVLPSDVFFSVHHLEAPDGSFPNIAKLSLIILLR (SEQ ID NO: 252).
Polynucleotides encoding these polypeptides are also provided.
The polypeptide of this gene has been determined to have two txansmembrane domains at about amino acid position 2 - 18 and 22 - 38 of the amino acid sequence referenced in Table I for this gene. Based upon these characteristics, it is believed that the protein product of this gene shares structural features to type IIIa membrane proteins.
This gene is expre.,sed in many tissues including brain, liver, prostate, testes, cartilage, gall bladder. Expression is also seen in a number of tumors including colon carcinoma, pancreas tumor, osteoclastoma, ovarian cancer, B cell lymphoma and acute lyrnphocytic leukemias.
Therefore, polynuc;Ieotides and polypeptides of the invention are useful as reagents for differential identification of the tissues} or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, tumors of various organs including the pancreas, colon, and bone.
Similarly, poiypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues}
or cell types}. For a number of disorders of the above tissues or cells, particularly of the !S!
major organs, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., neural, hepatic, metabolic, reproductive, testicular, skeletal; and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, amniotic fluid, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in tumors and proliferative tissues indicates that polynucleotides and polypeptides cowesponding to this gene are useful for treating or diagnosing tumors of sevevraI major organs including the pancreas and large intestine.
This protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment; and/or prevention of developmental diseases and disorders, including cancer, and other proliferative conditions.
Representative uses are described in the "Hyperproliferative Disorders" and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation and/or apoptosis in pattern formation.
Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product may have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polypeptides of the present invention are useful in treating, detecting, and/or preventing said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferati.ve conditions and diseases. The protein is useful in modulating the immune response to aberrant polypeptides, as may exist in proliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. Furthermore, the i52 protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above lasted tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID NO:? 1 amd may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope oiF the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 1565 of SEQ ID NO:? 1, b is an integer of 15 to 1579, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:71, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 62 This gene is expressed primarily in dendritic cells and fetal liver/spleen and to a lesser extent in many tissues including tonsils, fetal lung, stromal cell lines, bone marrow cell lines, placenta and tumors including hepatocellular carcinoma, pancreas tumor and osteosarcoma.
Therefore, polynuc;ieotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, diseases an~dlor disorders of the immune and hematopoietic system.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in dendritic cells and fetal liverlspleen indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnaosing and treating disorders of the immune system particularlly related to the control and generation of precursor cells. polynucleotides and polypeptides corresponding to this gene .are useful for the treatment and diagnosis of hematopoietic related disorders such as anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example I 1, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein. Briefly, the uses include bone marrow cell ex-vivo culture, bone marrow IS transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore, it can be used in immune disorders ,;uch as infection, inflammation, allergy, immunodeficiency etc. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proli~Feration of various cell types. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:72 and may hawe been publicly available prior to conception of the present invention. Preferably, such related poiynucleotides are specifically excluded from the scope oaF the present invention. To list every related sequence is iS4 cumbersome. Accordingly., preferably excluded from the present invention are one or more polynucleotides comvprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 1014 of SEQ ID N0:72, b is an integer of 15 to 1028, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:72, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 63 This gene is expressed primarily in adrenal gland tumor and endothelial cells.
Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, endocrine and vascular diseases and/or disorders, particularly diseases associated with the vascular endothelium. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the vascular system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., endocrine, vascular, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in endothelial cells indicates that polynucleotides and polypeptides corresponding to this gene are useful for diagnosing and treating disorders that involve the vascular system including diseases such as atherschlerosis, neoangiogenesis associated with tumor growth and conditions associated with inflammation. Moreover, the protein is useful in the detection, treatment, andlor prevention of a variety of vascular disorders and conditions, which include, but are not limited to miscrovascular disease, vascular leak syndrome, aneurysm, stroke, embolism, thrombosis, coronary artery disease, arteriosclerosis, andlor atherosclerosis. Alternatively, the protein is useful in the treatment, detection, and/or prevention of metabolic disorders, particularly lethargy and depression.
Furthermore, the protein may also be used to detern~ine biological activity, to raise antibodies; as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement.
Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:73 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 3660 of SEQ ID N0:73, b is an integer of i5 to 3674, where both a and b correspond to the positions of nucleotide residues shown in SEQ IE~ N0:73, and where b is greater than or equal to a +
14.
FEATURES OF PROTF,IN ENCODED BY GENE NO: 64 The translation product of this gene is related to bovine PAM precursor. See Genbank record gi~16348a incorporated herein by reference. Moreover, see following patent publications are also incorporated herein by reference: J043I 1386 and W08902460. Many bioactive peptides terminate with an amino acid alpha-amide at their COOH terminus. The enzyme responsible for this essential posttranslational modification is known as peptidyl-glycine alpha-amidating monooxygenase or PAM.
An NH2-terminal signal sequence and short propeptide precede the NH2 terminus of purified PAM. The sequevnces of several PAM cyanogen bromide peptides were localized in the NH2-tern~inal half of the predicted protein. The forms of PAM
purii ed from bovine neurointermediate pituitary is generated by endoproteolytic cleavage at a subset of the: 10 pairs of basic amino acids in the precursor.
High levels of PAM mRNA have been found in bovine pituitary and cerebral cortex. In corticotropic tumor cells, levels of PAM mRNA and pro-ACTHlendorphin mRNA
are known to be regulated in parallel by glucocorticoids and CRF.
This gene is express>ed primarily in endometrial tumors, dendritic cells, a multiple sclerosis library, kidney, hematopoietic cells, melanocytes, osteoblasts, the spleen, colon, ovary, stromal cells, fetal and adult brain, heart, and in tissues undergoing wound repair.
Therefore, polynuclleotides andl polypeptides of the invention are useful as reagents for differential ide;ntif°ication of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, endometriosis, endometrial cancer, multiple sclerosis, hematopoietic diseases, bone disease, and. wound healing. Similarly, polypeptides and antibodies directed to these poiypeptides are useful in providing immunological probes for differential identification o~f the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly the hematopoietic system and female reproduction. expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., reproductive, immune, hematopoieticm integumentary, skeletal, gastrointestinal, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, amniotic fluid, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in dend.ritic and hematopoietic cells and tissues indicates that polynucIeotides and polypeptides corresponding to this gene are useful as a therapuetic or diagno;~tic agent i's Diseases of hematopoietic origin as well as the female reproductive track due to the gene's primary pattern of expression.
polynucleotides and polyp~eptides corresponding to this gene are useful for the treatment and diagnosis of hematopoietic related disorders such as anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia since stromal cells are important in the production of cells of hematopoietic lineages. Representative uses are described in the "immune Activity" and "infectious disease" sections below, in Example i 1, 13, 14, 16, 1.8, 19, 20, and 27, and elsewhere herein. Briefly, the uses include bone marrow cell a:x-vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product nnay also be involved in lymphopoiesis, therefore, it can be used in immune disorders ouch as infection, inflammation, allergy, immunodeficiency etc. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood Iineages, and in the differentiation andlor proliferation of various cell types. The protein may also have a very wide range of biological activities. Representative uses are described in the "Chemotaxis" and "Binding Activity" sections below, in Examples 11, 12, 13, 14, 15, 16, 18, 19, and 20, and elsewhere herein. Briefly, the protein may possess the following activities: cytokine, cell proliferation/differentiation modulating activity or induction of other cytokines; imrnunostimulating/irnmunosuppressant activities (e.g.
for treating human immunodeficiency virus infection, cancer, autoimmune diseases and allergy); regulation of hematopoiesis (e.g. for treating anemia or as adjunct to chemotherapy); stimulation or growth of bone, cartilage, tendons, ligaments andlor nerves (e.g. for treating wounds, stimulation of follicle stimulating hormone (for control of fertility); chemcrtactic and chemokinetic activities (e.g. for treating infections, tumors); hemostatic or thrombolytic activity (e.g. for treating hemophilia, cardiac infarction etc.); anti-inflammatory activity (e.g. for treating septic shock, Crohn's Disease); as antin-~icrobials; for treating psoriasis or other hyperproliferative diseases; for regulation of metabolism, and behavior. Also contemplated is the use of the corresponding nucleic acid in gene therapy procedures. Protein, as well as, antibodies directed against the protein tray show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotiide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:74 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general WO 00/04140 PCTJUS99/15$49 formula of a-b, where a is any integer between 1 to 2783 of SEQ ID N0:74, b is an integer of 15 to 2797, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:74, and where b is greater than or equal to a +
14.
S FEATURES OF PROTEI1N ENCODED BY GENE NO: 65 The translation product of this gene shares sequence similarity with several G-protein coupled receptors (.See Genbank Accession No. gb~AAC77910.1 (AF061443); all references available through this accession are hereby incorporated herein by reference; for example, Mol" Endocrinol. 12, 1830-1845 {1998)). G-protein coupled receptors are well known in the are and affect a variety of functions.
In particular, the translation product of this gene shares similarity with Follical Stimulating Hormone Receptor.
Preferred polypeptides encoded by this gene comprise the following amino acid sequence:
GTRFPTGETPSLGFTV'F:LVLLNSLAFLLMAVIYTKLYCNLEKEDLSENSQSSMI
KHVAWLIFTNCIFFCPVAFFSFAPLITAISISPEIMKSVTLIFFP (SEQ ID NO:
253). Polynucleotides encoding such polypeptides are also provided.
A preferred polypevptide fragment of the invention comprises the following amino acid sequence: MIK:HVAWLIFTNCIFFCP
VAFFSFAPLITAISISPEIIVIKSVTLIFFPCLLA (SEQ ID NO: 254). Polynucleotides encoding these polypeptides are also provided.
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
GTRFPTGETPSLGFTVTLVLLNSLAFLLMAVIYTKLYCNLEK,EDLSENSQSSMI
KHVAWLIFTNCIFFCPV'AFFSFAPLITAISISPEIMKSVTLIFFPLPACLNPVLYVF
FNPKFKEDWKLLK:RRVTKKSGSVS VSISSQGGCLEQDFYYDCGMYSHLQGN
LTVCDCCESFLLTKPVSCKHLIKSHSCPALAVASCQRPEGYWSDCGTQSAHS
DYADEEDSFVSDSSDQVQACGRACFYQSRGFPLVRYAYNLPRVKD (SEQ ID
NO: 255). Polynucleotides encoding these polypeptides are also provided.

The polypeptide of this gene has been determined to have a transmembrane domain at about amino acid position 4~3 - 59 of the amino acid sequence referenced in Table 1 for this gene. Mora:over, a cytoplasmic tail encompassing amino acids 60 to 207 of this protein has also been determined. Based upon these characteristics, it is believed that the protein product of this gene shares structural features to type Ia membrane proteins. Included in this invention as preferred domains are Zinc finger, C2H2 type domains, which were identified using the ProSite analysis tool (Swiss Institute of Bioinformatics).'Zine finger' domains [1-5] are nucleic acid-binding protein structures first identified in the Xenopus transcription factor TFIIIA. These domains have since been found in numerous nucleic acid-binding proteins. A
zinc finger domain is composed of 25 to 30 amino-acid residues. There are two cysteine or histidine residues at both extremities of the domain, which are involved in the tetrahedral coordination of a zinc atom. It has been proposed that such a domain interacts with about five nucleotides. .A schematic representation of a zinc finger domain is shown below:
xx x x x x x x x x x x C H
x \ I x x Zn x x / \x C H
xxxxx xxxxx Many classes of zinc fingers are characterized according to the number and positions of the histidine and cysteine residues involved in the zinc atom coordination. In the first cl;iss to be characterized, called C2H2, the first pair of zinc coordinating residues are cysteines, while the second pair are histidines. A
number of experimental reports have demonstrated the zinc- dependent DNA or RNA binding property of some members of this class. Some of the proteins known to include C2H2-type zinc fingers are listed below. We have indicated, between brackets, the number of zinc finger regions found in each of these proteins; a'+' symbol indicates that only partial sequence data is available and that additional finger domains is present. In addition to the conserved zinc ligand residues it has been shown that a number of other positions are also important for the structural integrity of the C2H2 zinc fingers. The best conserved position is found four residues after the second cysteine; it is generally an aromatic or aliphatic residue. The concensus pattern is as follows: C-x(2,4)-C-x(3)-[LIVMFYWC]-x{8)-H-x(3,5)-H.
Preferred polypeptides of the invention comprise the following amino acid sequence: CDCCESFLLTI(~I'VSCKHLIKSH (SEQ ID NO: 256). Polynucleotides encoding these polypeptides are also provided. Further preferred are polypeptides comprising the Zinc finger, C2H2 type domain of the sequence referenced in Table for this gene, and at least 5, 10, 15, 20, 25, 30, 50, or 75 additional contiguous amino acid residues of this referenced sequence. The additional contiguous amino acid residues is N-terminal or C- terming! to the Zinc finger, C2H2 type domain.
Alternatively, the additional contiguous amino acid residues is both N-terminal and C-terminal to the Zinc finger, C2H2 type domain, wherein the total N- and C-terminal contiguous amino acid residues equal the specified number. The above preferred polypeptide domain is characteristic of a signature specific to zinc finger proteins.
Based on the sequence similarity, the translation product of this gene is expected to share at least some biologiical activities with G-coupled proteins, their receptors, and zinc finger proteins. Such activities are known in the art, some of which are described elsewhere herein.
This gene is expressed primarily in adult and fetal liver, human placenta, colon carcinoma cell lines and fibroblasts and to a lesser extent in the fetal and adult brain, the developing nervous system, lung, pancreas, salivary gland, breast tissue, and dendritic cells.

WO 00/04140 PCT/US99/i5849 Therefore, polynucleotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, diseases of the Liver, developmental abnormalities, neurologic diseases, S lung cancer, pancreatic cancer, and colon cancer. Similarly, poIypeptides and antibodies directed to these; polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the neurological and hepatic origin, as well as the proliferation and/or differentiation of numerous types of tissues.
expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types. (e.g., hepatic, immune, hematopoietic, neural, gastrointestinal, reproductive, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, amniotic fluid, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative 1S to the standard gene expre:>sion level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: i67 a~ residues: Pro-62 to Asp-6?, Arg-74 to Gly-80, Gln-146 to Glu-168. Polynucleotides encoding said polypeptides are also provided.
The tissue distribution in fetal liver indicates that polynucleotides and polypeptides corresponding to this gene are useful for a diagnositic marker or therapeutic in a wide variety of disease states. polynucleotides and polypeptides corresponding to this gene are useful for the treatment and diagnosis of hematopoietic related disorders such as anemia, panc:ytopenia, leukopenia, thrornbocytopenia or 2S leukemia since stromal cells are important in the production of cells of hematopoietic lineages. Representative u:>es are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16, 18, 19, 20, and 27, and elsewhere herein. Briefly, the uses include bone marrow cell ex-vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemotherapy of neoplasia.

The gene product may also be involved in lymphopoiesis, therefore, it can be used in immune disorders such as infection, inflammation, allergy, immunodeficiency etc. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation andlor proliferation of various cell types. Alternatively, the protein expression in placental and brain tissue indicates the protein is useful in the detection, treatment, and/or prevention of vascular conditions, which include, but are not limited to, microvasculac disease, vascular leak syndrome, aneurysm, stroke, atherosclerosis, arteriosclerosis, or emboli:cm. For example, this gene product may represent a soluble factor produced by smooth muscle that regulates the innervation of organs or regulates the survival of neighboring neurons. Likewise, it is involved in controlling the digestive process, and such actions as peristalsis. Similarly, it is involved in controlling the vasculature in areas where smooth muscle surrounds the endothelium of blood vessels. The protein is useful. in the treatment, detection, and/or prevention of bacterial, fungal, protozoan and viral infections, particularly infections caused by HIV-1 or HIV-2; pain; cancers; anorexia; bulimia; asthma; Parkinson's Disease;
acute heart failure; hypotension; hypertension; urinary retention;
osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; and psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, severe mental retardation and dyskinesias, such as Huntington's Disease or Gilles de Ia Tovurette's syndrome. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:75 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between I to 26$9 of SEQ ID N0:75, b is an integer of 15 to 2703, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:75, and where b is greater than or equal to a +
14.
FEATURE5 OF PROTEIN ENCODED BY GENE NO: 66 In another embodiment, poiypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
ALENSGSPGLQDSARAEIFNXSLRSFSFLRNQMYIFELSLYLEGTSFV V VLLFLL
ISVSLDSPPTTKGWDSVLHIWVPL,IVQ (SEQ ID NO: 257). Palynucieotides encoding these polypeptides axe also provided.
This gene is expressed primarily in placenta and in hematopoietic cells, especially those of T-cell and monocyte origin and to a lesser extent in the brain, endothelial cells, and the lungs.
Therefore, polynuc:leotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, hematopietic, vascular, and developmental diseases and/or disorders.
Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of dlisorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., vascular, immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.

Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 168 as residues: Ser-30 to Trp-37.
Poiynucieotides encoding said polypeptides are also provided.
The tissue distribution in hematopoietic cells indicates that polynucleotides and polypeptides corresponding to this gene are useful for therapeutic andlor diagnostic intervention in hematopoietic and developmental disorders.
Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, I3, 14, 16, 18, 19, 20, and 27, and elsewhere herein. Briefly, the uses include hone marrow cell e;x-vivo culture, bone marrow transplantation, bone marrow reconstitution, radiotherapy or chemoi:herapy of neoplasia.
The gene product nnay also be involved in lymphopoiesis, therefore, it can be used in immune disorders ouch as infection, inflammation, allergy, irnmunodeficiency etc. In addition, this gene product may have commercial utility in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types. Alternatively, the protein is useful in the detection, treatment, andJor prevention of vascular conditions, which include, but are not limited to, microvascular disease, vascular leak syndrome, aneurysm, stroke, atherosc:lerosis, arteriosclerosis, or embolism. For example, this gene product may represent a soluble factor produced by smooth muscle that regulates the innervation of organs or regulates the survival of neighboring neurons.
Likewise, it is involved in controlling the digestive process, and such actions as peristalsis. Similarly, it is involved in controlling the vasculature in areas where smooth muscle surrounds the endothelium of blood vessels. Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate: ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a. nutritional supglernent. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor iimmunotherapy targets four the above listed tissues.
Many polynucleotiide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:76 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope o~f the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more poiynucleotides corruprising a nucleotide sequence described by the general formula of a-b, where a is any integer' between 1 to 728 of SEQ ID N0:76, b is an integer of 15 to 742, where both a and b correspond to the positions of nucleotide residues shown in SEQ Iii NO:76, and where b is greater than or equal to a +
14.
FEATURES OF PROTI~CIN ENCODED BY GENE NO: G7 This gene is expressed primarily in the prostate and to a lesser extent in in human B-cell lymphomas.
Therefore, polynucleotides anal polypeptides of the invention are useful as reagents for differential idlentification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, prostate cancer and diseases of hematopoietic origin, particularly of B-cells. Similarly, poiypeptides and antibodies directed to these polypeptides are useful in providing immunologic;al probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the prostate and immune systems, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., prostate, reproductive, hematopoietic, and cancerous and wounded tissues) or bodily fluids {e.g., lymph, serum, plasma, urine, serrtinal fluid, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ I17 NO: 169 as residues: Asp-33 to Lys-42.
Polynucleotides encoding said polypeptides are also provided.
The tissue distribution in prostate tissue indicates that poIynucleotides and polypeptides corresponding to this gene are useful as a therapeutic or diagnostic marker for prostate cancer and disorders involving hematopoietic cells, especially those of B-cell origin. Moreover, the expression within cellular sources marked by proliferating cells indicates this protein may play a role in the regulation of cellular division, and may show utility in the diagnosis, treatment, andlor prevention of developmental diseases and disorders, including cancer, and other proliferative conditions. Representative. uses are described in the "Hyperproliferative Disorders"
and "Regeneration" sections below and elsewhere herein. Briefly, developmental tissues rely on decisions involving cell differentiation and/or apoptosis in pattern formation.
Dysregulation'of apoptosis cam result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Because of potential roles in proliferation and differentiation, this gene product rnay have applications in the adult for tissue regeneration and the treatment of cancers. It may also act as a morphogen to control cell and tissue type specification.
Therefore, the polynucleotides and polypeptides of the present invention are useful in treating, detecting, andlor preventi~ag said disorders and conditions, in addition to other types of degenerative conditions. Thus this protein may modulate apoptosis or tissue differentiation and is useful in the detection, treatment, and/or prevention of degenerative or proliferative conditions and diseases. The protein is useful in modulating the immune rf;sponse to aberrant polypeptides, as may exist in groliferating and cancerous cells and tissues. The protein can also be used to gain new insight into the regulation of cellular growth and proliferation. The protein is useful in modulating the immune response to aberrant proteins and poiypeptides, as may exist in rapidly proliferating cells and tissues. Furthermore, the protein may also be used to determine biological activity, to raise. antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional suF~plement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.

Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:77 .and may have been publicly available prior to conception of the present invention. Preferably, such related poiynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1811 of SEQ ID N0:77, b is an integer of 15 to 1825, where both a and b correspond to the positions of nucleotide residues shown in SEQ IDS N0:77, and where b is greater than or equal to a +
14.
FEATURES OF PROT1G:IN ENCODED BY GENE NO: 68 When tested against U937 cell lines, supernatants removed from cells containing this gene activated the GAS (gamma activating sequence) promoter element. Thus, it is likely that this gene activates myeloid cells through the JAK-STAT signal transduction pathway. GAS is a promoter element found upstream of many genes which are involved in the Jak-STAT pathway. The Jak-STAT pathway is a large, signal transduction pathway involved in the differentiation and proliferation of cells. Therefore, activation of the Jak-STAT pathway, reflected by the binding of the GAS element, can be used to indicate proteins involved in the proliferation and differentiation of cells.
In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequence:
GHESICGSCRSWIYFSI:RCRRRMRPWWSLLLEACATCAQTGPTRSTSCTQEVS
HSSSTAYPAPMRRRCC'.L PSPRSCT (SEQ ID NO: 258). Polynucleotides encoding these polypeptides are also provided.
The gene encoding; the disclosed cDNA is believed to reside on chromosome 17. Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis for chromosome 17.

This gene is expressed primarily in the brain and the developing embryo and to a lesser extent in the heart, colon, adipose tissue, kidney, mammary tissue, activated T-cells and dendntic cells.
Therefore, poIynucleotides and polypeptides of the invention are useful as reagents for differernial id~mtification of the tissues) or cell types) present in a biological sample and far diagnosis of diseases and conditions which include, but are not limited to, neurological diseases, developmental conditions, colon cancer, and hematopoietic diseases, especially of T-cell origin . Similarly, polypeptides and antibodies directed to thesa; polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the central nervous system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell type:e (e.g., neural, developmental, cardiovascular, adipose, immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ IDS NO: 170 as residues: Thr-18 to Cys-26, Glu-29 to Thr-36, Ser-50 to Thr-55. Polynucleotides encoding said polypeptides are also provided.
The tissue distribution in brain, combined with the detected GAS biological activity, indicates that pol:ynucleotides and poIypeptides corresponding to this gene are useful for therapeutic and/or diagnostic agents in neurological diseases, developmental abnormalities, colon cancer, and hematopoietic diseases, especially those of T-cell origin. Representative uses are described in the "Regeneration" and "Hyperproliferative Dison~ers" sections below, in Example 11, 15, and 18, and elsewhere herein. Briefly, the uses include, but are not limited to the detection, treatment, andlor prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases, peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia andl infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia., obsessive compulsive disorder, depression, panic disorder, learning disabilities, ALS, psychoses, autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, elevated expression of this gene product in regions of the brain indicates it plays a role in normal neural function.
Potentially, this gene product is involved in synapse formation, neurotransmission, (earning, cognition, homeostasis, or neuronal differentiation or survival. Furthermore, the protein may also be used to determine biological activity, ;
to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:78 ;and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1660 of SEQ ID N0:78, b is an integer of 15 to 1674, whexe both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:78, and where b is greater than or equal to a +
14.
FEATURES OF PROT~;IN ENCODED BY GENE NO: lag The polypeptide o1F this gene has been determined to have a transmembrane domain at about amino acid position 2 - 18 of the amino acid sequence referenced in Table 1 for this gene. Based upon these characteristics, it is believed that the protein product of this gene sharers structural features to type II membrane proteins.

WO 00104140 PCT/US99/IS$49 In another embodiment, polypeptides comprising the amino acid sequence of the open reading frame upstream of the predicted signal peptide are contemplated by the present invention. Specifically, polypeptides of the invention comprise the following amino acid sequf:nce:
KRAGVEVGGLVMALAc;SVFVLGGVLVLCVERNGEGEMGWPQHLPKSQPLS
PPVAVRRCSFERSWIDLLVETSSSMVTCRQQVGTPNGMEGRGGGPKTTFPIRL
QLSGACAVRPEIQWEV (SEQ ID NO: 2S9). Polynucieotides encoding these polypeptides are also provided.
This gene is expressed primarilly in activated monocytes, dendritic cells, and in the tonsils.
Therefore, polynucl.eotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but axe not limited to, immune and hematopoietic diseases and/or disorders, particularly leukemia, lymphomas, tumors of hematopoietic origin. Similarly, polypeptides and antibodies directed to these: poiypeptides are useful in providing immunologicai probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the hematopoietic system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e.;g., lymph, serum, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an iindividual not having the disorder.
Preferred polypeptides of the present invention comprise immunogenic epitopes shown in SEQ ID NO: 171 as residues: Gln-30 to Leu-38, Asn-75 to Thr-86.
Polynucleotides encoding ;>aid polypeptides are also provided.
The tissue distribution in activated monocytes, dendritic cells, and tonsils indicates that polynucleotides and polypeptides corresponding to this gene are useful as a therapeutic and/or dial;nostic agent for leukemias, lymphomas, and other diseases associated with cells of hematopoietic origin. Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16, I8, 19, 20, and 27, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival;
differentiation; and/or activation of hematopoietic; cell lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer (e.g. -by boasting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in imrrmne functions. Therefore it is also useful as an agent for immunologicaI disorders including arthritis, asthma, immunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne:, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoimmunity disorders, such as autoimrrmne infertility, tense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's Disease, and scleroderma. Moreover, the protein may represent a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hernatopoietic cells to site:; of injury. 'Thus, this gene product is thought to be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation and/or proliferation of various cell types.
Furthermore, the protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate: ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement. Protein, as well as, antibodies directed against: the protein may show utility as a tumor marker and/or immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:79 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the preserdt invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comvprising a nucleotide sequence described by the general formula of a-b, where a is .any integer between 1 to 2177 of SEQ ID N0:79, b is an integer of 15 to 2191, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:79, and where b is greater than or equal to a +
14.
FEATURES OF PROTEIN ENCODED BY GENE NO: 74 When tested again:;t U937 cell lines, supernatants removed from cells containing this gene activated the GAS (gamma activating sequence) promoter element. Thus, it is likely that this gene activates myeloid cells, and to a lesser extent, other immune cells and tissue cell types, through the JAK-STAT signal transduction pathway. GAS is a promoter element found upstream of many genes which are involved in the Jak-STAT pathway. The Jak-STAT pathway is a large, signal transduction pathway involved in the differentiation and proliferation of cells.
1S Therefore, activation of the Jak-STA7C pathway, reflected by the binding of the GAS
element, can be used to indicate proteins involved in the proliferation and differentiation of cells.
The gene encoding; the disclosed cDNA is believed to reside on chromosome 12. Accordingly, polynucleotides related to this invention are useful as a marker in linkage analysis for chromosome 12.
This gene is expressed primarily in the placenta, brain, and liver and to a lesser extent in most other tissues.
Therefore, polynuc;leotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, hematopoie;tic, neurological, vascular, and developmental diseases andlor disorders, particularly cancers. Similarly, poiypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissue (s) or cell type(s). For a number of disorders of the above tissues or cells, particularG.y of the immune and nervous systems, expression of this gene at significantly highE:r or lower levels is routinely detected in certain tissues or cell types (e.g., hematopoietic, neurological, vascular, developmental, and cancerous and wounded tissues) or bodily fluids (e.g., lymph, serum, amniotic fluid, bile, plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disarder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
The tissue distribution in brain tissue indicates that polynucleotides and polypeptides corresponding to this gene are useful therapeutic and/or diagnostic agent in a multitude of disease states, particularly those involving the immune and neurologic systems. Representative uses are described in the "Regeneration"
and "Hyperproliferative Disorders" sections below, in Example 1 l, 15, and 18, and elsewhere herein. Briefly, the uses include, but are not limited to the detection, treatment, and/or prevention of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Tourette Syndrome, meningitis, encephalitis, demyelinating diseases; peripheral neuropathies, neoplasia, trauma, congenital malformations, spinal cord injuries, ischemia and infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia, obsessive compulsive disorder, depression, panic disorder, learning disabilities, ALS" psychoses., autism, and altered behaviors, including disorders in feeding, sleep patterns, balance, and perception. In addition, elevated expression of this gene product in regions of the brain indicates it plays a role in normal neural function.
Potentially, this gene product is involved in synapse formation, neurotransmission, learning, cognition, homeostasis, or neuronal differentiation or survival. Moreover, the protein is useful in the detection, treatment, and/or prevention of a variety of vascular disorders and conditions, which include, but are not limited to miscrovascular disease, vascular leak. syndrome, aneurysm, stroke, embolism, thrombosis, coronary artery disease, arteriosclerosis, and/or atherosclerosis.
Furthermore, the protein may also be used to determine biological activity, to raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to its use as a nutritional supplement.

Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:80 and may have been publicly available prior to conception of the present invention. Preferably, such related polynucIeotides axe specifically excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1321 of SEQ ID N0:80, b is an integer of 15 to 1335, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID N0:80, and where b is greater than or equal to a +
14.
FEATURES OF PROT)E;IN ENCODED BY GENE NO: 71 The translation product of this gene shares sequence homology with the murine Figi (interleukin-four induced gene I) which shares homology to the monoamine oxidases, parl:icularly in domains responsible for FAD binding.
Preferred polypeptides encoded by this gene comprise the following amino acid sequence:
QDWKAERSQDPFEKCIVIQDPDYEQLLKVTILEADNRIGGRIFTYRDQXTGWIG
ELGAMRMPSSHRILHIt:LCQGLGLNLTKFTQYDKNTWTEVHEXKLRNYVVEK
VPEKLGYALRPQEKGHSPEDIYQMALNQALKDLKALGCRKAMKKFERHTLL
EYLLGEGNLSRPA V QL,LGD VMSEDGFFYLSFAEALRAXS CLSDRLQYSRIV G
GWDLLPRALLSSLSGLVLLNAPVVAMTQGPHDVHVQIETSPPARNLKVLKAD
VVLLTASGPAVKRITFS (SEQ ID NO: 260), and/or LPRHMQEALRRLHYV'.PATKVFLSFRRPFWREEHIEGGHSNTDRPSRMIFYPPP
REGALLLASYTWSDAAAAFA.GLSREEALRLALDDVAALHGPVVRQLWDGT
GVVKRWAEDQHSQGtJFVVQXPALWQTEKDDWTVPYGRIYFAGEHTAYPHG
WVETAVKSALRAAIKI:NSRKGPASDTASPEGHASDMEGQGHVHGVASSPSH
DLAKEEGS (SEQ ID NO: 26I). Polynucleotides encoding such polypeptides are also provided.

A preferred polypeptide fragment of the invention comprises the following amino acid sequence:
MAPLALHLLVLVPILLSILVASQDV~KAERSQDPFEKCMQDPDYEQLLKVTIL
EADNRIGGRIFTYRDQXTGWIGELGAMRMPSSHRILHKLCQGLGLNLTKFTQ
YDKNTVVTEVHEXKLRNYVVEKVPEKLGYALRPQEKGHSPEDIYQMALNQA
LKDLKALGCRKAMKKI~RHTLLE,YLLGEGNLSRPAVQLLGDVMSEDGFFYL -SFAEALRAXSCLSDRLQ!YSRIVGGWDLLPRALLSSLSGLVLLNAPV VAMTQG
PHDVH
VQIETSPPARNLKVLKADVVLLTASGPAVKRITFSPRCPATCRRRCGGCTTCR
PPRCS (SEQ ID NO: 262). Based on the sequence similarity, the translation product of this gene is expected to ;.hare at least some biological activities with monoamine oxidases, disintegrins, metalloproteinases, and apoptosis modulating proteins.
Such activities are known in the art, some of which are described elsewhere herein.
Polynucleotides encoding these polypeptides are also provided.
The polypeptide of this gene has been determined to have a transmembrane domain at about amino acid position 235 - 251 of the amino acid sequence referenced in Table 1 for this gene. Moreover, a cytoplasmic tail encompassing amino acids 252 to 319 of this protein has allso been determined. Based upon these characteristics, it is believed that the protein product of this gene shares structural features to type Ia membrane proteins.
This gene is expressed primarilly in hematopoietic cells, particularly in dendritic cells, and activated monocytes and to a lesser extent in T-cells, endothelial cells, and cells associated with ulcerative colitis.
Therefore, polynucaeotides and polypeptides of the invention are useful as reagents for differential identification of the tissues) or cell types) present in a biological sample and for diagnosis of diseases and conditions which include, but are not limited to, Ieukemias, lymphomas, and diseases associated with antigen presenting cells, in addition to apoptosis dependant events. Similarly, polypeptides and antibodies directed to these polypeptides are useful in providing immunological probes for differential identification of the tissues) or cell type(s). For a number of disorders of the above tissues or cells, particularly of the immune system, expression of this gene at significantly higher or lower levels is routinely detected in certain tissues or cell types (e.g., immune, hematopoietic, and cancerous and wounded tissues) or bodily fluids (e."., lymph, serum; plasma, urine, synovial fluid and spinal fluid) or another tissue or cell sample taken from an individual having such a disorder, relative to the standard gene expression level, i.e., the expression level in healthy tissue or bodily fluid from an individual not having the disorder.
Preferred polypeptides of the present invention comprise irnmunogenic epitopes shown in SEQ ID NO: 173 as residues: Gln-22 to Gln-44, Ala-90 to Gly-95, Lys-137 o Trp-146, Arg-171 to Asp-1.81, Glu-370 to Ser-380, Asp-44.7 to Gly-452, Gln-463 to Trp-469, Asn-504 to Ala-510, Asp-S I2 to His-519, Ala-541 to Vai-550, Asn-558 to His-566. Polynucleotides encoding said polypeptides are also provided.
The tissue distribution immune and hematopoietic cells and tissues, combined with the homology to the routine Fig 1 gene indicates that golynucleotides and polypeptides corresponding to this gene are useful as a therapeutic andlor diagnostic agent for hematopoietic diseases, especially those associated with antigen presenting cells. Representative uses are described in the "Immune Activity" and "infectious disease" sections below, in Example 11, 13, 14, 16; 18, 19, 20, and 27, and elsewhere herein. Briefly, the expression of this gene product indicates a role in regulating the proliferation; survival; difi:erentiation; and/or activation of hematopoietic cell lineages, including blood stem cells. This gene product is involved in the regulation of cytokine production, antigen presentation, or other processes suggesting a usefulness in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the natural gene product is involved in immune functions. Therefore it is also useful as an agent for immunological disorders including arthritis, asthma, irnmunodeficiency diseases such as AIDS, leukemia, rheumatoid arthritis, granulomatou's Disease, inflammatory bowel disease, sepsis, acne, neutropenia, neutrophilia, psoriasis, hypersensitivities, such as T-cell mediated cytotoxicity; immune reactions to transplanted organs and tissues, such as host-versus-graft and graft-versus-host diseases, or autoirnmunity disorders, such as autoimrnune infertility, sense tissue injury, demyelination, systemic lupus erythematosis, drug induced hemolytic anemia, rheumatoid arthritis, Sjogren's f77 Disease, and scleroderma. Moreover, the protein may~represenc a secreted factor that influences the differentiation or behavior of other blood cells, or that recruits hematopoietic cells to sites of injury. Thus, this gene product is thought to be useful in the expansion of stem cells and committed progenitors of various blood lineages, and in the differentiation andlor proliferation of various cell types.
Furthermore, the protein may also be used to determine biological activity, raise antibodies, as tissue markers, to isolate cognate ligands or receptors, to identify agents that modulate their interactions, in addition to i,ts use as a nutritional supplement. Protein, as well as, antibodies directed against the protein may show utility as a tumor marker andlor i0 immunotherapy targets for the above listed tissues.
Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases. Some of these sequences are related to SEQ ID N0:8i and may have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specificaliy i5 excluded from the scope of the present invention. To list every related sequence is cumbersome. Accordingly, preferably excluded from the present invention are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 to 1853 of SEQ ID N0:81, b is an integer of 15 to 1867, where both a and b correspond to the positions of nucleotide 20 residues shown in SEQ ID NO:81, and where b is greater than or equal to a +
14.

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Table i summarizes the information corresponding to each "Gene No."
described above. The nucleotide sequence identified as "NT SEQ ID NO:X" was assembled from partially homologous ("overlapping") sequences obtained from the "cDNA clone ID" identified in Table 1 and, in some cases, from additional related S DNA clones. The overlapping sequences were assembled into a single contiguous sequence of high redundancy (usually three to five overlapping sequences at each nucleotide position), resulting in a final sequence identified as SEQ ID NO:X.
The cDNA Clone ID was deposited on the date and given the corresponding deposit number listed in "ATCC Deposit No:Z and Date." Some of the deposits contain multiple different clones corresponding to the same gene. "Vector"
refers to the type of vector contained in the cDNA Clone ID
"Total NT Seq." refers to the total number of nucleotides in the contig identified by "Gene No." The deposited clone may contain all or most of these sequences, reflected by the nucleotide position indicated as "5' NT of Clone Seq:' and the "3' NT of Clone Seq." of SEQ ID NO:X. The nucleotide position of SEQ
ID
NO:X of the putative start codon (methionine) is identified as "5' NT of Start Codon:' Similarly , the nucleotide position of SEQ iD NO:X of the predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
The translated amino acid sequence, beginning with the methionine, is identified as "AA SEQ ID NO:Y," although other reading frames can also be easily translated using known molecular biology techniques. The polypeptides produced by these alternative open reading frames are specifically contemplated by the present invention.
The first and last amino acid position of SEQ ID NO:Y of the predicted signal peptide is identified as "First AA of Sig Pep" and "Last AA of Sig Pep." The predicted first amino acid position of SEQ ID NO:Y of the secreted portion is identified as "Predicted First AA of Secreted Portion." Finally, the amino acid position of SEQ ID NO:Y of the last amino acid in the open reading frame is identified as "Last AA of ORF."
SEQ ID NO:X and the translated SEQ ID NO:Y are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below. For instance, SEQ ID NO:X is useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA contained in the deposited clone. These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling a variety of forensic and diagnostic methods of the invention. Similarly, polypeptides identified from SEQ TD
NO:Y may be used to generate antibodies which bind specifically to the secreted proteins encoded by the cDNA clones identified in Table 1.
Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletiton in an open reading frame of over 1000 bases}.
Accordingly, for those applications requiring precision in the nucleotide sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X and the predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA containing a human cDNA of the invention deposited with the ATCC, as set forth in Table 1. The nucleotide sequence of each deposited clone can readily be determined by sequencing the deposited clone in accordance with known methods.
The predicted amino acid sequence can then be verified from such deposits.
Moreover, the amino acid sequence of the protein encoded by a particular clone can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell containing the deposited human cDNA, collecting the protein, and determining its sequence.
The present invention also relates to the genes corresponding to SEQ ID
NO:X, SEQ LD NO:Y, or the deposited clone. The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic maternal.
Also provided in the present invention are species homoIogs. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for the desired homologue.
The polypeptides of the invention can be prepared in any suitable manner.
Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art.
The polypeptides may be in the form of the secreted protein, including the mature form, or may be a part of a larger protein, such as a fusion protein (see below).
It is often advantageous to include an additional amino acid sequence which contains secretory or leader sequences, pro-sequences, sequences which aid in purification , such as multiple histidine residues, or an additional sequence for stability during recombinant production.
The polypeptides of the present invention are preferably provided in an isolated form, and preferably are substantially purified. A recombinantly produced version of a polypeptide, including the secreted polypeptide, can be substantially purified by the one-step method described in Smith and Johnson, Gene 67:31-40 (1988). Polypeptides of the invention also can be purified from natural or recombinant sources using antibodies of the invention raised against the secreted protein in methods which are well known in the art.
Signal Sequences Methods far predicting whether a protein has a signal sequence, as well as the cleavage point for that sequence, are available. For instance, the method of McGeoch, Virus Res. 3:271-286 (1985), uses the information from a short N-terminal charged region and a subsequent uncharged region of the complete (uncleaved) protein. The method of von Heinje, Nucleic Acids Res. 14:4683-4690 ( 1986) uses the information from the residues surrounding the cleavage site, typically residues -I3 to +2, where +1 indicates the amino terminus of the secreted protein. The accuracy of predicting the cleavage points of known mammalian secretory proteins for each of these methods is in the range of '75-80%. (von Heinje, supra.) However, the two methods do not always produce the same predicted cleavage point{s) for a given protein.
In the present case, the deduced amino acid sequence of the secreted polypeptide was analyzed by a computer program called SignaIP (Henrik Nielsen et al., Protein Engineering 10:1-6 (1997)), which predicts the cellular location of a.
protein based on the amino acid sequence. As part of this computational prediction of localization, the methods of McGeoch and von Heinje are incorporated. The analysis of the amino acid sequences of the secreted proteins described herein by this program provided the results shown in Table 1.
As one of ordinary skill would appreciate, however, cleavage sites sometimes vary from organism to organism and cannot be predicted with absolute certainty.
Accordingly, the present invention provides secreted polypeptides having a sequence shown in SEQ ID NO:Y which have an N-terminus beginning within 5 residues (i.e., + or - 5 residues) of the predicted cleavage point. Similarly; it is also recognized that in some cases, cleavage of the signal sequence from a secreted protein is not entirely uniform, resulting in more than one secreted species. These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.
Moreover, the signal sequence identified by the above analysis may not necessarily predict the naturally occurring signal sequence. For example, the naturally occurring signal sequence may be further upstream from the predicted signal sequence. However, it is likely that the predicted signal sequence wiI! be capable of directing the secreted protein to the ER. These polypeptides, and the polynucleotides encoding such polypeptides, are contemplated by the present invention.
Polynucleotide and Polypeptide Variants "Variant" refers to a polynucleotide or polypeptide differing from the polynucleotide or polypeptide of the present invention; but retaining essential properties thereof. Generally, variants are overall closely similar, and, in many regions, identical to the polynucleotide or polypeptide of the present invention.
By a polynucleotide having a nucleotide sequence at least, for example, 95%
"identical" to a reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence encoding the polypeptide. In other words, to obtain a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. The query sequence may be an entire sequence shown inTable 1, the ORF (open reading frame), or any fragement specified as described herein.
As a practical matter, whether any particular nucleic acid molecule or polypeptide is at least 90%, 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the presence invention can be determined conventionally using known computer programs. A preferred method for determing the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp.
App.
Biosci. (1990) 6:237-245). In a sequence alignment the query and subject sequences are both DNA sequences. An RNA sequence can be compared by converting U's to T's. The result of said global sequence alignment is in percent identity.
Preferred parameters used in a FASTDB alignment of DNA sequences to calculate percent identiy are: Matrix=Unitary, k-tuple=4, Mismatch Penalty=1, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or the lenght of the subject nucleotide sequence, whichever is shorter.

If the subject sequence is shorter than the query sequence because of S' or 3' deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for S' and 3' truncations of the subject sequence when calculating percent identity. For subject S sequences truncated at the 5' or 3' ends, relative to the the query sequence, the percent identity is corrected by calculating the number of bases of the query sequence that are S' and 3' of the subject sequence, which are not matched/aiigned, as a percent of the total bases of the query sequence. Whether a nucleotide is rnatchedlaligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This corrected score is what is used for the purposes of the present invention. Only bases outside the 5' and 3' bases of the subject equence, as displayed by the FASTDB alignment, which are not matchedlaligned with the query sequence, are calculated for the purposes of manually adjusting the percent identity score.
For example, a 90 base subject sequence is aligned to a 100 base query sequence to determine percent identity. The deletions occur at the 5' end of the subject sequence and therefore, the FASTDB alignment does not show a matchedlalignement of the first 10 bases at S' end. The 10 unpaired bases represent 10% of the sequence (number of bases at the 5' and 3' ends not matchedltotal number of bases in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 bases were perfectly matched the final percent identity would be 90%. In another example, a 90 base subject sequence is compared with a 100 base query sequence. This time the 2S deletions are internal deletions so that there are no bases on the S' or 3' of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only bases 5' and 3' of the subject sequence which are not matched/aligned with the query sequnce are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
By a polypeptide having an amino acid sequence at least, for example, 95%

"identical" to a query amino acid sequence of the present invention, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. In other words, to obtain a polypeptide having an amino acid sequence at least 95%
identical to a query amino acid sequence, up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, (indels) or substituted with another amino acid.
These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.
As a practical matter, whether any particular polypeptide is at least 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, the amino acid sequences shown in Table 1 or to the amino acid sequence encoded by deposited DNA clone can be determined conventionally using known computer programs. A preferred method for determing the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci. (1990) 6:237-245). In a sequence alignment the query and subject sequences are either both nucleotide sequences or both amino acid sequences. The result of said global sequence alignment is in percent identity.
Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=I, Joining Penalty=20, Randomization Group Length=0, Cutoff Score=I, Window Size=sequence length, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of the subject amino acid sequence, whichever is shorter, If the subject sequence is shorter than the query sequence due to N- or C-terminal deletions; not because of internal deletions, a manual correction must be made to the results. This is becuase the FASTDB program does not account for N-and C-terminal truncations of the subject sequence when calculating global percent identity. For subject sequences truncated at the N- and C-termini, relative to the the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matchedlaligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence; are considered for the purposes of manually adjusting the percent identity score. That is, on3y query residue positions outside the farthest N- and C-terminal residues of the subject sequence.
For example, a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity. The deletion occurs at the N
terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/aIignment of the first 10 residues at the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N-and C-termini not matched/totai number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program.
If the remaining 90 residues were perfectly matched the final percent identity would be 90%. In another example, a 90 residue subject sequence is compared with a i00 residue query sequence. This time the deletions axe internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequnce are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
The variants may contain alterations in the coding regions, non-coding regions. or both. Especially preferred are polynucieotide variants containing alterations which produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. Nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are preferred.
Moreover, variants in which S-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination are also preferred. Polynucleotide variants can be produced S for a variety of reasons, e.g., to optimize codon expression for a particular host (change codans in the human mRNA to those preferred by a bacterial host such as E.
coli).
Naturally occurring variants are called "allelic variants," and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism. {Genes II, Lewin, B., ed., John Wiley & Sons, New York (1985).) These allelic variants can vary at either the poiynucleotide and/or polypeptide level.
Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis.
Using known methods of protein engineering and recombinant DNA
technology, variants may be generated to improve or alter the characteristics of the polypeptides of the present invention. For instance, one or more amino acids can be deleted from the N-terminus or C-terminus of the secreted protein without substantial loss of biological function. The authors of Ron et al., J. Biol. Chem. 268:

{1993), reported variant KGF proteins having heparin binding activity even after deleting 3, 8, or 27 amino-terminal amino acid residues. Similarly, Interferon gamma exhibited up to ten times higher activity after deleting 8-10 amino acid residues from the carboxy terminus of this protein. (Dobeli et al., J. Biotechnology 7:199-{1988).) Moreover, ample evidence demonstrates that variants often retain a biological activity similar to that of the naturally occurring protein. For example, Gayle and coworkers (J. Biol. Chem 268:22105-22111 (1993)) conducted extensive mutational analysis of human cytokine IL-la. They used random mutagenesis to generate over 3,500 individual 1L-la mutants that averaged~2.5 amino acid changes per variant over the entire length of the molecule. Multiple mutations were examined at every possible amino acid position. The investigators found that "[m]ost of the molecule could be altered with little effect on either [binding or biological activity]." {See, Abstract.) In fact, only 23 unique amino acid sequences, out of more than 3,500 nucleotide sequences examined, produced a protein that significantly differed in activity from wild-type.
Furthermore, even if deleting one or more amino acids from the N-terminus or C-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities may still be retained. For example, the ability of a deletion variant to induce and/or to bind antibodies which recognize the secreted form will likely be retained when less than the majority of the residues of the secreted form are removed from the N-terminus or C-terminus. Whether a particular polypeptide lacking N- or C-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.
Thus, the invention further includes polypeptide variants which show substantial biological activity. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity. For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie, J. U. et al., Science 247:1306-1310 (1990), wherein the authors indicate that there are two main strategies for studying the tolerance of an amino acid sequence to change.
The first strategy exploits the tolerance of amino acid substitutions by natural selection during the process of evolution. By comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.
The second strategy uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene to idemify regions critical for protein function.
For example, site directed mutagenesis or alanine-scanning mutagenesis'(introduction of single alanine mutations at every residue in the molecule) can be used.

WO 00104140 PCT/US99/15~49 t98 (Cunningham and Wells, Science 244:1081-10$5 ( 1989}.) The resulting mutant molecules can then be tested for biological activity.
As the authors state, these two strategies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at certain amino acid positions in the protein. For example, most buried (within the tertiary structure of the protein) amino acid residues require nonpoIar side chains, whereas few features of surface side chains are generally conserved. Moreover, tolerated conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and Ile; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gln, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly.
Besides conservative amino acid substitution, variants of the present invention include (i) substitutions with one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) substitution with one or more of amino acid residues having a substituent group, or (iii) fusion of the mature polypeptide with another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), or (iv) fusion of the polypeptide with additional amino acids, such as an IgG Fc fusion region peptide, or leader or secretory sequence, or a sequence facilitating purification. Such variant polypeptides are deemed to be within the scope of those skilled in the art from the teachings herein.
For example, polypeptide variants containing amino acid substitutions of charged amino acids with other charged or neutral amino acids may produce proteins with improved characteristics, such as less aggregation. Aggregation of pharmaceutical formulations both reduces activity and increases clearance due to the aggregate's immunogenic activity. (Pinckard et al., Clin. Exp. Immunol. 2:331-(I967); Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit.
Rev.
Therapeutic Drug Carrier Systems 10:307-377 ( 1993).) A further embodiment of the invention relates to a polypeptide which comprises the amino acid sequence of the present invention having an amino acid sequence which contains at least one amino acid substitution, but not more than 50 amino acid substitutions, even more preferably, not more than 40 amino acid substitutions, still more preferably, not more than 30 amino acid substitutions, and still even more preferably, not more than 20 amino acid substitutions. Of course, in order of ever-increasing preference, it is highly preferable for a polypeptide to have an amino acid sequence which comprises the amino acid sequence of the present invention, which contains at least one, but not more than 10, 9, 8, 7, 6, S, 4, 3, 2 or i amino acid substitutions: In specific embodiments, the number of additions, substitutions, and/or deletions in the amino acid sequence of the present invention or fragments thereof (e.g., the mature form and/or other fragments described herein), is 1-5, 5-10, 5-25, 5-50, 10-50 or SO-150, conservative amino acid substitutions are preferable.
Polynucleotide and Polypeptide Fra~rnents In the present invention, a "polynucleotide fragment" refers to a short polynucleotide having a nucleic acid sequence contained in the deposited clone or shown in SEQ ID NO:X. The short nucleotide fragments are preferably at least about 15 nt, and more preferably at least about 20 nt, still more preferably at Least about 30 nt, and even more preferably, at least about 40 nt in length. A fragment "at least 20 nt in length," for example, is intended to include 20 or more contiguous bases from the cDNA sequence contained in the deposited clone or the nucleotide sequence shown in SEQ ID NO:X. These nucleotide fragments are useful as diagnostic probes and primers as discussed herein. Of course, larger fragments (e.g., 50, 150, 500, 600, 2000 nucleotides) are preferred.
Moreover, representative examples of polynucleotide fragments of the invention, include, for example, fragments having a sequence from about nucleotide number 1-50, S1-100, 101-150, 151-200, 201-25Q, 25I-300, 301-350, 351-400, 401-450, 451-500, SO1-550, SS1-600> 651-700, 701-750, 751-800, 800-850, 851-900, 950; 9S1-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200, 1201-1250, 1251-WO 00/04140 PCTlUS99/15849 1300, 1301-1350, i35I-I400, 1401-1450, 1451-1500, 1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800, 1801-1850, 1851-1900, 1901-1950, l95L-2000, or 2001 to the end of SEQ ID NO:X or the cDNA contained in the deposited clone. In this context "about" includes the particularly recited ranges, larger or ' smaller by several (5, 4, 3, 2; or 1) nucleotides, at either terminus or at both termini.
Preferably, these fragments encode a polypeptide which has biological activity. More preferably, these polynucleotides can be used as probes or primers as discussed herein.
In the present invention, a "polypeptide fragment" refers to a short amino acid sequence contained in SEQ ID NO:Y or encoded by the cDNA contained in the deposited clone. Protein fragments may be "free-standing," or comprised within a larger polypeptide of which the fragment forms a part or region, most preferably as a single continuous region. Representative examples of polypeptide fragments of the invention, include, for example, fragments from about amino acid number I-20, 40, 41-60, 6I-80, 81-100, 102-120, 121-140, 141-160, or 161 to the end of the coding region. Moreover, polypeptide fragments can be about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 amino acids in length. In this context "about"
includes the particularly recited ranges, larger or smaller by several (5, 4, 3; 2, or 1) amino acids, at either extreme or at both extremes.
Preferred polypeptide fragments include the secreted protein as well as the mature form. Further preferred polypeptide fragments include the secreted protein or the mature form having a continuous series of deleted residues from the amino or the carboxy terminus, or both. For example, any number of amino acids, ranging from 1-60, can be deleted from the amino terminus of either the secreted polypeptide or the mature form. Similarly, any number of amino acids, ranging from i-30, can be deleted from the carboxy terminus of the secreted protein or mature form.
Furthermore, any combination of the above amino and carboxy terminus deletions are preferred. Similarly, polynucleotide fragments encoding these polypeptide fragments are also preferred.
Also preferred are polypeptide and polynucleotide fragments characterized by structural or functional domains, such as fragments that comprise alpha-helix and alpha-helix forming regions, beta-sheet and beta-sheet-forming regions, turn and turn-forming regions, coil and coil-forming regions, hydrophilic regions, hydrophobic regions, alpha amphipathic regions, beta amphipathic regions, flexible regions, surface-forming regions, substrate binding region, and high antigenic index regions.
Polypeptide fragments of SEQ ID NO:Y falling within conserved domains are specifically contemplated by the present invention. Moreover, polynucleotide fragments encoding these domains are also contemplated.
Other preferred fragments are biologically active fragments. Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.
E~itapes & Antibodies i5 In the present invention, "epitopes" refer to polypeptide fragments having antigenic or immunogenic activity in an animal, especially in a human. A
preferred embodiment of the present invention relates to a polypeptide fragment comprising an epitope, as well as the polynucleotide encoding this fragment. A region of a protein molecule to which an antibody can bind is defined as an "antigenic epitope."
In contrast, an "immunogenic epitope" is defined as a part of a protein that elicits an antibody response. (See, for instance, Geysen et al., Proc. Natl. Acad. Sci.
USA
81:3998-4002 {1983).) Fragments which function as epitopes may be produced by any conventional means. (See, e.g., Houghten, R. A., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985) further described in U.S. Patent No. 4,631,211.) In the present invention, antigenic epitopes preferably contain a sequence of at least seven, more preferably at least nine, and most preferably between about 15 to about 30 amino acids. Antigenic epitopes are useful to raise antibodies, including monaclonal antibodies, that specifically bind the epitope. (See, for instance, Wilson et al., Cell 37:767-778 (1984); Sutcliffe, J. G. et al., Science 219:660-666 (1983).) Similarly, immunogenic epitopes can be used to induce antibodies according to methods well known in the art. (See, far instance, Sutcliffe et al., supra;
Wilson et al., supra; Chow, M. et al., Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle, F. J. et al., J. Gen. Virol. 66:2347-2354 (1985).) A preferred immunogenic epitope includes S the secreted protein. The imrnunogenic epitopes may be presented together with a corner protein, such as an albumin, to an animal system (such as rabbit or mouse) or, if it is long enough (at least about 25 amino acids), without a carrier.
However, immunagenic epitopes comprising as few as 8 to 10 amino acids have been spawn to be sufficient to raise antibodies capable of binding to, at the very least, linear epitopes in a denatured polypeptide (e.g., in Western blotting.) As used herein, the term "antibody" (Ab} or "monoclonal antibody" (Mob) is meant to include intact molecules as well as antibody fragments (such as, for example, Fab and F(ab')2 fragments) which are capable of specifically binding to protein. Fab and Flab'}2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding than an intact antibody. (Wahl et al., J. Nucl. Med. 24:316-325 (1983).) Thus, these fragments are preferred, as well as the products of a FAB or other immunoglobulin expression library. Moreover, antibodies of the present invention include chimeric, single chain, and humanized antibodies.
Fusion Proteins Any polypeptide of the present invention can be used to generate fusion proteins. -For example, the poiypeptide of the present invention, when fused to a second protein, can be used as an antigenic tag. Antibodies raised against the polypeptide of the present invention can be used to indirectly detect the second protein by binding to the polypeptide. Moreover, because secreted proteins target cellular locations based on trafficking signals, the polypeptides of the present invention can be used as targeting molecules once fused to other proteins.
Examples of domains that can be fused to polypeptides of the present invention include not only heteroiogaus signal sequences, but also other heterologous functional regions. The fusion does not necessarily need to be direct, but may occur through linker sequences.
Moreover, fusion proteins may also be engineered to improve characteristics of the polypeptide of the present invention. For instance, a region of additional amino acids; particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence during purification from the host cell or subsequent handling and storage. Also, peptide moieties may be added to the polypeptide to facilitate purification. Such regions may be removed prior to final preparation of the polypeptide. The addition of peptide moieties to facilitate handling IO of polypeptides are familiar and routine techniques in the art.
Moreover, polypeptides of the present invention, including fragments, and specifically epitopes, can be combined with parts of the constant domain of immunoglobulins (IgG)> resulting in chimeric polypeptides. These fusion proteins facilitate purification and show an increased half life in vivo. One reported example 15 describes chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. (EP A 394,827; Traunecker et al., Nature 331:84-86 (1988).) Fusion proteins having disulfide-linked dimeric structures (due to the IgG) can also be more efficient in binding and neutralizing other molecules, than the 20 monomeric secreted protein or protein fragment alone. (Fountoulakis et al., J.
Biochem. 270:3958-3964 (1995).) Similarly, EP-A-~ 464 533 (Canadian counterpart 2045869) discloses fusion proteins comprising various portions of constant region of immunoglobulin molecules together with another human protein or part thereof. In many cases, the Fc part in a 25 fusion protein is beneficial in therapy and diagnosis, and thus can result in, for example, improved pharmacokinetic properties. (EP-A 0232 262.) Alternatively, deleting the Fc part after the fusion protein has been expressed, detected, and purified, would be desired. For example, the Fc portion may hinder therapy and diagnosis if the fusion protein is used as an antigen for immunizations. In drug discovery, for 30 example, human proteins, such as hIL-5, have been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5.
(See, WO 00/04140 PCT/US99/15$49 D. Bennett et al., J. Molecular Recognition 8:52-58 (1995); K. Johanson et al., J. Biol.
Chem. 270:9459-9471 ( 1995). ) Moreover, the polypeptides of the present invention can be fused to marker sequences, such as a peptide which facilitates purification of the fused polypeptide.
In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), among others, many of which are commercially available.
As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein.
Another peptide tag useful for purification, the "HA" tag, corresponds to an epitope derived from the influenza hemagglutinin protein. (Wilson et al., Cell 37:767 { 1984).) Thus, any of these above fusions can be engineered using the polynucleotides or the polypeptides of the present invention.
Vectors , Host Cells. and Protein Production The present invention also relates to vectors containing the polynucleotide of the present invention, host cells, and the production of polypeptides by recombinant techniques. The vector may be, for example, a phage, plasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.
The polynucleotides may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid.
If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.
The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E. coli lac, trp, phoA and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation.
termination, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the transcripts expressed by the constructs will preferably include a translation initiating codon at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.
As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, 6418 or neomycin resistance for eukaryotic cell culture and tetracycline, kanamycin or ampicillin resistance genes for culturing in E. roll and other bacteria. Representative examples of appropriate hosts include, but are not limited to, bacterial cells, such as E. coil, Streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells;
insect veils such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowes melanoma cells; and plant cells. Appropriate culture mediums and conditions for the above-described host cells are known in the art.
Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNHBA, pNHl6a, pNHl8A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRITS available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pVVLNEO, pSV2CAT, pOG44., pXTI
and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Other suitable vectors will be readily apparent to the skilled artisan.
Introduction of the construct into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods 2S are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.
A polypeptide of this invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction. anion or ration exchange chromatography, phosphoceilulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography ("HPLC") is employed for purification.
Polypeptides of the present invention, and preferably the secreted form, can also be recovered from: products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the poiypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host-mediated processes. Thus, it is weal known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.
In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., coding sequence), and/or to include genetic material (e.g., heterologous polynucleotide sequences) that is operably associated with the polynucleotides of the invention, and which activates, alters, and/or amplifies endogenous polynucleotides. For example, techniques known in the art may be used to operably associate heterologous control regions (e.g., promoter and/or enhancer) and endogenous polynucleotide sequences via homologous recombination (see, e.g., U.S. Patent No. 5,641,670, issued June 24, 1997; International Publication No. WO 96/29411, published September 26, 1996;
International Publication No. WO 94/12650, published August 4, 1994: Koller et al., Proc. Natl. Acad. Sci. USA 86:8932-8935 (1989); and Zijlstra et al., Nature 342:435-438 (1989), the disclosures of each of which are incorporated by reference in their entireties).
~.Jses of the Polynucleotides Each of the polynucleotides identified herein can be used in numerous ways as reagents. The following description should be considered exemplary and utilizes known techniques.
The polynucleotides of the present invention are useful for chromosome identification. There exists an ongoing need to identify new chromosome markers, since few chromosome marking reagents, based on actual sequence data (repeat polymorphisms), are presently available. Each polynucleotide of the present invention can be used as a chromosome marker.
Briefly, sequences can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp) from the sequences shown in SEQ ID NO:X. Primers can be selected using computer analysis so that primers do not span more than one predicted exon in the genomic DNA. These primers are then used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the SEQ ID NO:X will yield an amplified fragment.
Similarly, somatic hybrids provide a rapid method of PCR mapping the polynucleotides to particular chromosomes. Three or more clones can be assigned per day using a single thermal cycler. Moreover, sublocalization of the polynucleotides can be achieved with panels of specific chromosome fragments. Other gene mapping strategies that can be used include in situ hybridization, prescreening with labeled flow-sorted chromosomes; and preselection by hybridization to construct chromosome specific-cDNA libraries.
Precise chromosomal location of the polynucleotides can also be achieved using fluorescence in situ hybridization (FISH) of a metaphase chromosomal spread.
This technique uses polynucleotides as short as 500 or 600 bases; however, zos polynucIeotides 2,000-4,000 by are preferred. For a review of this technique, see Verma et al., "Human Chromosomes: a Manual of Basic Techniques." Pergamon Press, New York (1988).
For chromosome mapping, the polynucleotides can be used individually (to mark a single chromosome or a single site on that chromosome) or in panels (for' marking multiple sites andlor multiple chromosomes). Preferred polynucleotides correspond to the noncoding regions of the cDNAs because the coding sequences are more likely conserved within gene families, thus increasing the chance of cross hybridization during chromosomal mapping.
IO Once a polynucleotide has been mapped to a precise chromosomal location, the physical position of the polynucleotide can be used in linkage analysis.
Linkage analysis establishes coinheritance between a chromosomal location and presentation of a particular disease. (Disease mapping data are found, for example, in V.
McKusick, Mendelian Inheritance in Man {available on line through Johns Hopkins University Welch Medical Library) .) Assuming I megabase mapping resolution and one gene per 20 kb, a cDNA precisely localized to a chromosomal region associated with the disease could be one of 50-500 potential causative genes.
Thus, once coinheritance is established, differences in the polynucleotide and the corresponding gene between affected and unaffected individuals can be examined.
First, visible structural alterations in the chromosomes, such as deletions or translocations, are examined in chromosome spreads or by PCR. If no structural alterations exist, the presence of point mutations are ascertained. Mutations observed in some or all affected individuals, but not in normal individuals, indicates that the mutation may cause the disease. However, complete sequencing of the polypeptide and the corresponding gene from several normal individuals is required to distinguish the mutation from a polymorphism. If a new polymorphism is identified, this polymorphic polypeptide can be used for further linkage analysis.
Furthermore, increased or decreased expression of the gene in affected individuals as compared to unaffected individuals can be assessed using polynucieotides of the present invention. Any of these alterations (altered expression, WO 00/04140 PCT/US99/15$49 chromosomal rearrangement, or mutation) can be used as a diagnostic or prognostic marker.
In addition to the foregoing, a polynucieotide can be used to control gene expression through triple helix formation or antisense DNA or RNA. Both methods rely on binding of the polynucleotide to DNA or RNA. For these techniques, preferred polynucleotides are usually 20 to 40 bases in length and complementary to either the region of the gene involved in transcription (triple helix - see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et aL, Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991} ) or to the mRNA itself (antisense - Okano, J.
Neurochem. 56:560 (1991); Oligodeoxy-nucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, FL {1988).) Triple helix formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA
hybridization blocks translation of an mRNA molecule into poiypeptide. Both techniques are effective in model systems, and the information disclosed herein can be used to design antisense or triple helix polynucleotides in an effort to treat disease.
PoIynucleotides of the present invention are also useful in gene therapy. One goal of gene therapy is to insert a normal gene into an organism having a defective gene, in an effort to correct the genetic defect. The polynucleotides disclosed in the present invention offer a means of targeting such genetic defects in a highly accurate manner. Another goal is to insert a new gene that was not present in the host genome, thereby producing a new trait in the host cell.
The polynucleotides are also useful for identifying individuals from minute biological samples. The United States military, for example, is considering the use of restriction fragment length polymorphism (RFLP) for identification of its personnel.
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 identifying personnel. This method does not suffer from the current limitations of "Dog Tags" which can be lost, switched, or stolen, making positive identification difficult. The polynucleotides of the present invention can be used as additional DNA
markers for RFLP.

The polynucleotides of the present invention can also be used as an alternative to RFLP, by determining the actual base-by-base DNA sequence of selected portions of an individual's genome. These sequences can be used to prepare PCR primers for amplifying arid isolating such selected DNA, which can then be sequenced.
Using this technique, individuals can be identified because each individual will have a unique set of DNA sequences. Once an unique ID database is established for an individual, positive identification of that individual, living or dead, can be made from extremely small tissue samples.
Forensic biology also benefits from using DNA-based identification techniques as disclosed herein. DNA sequences taken from very small biological samples such as tissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, semen, etc., can be amplified using PCR. In one prior art technique, gene sequences amplified from polymorphic loci, such as DQa class II HLA gene, are used in forensic biology to identify individuals. (Eriich, H., PCR Technology, Freeman and Co.
(1992).) Once these specific polymorphic loci are amplified, they are digested with one or more restriction enzymes. yielding an identifying set of bands on a Southern blot probed with DNA corresponding to the DQa class II HLA gene. Similarly, polynucleotides of the present invention can be used as polymorphic markers for forensic purposes.
There is also a need for reagents capable of identifying the source of a particular tissue. Such need arises, for example, in forensics when presented with tissue of unknown origin. Appropriate reagents can comprise, for example, DNA
probes or primers specific to particular tissue prepared from the sequences of the present invention. Panels of such reagents can identify tissue by species and/or by organ type. In a similar fashion, these reagents can be used to screen tissue cultures for contamination.
In the very least, the polynucleotides of the present invention can be used as molecular weight markers on Southern gels, as diagnostic probes for the presence of a specific mRNA in a particular cell type, as a probe to "subtract-out" known sequences in the process of discovering novel polynucleotides, far selecting and making oligomers for attachment to a "gene chip" or other support, to raise anti-DNA

antibodies using DNA immunization techniques, and as an antigen to elicit an immune response.
Uses of the Pol~rpeptides Each of the polypeptides identified herein can be used in numerous ways. The following description should be considered exemplary and utilizes known techniques.
A polypeptide of the present. invention can be used to assay protein levels in a biological sample using antibody-based techniques. For examgie, protein expression in tissues can be studied with classical imrnunohistological methods.
(Jaikanen, M., et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., et al., J. Cell .
Biol. 105:3087-3096 (1987).) Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase, and radioisotopes, such as iodine (125I, 121I), carbon (14C), sulfur (35S), tritium (3H), indium (112In), and technetium (99mTc), and fluorescent labels, such as fluorescein and rhodamine, and biotin.
In addition to assaying secreted protein levels in a biological sample, proteins can also be detected in vivo by imaging. Antibody labels or markers fox in vivo imaging of protein include those detectable by X-radiography, NMR or ESR. For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the antibody by labeling of nutrients for the relevant hybridoma.
A protein-specific antibody or antibody fragment which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example, 131I, 112In, 99mTc), a radio-opaque substance, or a material detectable by nuclear magnetic resonance, is introduced (for example, parenterally, subcutaneously, or intraperitoneally) into the mammal. It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99mTc. The labeled antibody or antibody fragment will then preferentially accumulate at the location of cells which contain the specific protein.
In vivo tumor imaging is described in S.W. Burchiel et aL, "Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments." (Chapter 13 in Tumor Imaging:
The Radiochemical Detection of Cancer, S.W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982).) Thus, the invention provides a diagnostic method of a disorder, which involves (a) assaying the expression of a polypeptide of the present invention in cells or body fluid of an individual; (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed polypeptide gene expression level compared to the standard expression level is indicative of a disorder.
Moreover, polypeptides of the present invention can be used to treat disease.
For example, patients can be administered a polypeptide of the present invention in an effort to replace absent or decreased levels of the polypeptide (e.g., insulin), to supplement absent or decreased levels of a different polypeptide (e.g., hemoglobin S
for hemoglobin B), to inhibit the activity of a polypeptide (e.g., an oncogene), to activate the activity of a polypeptide (e.g., by binding to a receptor), to reduce the activity of a membrane bound receptor by competing with it for free ligand (e.g., soluble TNF receptors used in reducing inflammation), or to bring about a desired response (e.g., blood vessel growth).
Similarly, antibodies directed to a polypeptide of the present invention can also be used to treat disease. For example, administration of an antibody directed to a polypeptide of the present invention can bind and reduce overproduction of the polypeptide. Similarly, administration of a.n antibody can activate the polypeptide, such as by binding to a polypeptide bound to a membrane (receptor).
At the very least, the polypeptides of the present invention can be used as molecular weight markers on SDS-PAGE gels or on molecular sieve gel filtration columns using methods well known to those of skill in the art. Polypeptides can also be used to raise antibodies, which in turn are used to measure protein expression from a recombinant cell, as a way of assessing transformation of the host cell.
Moreover, the polypeptides of the present invention can be used to test the following biological activities.
Biological Activities The polynucleotides and polypeptides of the present invention can be used in assays to test for one or more biological activities. If these polynucieotides and polypeptides do exhibit activity in a particular assay, it is likely that these molecules may be involved m the diseases associated with the biological activity. Thus, the polynucleotides and polypeptides could be used to treat the associated disease.
Immune Activity A polypeptide or polynucleotide of the present invention may be useful in treating deficiencies or disorders of the immune system, by activating or inhibiting the proliferation, differentiation, or mobilization (chemotaxis) of immune cells.
Immune cells develop through a process called hematopoiesis, producing myeloid (platelets, red blood cells, neutrophils, and macrophages) and lymphoid (B and T
lymphocytes) cells from pluripotent stem cells. The etiology of these immune deficiencies or disorders may be genetic, somatic, such as cancer or some autoimmune disorders, acquired (e.g., by chemotherapy or toxins), or infectious. Moreover, a polynucleotide or polypeptide of the present invention can be used as a marker or detector of a particular immune system disease or disorder.
A polynucleotide or polypeptide of the present invention may be useful in treating or detecting deficiencies or disorders of hematopoietic cells. A
polypeptide or polynucleotide of the present invention could be used to increase differentiation and proliferation of hematopoietic cells, including the pluripotent stem cells, in an effort to treat those disorders associated with a decrease in certain (or many) types hematopoietic cells. Examples of immunologic deficiency syndromes include, but are not limited to: blood protein disorders (e.g.
agammaglobulinemia, dysgammaglobulinemia). ataxia telangiectasia, common variable imrnunodeficiency, ?t4 Digeorge Syndrome, HIV infection, HTLV-BLV infection, leukocyte adhesion deficiency syndrome, lymphopenia, phagocyte bactericidal dysfunction, severe combined immunodeficiency (SCIDs), Wiskott-Aldrich Disorder, anemia, thrombocytopenia, or hemoglobinuria.
Moreover, a polypeptide or palynucleotide of the present invention could also be used to modulate hemostatic {the stopping of bleeding) or thrombolytic activity {clot formation). For example, by increasing hemostatic or thrombolytic activity, a polynucleotide or polypeptide of the present invention could be used to treat blood coagulation disorders (e.go, afibrinogenemia, factor deficiencies), blood platelet disorders (e.g. thrombocytopenia), or wounds resulting from trauma, surgery, or other causes. Alternatively, a polynucleotide or polypeptide of the present invention that can decrease hemostatic or thrombolytic activity could be used to inhibit or dissolve clotting. These molecules could be important in the treatment of heart attacks (infarction), strokes, or scarnng.
A polynucleotide or polypeptide of the present invention may also be useful in treating or detecting autoimmune disorders. Many autoimmune disorders result from inappropriate recognition of self as foreign material by immune cells. This inappropriate recognition results in an immune response leading to the destruction of the host tissue. Therefare, ehe administration of a polypeptide or polynucleotide of the present invention that inhibits an immune response, particularly the proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing autoimmune disorders.
Examples of autoimmune disorders that can be treated or detected by the present invention include, but are not limited to: Addison's Disease, hemolytic anemia, antiphospholipid syndrome, rheumataid arthritis, dermatitis, allergic encephalomyelitis, glomerulonephritis, Goodpasture's Syndrome, Graves' Disease, Multiple Sclerosis, Myasthenia Gravis, Neuritis, Ophthalmia, Bullous Pemphigoid, Pemphigus, Polyendocrinopathies, Purpura, Reiter's Disease, Stiff-Man Syndrome, Autoimmune Thyroiditis, Systemic Lupus Erythematosus, Autoimmune Pulmonary Inflammation, Guillain-Barre Syndrome, insulin dependent diabetes mellitis, and autaimmune inflammatory eye disease.

Similarly, allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems, may also be treated by a polypeptide or polynucleotide of the present invention. Moreover, these molecules can be used to treat anaphylaxis, hypersensitivity to an antigenic molecule, or blood group incompatibility.
A polynucleotide or polypeptide of the present invention may also be used to treat andlor prevent organ rejection or graft-versus-host disease (GVHD).
Organ rejection occurs by host immune cell destruction of the transplanted tissue through an immune response. Similarly, an immune response is also involved in GVHD, but, in this case, the foreign transplanted immune cells destroy the host tissues. The administration of a polypeptide or polynucleotide of the present invention that inhibits an immune response, particularly the proliferation, differentiation, or chemotaxis of T-cells, may be an effective therapy in preventing organ rejection or GVHI7.
Similarly, a polypeptide or polynucleotide of the present invention may also be used to modulate inflammation. For example, the polypeptide or polynucleotide may inhibit the proliferation and differentiation of cells involved in an inflammatory response. These molecules can be used to treat inflammatory conditions, both chronic and acuee conditions, including inflammation associated with infection (e.g., septic shock, sepsis, or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine induced lung injury, inflammatory bowel disease, Crohn's disease, or resulting from over production of cytokines (e.g., TNF or IL-1.) I~vnerproliferative Disorders A polypeptide or polynucleotide can be used to treat or detect hyperproliferative disorders, including neoplasms. A polypeptide or polynucleotide of the present invention may inhibit the proliferation of the disorder through direct or indirect interactions. Alternatively, a polypeptide or polynucleotide of the present invention may proliferate other cells which can inhibit the hypetproliferative disorder.

For example, by increasing an immune response, particularly increasing antigenic qualities of the hyperproliferYztive disorder or by proliferating, differentiating, or mobilizing T-cells, hyperproliferative disorders can be treated.
This immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response. Alternatively, decreasing an immune response may also be a method of treating hyperproliferative disorders, such as a chernotherapeutic agent.
Examples of hyperproiiferative disorders that can be treated or detected by a polynucleotide or polypeptide of the present invention include, but are not limited to neoplasms located in the: abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, and urogenital.
Similarly, other hyperproliferative disorders can also be treated or detected by a polynucleotide or polypeeptide of the present invention. Examples of such hyperproliferative disorders include, but are not limited to:
hypergammaglobulinemia, lymphopro~liferative disorders, paraproteinemias, purpura, sarcoidosis, Sezary Syndrome, Waldenstron's Macroglobulinemia, Gaucher's Disease, histiocytosis, and any other hyperproliferative disease, besides neoplasia, located in an organ system listed above.
Infectious Disease A polypeptide or polynucieotide of the present invention can be used to treat or detect infectious agents. For example, by increasing the immune response, particularly increasing the proliferation and differentiation of B andlor T
cells, infectious diseases may be treated. The immune response may be increased by either enhancing an existing immune response, or by initiating a new immune response.
Alternatively, the polypepnide or polynucleotide of the present invention may also directly inhibit the infectious agent, without necessarily eliciting an immune response.
Viruses are one example of an infectious agent that can cause disease or symptoms that can be treated or detected by a polynucleotide or polypeptide of the present invention. Examples of viruses, include, but are not limited to the following DNA and RNA viral familiea: Arbovirus, Adenoviridae, Arenaviridae, Arterivirus, Birnaviridae, Bunyaviridae, Calicivirid:~e, Circoviridae, Coronaviridae, Flaviviridae, Hepadnaviridae (Hepatitis), Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, Herpes Zoster}, Mononegavirus (e.g., Paramyxoviridae, Morbillivirus, Rhabdoviridae}, Orthomyxowiridae (e.g., Influenza), Papovaviridae, Parvoviridae, Picornaviridae, Poxviridae (such as Smallpox or Vaccinia), Reoviridae {e.g., Rotavirus), Retroviridae (H'CLV-I, HTLV-II, Lentivirus), and'Togaviridae (e.g., Rubivirus). Viruses falling within these families can cause a variety of diseases or symptoms, including, but not limited to: arthritis, bronchiollitis, encephalitis, eye infections (e.g., conjunctivitis, keratitis), chronic fatigue syndrome, hepatitis (A, B, C, E, Chronic Active, Delta), meningitis, opportunistic infections (e.g., AIDS), pneumonia, Bui-kitt's Lymphoma, chickenpox , hemorrhagic fever, Measles, Mumps, Parainfluenza, Rabies, the common cold, Polio, leukemia, Rubella, sexually transmitted diseases, skin diseases (e.g., Kaposi's, warts), and viremia. A
polypeptide or polynucleotide of the present invention can be used to treat or detect any of these symptoms or diseases.
Similarly, bacterial or fungal agents that can cause disease or symptoms and that can be treated or detected by a polynucleotide or polypeptide of the present invention include, but not limited to, the following Gram-Negative and Gram-positive bacterial families and fungi.. Actinomycetales (e.g., Corynebacterium, Mycobacterium, Norcardia), Aspergillosis, Bacillaceae (e.g., Anthrax, Clostridium), Bacteroidaceae, Blastomycosis, Bordet;ella, Borrelia, Brucellosis, Candidiasis, CampyIobacter, Coccidioid~mycosis, Cryptococcosis, Dermatocycoses, Enterobacteriaceae (KlebsiE;lla, Salmonella, Serratia, Yersinia), Erysipelothrix, Helicobacter, Legionellosis, Leptospirosis, Listeria, Mycoplasmatales, Neisseriaceae (e.g., Acinetobacter> Gonorrhea, Menigococcal), Pasteurellacea Infections (e.g., Actinobacillus, Heamophilus, Pasteurella), Pseudomonas, Rickettsiaceae, Chlamydiaceae, Syphilis, and Staphylococcal. These bacterial or fungal families can cause the following diseases or symptoms, including, but not limited to:
bacteremia, endocarditis, eye infections (conjunctivitis, tuberculosis, uveitis), gingivitis, opportunistic infections (e."., AIDS related infections}, paronychia, prosthesis-related infections, Reiter's Disease, respiratory tract infections, such as Whooping Cough or Empyema, sepsis, Lyme Diasease, Cat-Scratch Disease, Dysentery, Paratyphoid Fever, food poisoning, Typhoid, pneumonia, Gonorrhea, meningitis, Chlamydia, Syphilis, Diphtheria, Leprosy, Paratuberculosis, Tuberculosis, Lupus, Botulism, gangrene, tetanus, impetigo, Rheumatic Fever, Scarlet Fever, sexually transmitted diseases, skin diseases (e.g., cellulitis, dermatocycos~es), toxemia, urinary tract infections, wound infections. A polypeptide or polynucleotide of the present invention can be used to treat or detect any of these symptoms or diseases.
Moreover, parasitic agents causing disease or symptoms that can be treated ar detected by a polynucleotide or poiypeptide of the present invention include, but not limited to> the following families: Amebiasis, Babesiosis, Coccidiosis, Cryptosporidiosis, Dientamoebiasis, Dourine, Ectoparasitic, Giardiasis, Helminthiasis, Leishmaniasis, Theileriasis, Toxoplasmosis, Trypanosomiasis, and Trichomonas. These parasites can cause a variety of diseases or symptoms, including, but not limited to: Scabies, Trombiculiasis, eye infections, intestinal disease (e.g., dysentery, giardiasis), liver disease, lung disease, opportunistic infections (e.g., AIDS
related), Malaria, pregnancy complications, and toxoplasmosis. A polypeptide or polynucieotide of the present invention can be used to treat or detect any of these symptoms or diseases.
Preferably, treatment using a polypeptide or polynucleotide of the present invention could either be b~y administe;ring an effective amount of a poiypeptide to the patient, or by removing cells from the patient, supplying the cells with a polynucleotide of the present invention, and returning the engineered cells to the 2S patient {ex viva therapy). Moreover, the polypeptide or polynucleotide of the present invention can be used as av antigen in a vaccine to raise an immune response against infectious disease.
Regeneration A poiynucleotide or palypeptide of the present invention can be used to differentiate, proliferate. and attract cells, leading to the regeneration of tissues. (See, Science 276:59-87 (1997).',1 The regeneration of tissues could be used to repair, replace, or protect tissue damaged by congenital defects, trauma (wounds, burns, incisions, or ulcers); age, disease (e.g. osteoporosis, osteocarthritis, periodontal disease, liver failure), surgery, including cosmetic plastic surgery, fibrosis, reperfusion injury, or systemic cytokine damage.
Tissues that could tre regenerated using the present invention include organs (e.g., pancreas, liver, intestine, kidney., skin, endothelium), muscle (smooth, skeletal or cardiac), vasculature (including vascular and lymphatics), nervous, hematopoietic, and skeletal (bone, cartilage, tendon, and ligament) tissue. Preferably, regeneration occurs without or decreased scarring. Regeneration also may include angiogenesis.
Moreover, a polynucleotide or polypeptide of the present invention may increase regeneration of tissues difficult to heal. For example, increased tendon/ligament regeneration would guicken recovery time after damage. A
poiynucleotide or polypeptide of the present invention could also be used prophylactically in an effort to avoid damage. Specific diseases that could be treated include of tendinitis, carpal tunnel syndrome, and other tendon or ligament defects. A
further example of tissue regeneration of non-healing wounds includes pressure ulcers, ulcers associated with vascular insufficiency, surgical, and traumatic wounds.
Similarly, nerve and brain tissue could also be regenerated by using a polynucleotide or polypeptide of the present invention to proliferate and differentiate nerve cells. Diseases that could be treated using this method include central and peripheral nervous system diseases, neuropathies, or mechanical and traumatic disorders (e.g:, spinal cord disorders, head trauma, cerebrovascular disease, and stoke). Specifically, diseases associated with peripheral nerve injuries, peripheral neui-opathy (e.g., resulting from chemotherapy or other medical therapies), localized neuropathies, and central nervous system diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome), could all be treated using the polynucleotide or polypeptide of the present invention.
Chemotaxis Wfl 00104140 PCT/US99/15849 A polynucleotide or polypeptide of the present invention may have chemotaxis activity. A che:motaxic molecule attracts or mobilizes cells (e.g., monocytes, fibrobtasts, neutrophiIs, T-cells, mast cells, eosinophils, epithelial andlor endothelial cells) to a particular site in the body, such as inflammation, infection, or site of hyperproliferation. 'Che mobilized cells can then fight off and/or heal the particular trauma or abnorrnaiity.
A polynucleotide or polypeptide of the present invention may increase chemotaxic activity of particular cells. These chemotactic molecules can then be used to treat inflammation, infection, hyperproliferative disorders, or any immune system disorder by increasing the number of cells targeted to a particular location in the body.
For example, chemotaxic molecules can be used to treat wounds and other trauma to tissues by attracting immune cells to the injured location. Chemotactic molecules of the present invention can also attract fibroblasts, which can be used to treat wounds.
It is also contemplated that a polynucleotide or polypeptide of the present invention may inhibit chem.otactic activity. These molecules could also be used to treat disorders. Thus, a polynucleotide; or polypeptide of the present invention could be used as an inhibitor of chemotaxis.
Binding Activity A polypeptide of the present invention may be used to screen for molecules that bind to the polypeptide: or for molecules to which the polypeptide binds.
The binding of the polypeptide and the mo:lecuie may activate (agonist), increase, inhibit (antagonist), or decrease activity of the polypeptide or the molecule bound.
Examples of such molecules include antibodies, oligonucleotides, proteins (e.g., receptors),or small molecules.
Preferably, the molecule is closely related to the natural ligand of the polypeptide, e.g., a fragment of the ligand, or a natural substrate, a ligand, a structural or functional mimetic. (See, CoIigan et al., Current Protocols in Immunology 1(2):Chapter 5 (1991).) Similarly, the molecule can be closely related to the natural receptor to which the polypeptide binds, or at least, a fragment of the receptor capable of being bound by the polypeptide (e.g., active site). In either case, the molecule can be rationally designed using known techniques.
Preferably, the screening for these molecules involves producing appropriate cells which express the polypeptide, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E.
coli.
Cells expressing the polype;ptide (or cell membrane containing the expressed polypeptide) are then preferably contacted with a test compound potentially containing the molecule to observe binding, stimulation, or inhibition of activity of either the polypeptide or the molecule.
The assay may simply test binding of a candidate compound to the polypeptide, wherein binding is detected by a label, or in an assay involving competition with a labeled competitor. Further, the assay may test whether the candidate compound results in a signal generated by binding to the polypeptide.
Alternatively, the assay can be earned out using cell-free preparations, I5 polypeptide/rnolecule affixed to a solid support, chemical libraries, or natural product mixtures. The assay may also simply comprise the steps of mixing a candidate compound with a solution containing a polypeptide, measuring poiypeptide/molecule activity or binding, and comparing the: polypeptide/rnolecule activity or binding to a standard.
Preferably, an ELI;iA assay ca.n measure polypeptide level or activity in a sample (e.g., biological sample) using a monoclonal or polyclonai antibody.
The antibody can measure polypeptide level or activity by either binding, directly or indirectly, to the polypeptide or by competing with the polypeptide for a substrate.
All of these above .assays can be used as diagnostic or prognostic markers.
The molecules discovered using these assays can be used to treat disease or to bring about a particular result in a patient (e.g., blood vessel growth) by activating or inhibiting the polypeptide/molecule. Moreover, the assays can discover agents which may inhibit or enhance the production of the polypeptide from suitably manipulated cells or tissues.
Therefore, the invention includes a method of identifying compounds which bind to a polypeptide of the invention comprising the steps of: (a) incubating a candidate binding compound with a polypeptide of the invention; and (b) determining if binding has occurred. Moreover, the invention includes a method of identifying agonists/antagonists comprising the steps of: (a) incubating a candidate compound with a polypeptide of the invention, (b} assaying a biological activity . and (b) determining if a biological activity of the polypeptide has been altered.
Other Activities A polypeptide or polynucleotide of the present invention may also increase or decrease the differentiation or proliferation of embryonic stem cells, besides, as discussed above, hematopoietic lineage.
A polypeptide or polynucleotide of the present invention may also be used to modulate mammalian characteristics, such as body height, weight, hair color, eye color, skin, percentage of adipose tissue, pigmentation, size, and shape (e.g., cosmetic surgery). Similarly, a polypeptide or polynucleotide of the present invention may be 1S used to modulate mammalian metaboliism affecting catabolism, anabolism, processing, utilization, and storage of energy.
A polypeptide ar p~olynucleotide of the present invention may be used to change a mammal's mental state or physical state by influencing biorhythms, caticadic rhythms, depression (including depressive disorders}, tendency for violence, tolerance for pain, reproductive capabilities (preferably by Activin or Inhibin-like activity), hormonal or endocrine levels, appetite, libido, memory, stress, or other cognitive qualities.
A polypeptide or polynucleotide of the present invention may also be used as a food additive or preservative, such as to increase or decrease storage capabilities, fat 2S content, lipid, protein, carbohydrate; vitamins, minerals, cofactors or other nutritional components.
Other Preferred Embodiiments Other preferred embodiments of the claimed invention include an isolated nucleic acid molecule corryprising a nucleotide sequence which is at least 9S%

identical to a sequence of at least about 50 contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1.
Also preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is included in the nucleotide sequence of SEQ ID NO:X in the range of positions beginning with the nucleotide at about the position of the 5' Nucleotide of the Clone Sequence and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X in Table I.
Also preferred is a nucleic acid. molecule wherein said sequence of contiguous nucleotides is included in t'he nucleotide sequence of SEQ ID NO:X in the range of positions beginning with the nucleotide at about the position of the 5' Nucleotide of the Start Codon and ending; with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X in Table 1.
Similarly preferred is a nucleic acid molecule wherein said sequence of contiguous nucleotides is i;-ncluded in the nucleotide sequence of SEQ ID NO:X
in the range of positions beginning with the nucleotide at about the position of the 5' Nucleotide of the First Amino Acid of the Signal Peptide and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X in Table; 1.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least'95% identical to a sequence of at least about 150 contiguous nucteotides in t:he nucleotide sequence of SEQ ID NO:X.
Further preferred i~; an isolatedl nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence of at least about 500 contiguous nucleotides in t:he nucleotide sequence of SEQ ID NO:X.
2S A further preferred embodiment is a nucleic acid molecule comprising a nucleotide sequence which is at least !a5% identical to the nucleotide sequence of SEQ
ID NO:X beginning with the nucleotide at about the position of the 5' Nucleotide of the First Amino Acid of the Signal Peptide and ending with the nucleotide at about the position of the 3' Nucleotide of the Clone Sequence as defined fox SEQ ID
NO:X
in Table 1.

WO 00104140 1'CT/US99/15849 A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence of SEtz ID NO:X
Also preferred is an isolated nucleic acid molecule which hybridizes under S stringent hybridization conditions to a nucleic acid molecule, wherein said nucleic acid molecule which hybridizes does root hybridize under stringent hybridization conditions to a nucleic acicd molecule having a nucleotide sequence consisting of only A residues or of only T residues.
Also preferred is a composition of matter comprising a DNA molecule which comprises a human cDNA clone identified by a cDNA Clone Identifier in Table 1, which DNA molecule is contained in the material deposited with the American Type Culture Collection and given the ATCC Deposit Number shown in Table 1 for said cDNA Clone Identifier.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least !~5% identical to a sequence of at least 50 contiguous nucleotides in the nucleotide sequence. of a human cDNA clone identified by a cDNA
Clone Identifier in Table 1, which DNA molecule is contained in the deposit given the ATCC Deposit Number shown in Table 1.
Also preferred is an isolated nucleic acid molecule, wherein said sequence of at least 50 contiguous nucleotides is included in the nucleotide sequence of the complete open reading frame sequence encoded by said human cDNA clone.
Also preferred is an isolated nucteic acid molecule comprising a nucleotide sequence which is at least 95% identi<;al to sequence of at least 150 contiguous nucleotides in the nucleotide sequence encoded by said human eDNA clone.
A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence whiich is at least 95% identical to sequence of at least 500 contiguous nucleotides in the nucleotide sequence encoded by said human cDNA clone.
A further preferred embodiment is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to the complete nucleotide sequence encoded by said human cDNA clone.

A further preferred embodiment is a method for detecting in a biological sample a nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a sequence; of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: .a nucleotide sequence of SEQ ID NO:X
wherein X is any integer as defined in Table 1; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATC.'C Deposit Number shown for said cDNA clone in Table 1; which method comprises a step of comparing a nucleotide sequence of at least one nucleic acid molecule in said sample with a sequence selected from said group and determining whether the sequence of said nucleic acid molecule in said sample is at least 95% identical to said ;>eiected seqiuence.
Also preferred is tha: above method wherein said step of comparing sequences comprises determining the extent of nucleic acid hybridization between nucleic acid molecules in said sample a~zd a nucleic: acid molecule comprising said sequence selected from said group. Similarly, also preferred is the above method wherein said step of comparing sequences is perfornned by comparing the nucleotide sequence determined from a nucleic .acid molecule in said sample with said sequence selected from said group. The nuclE:ic acid molecules can comprise DNA molecules or RNA
molecules.
A further preferred embodiment is a method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting nucleic acid molecules in said sample, if any, comprising a nucleotide sequence that is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X
wherein X is any integer as defined in Table l; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the AT(~C Deposit Number shown for said cDNA clone in Table 1.
The method for identifying the species, tissue or cell type of a biological sample can comprise a step of detecting nucleic acid molecules comprising a nucleotide sequence in a p;~nel of at least two nucleotide sequences, wherein at least one sequence in said panel is at least 95% identical to a sequence of at least contiguous nucleotides in a sequence selected from said group.
Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal svtructure or expression of a gene encoding a secreted protein identified in Table L, which method comprises a step of detecting in a biological sample obtained from said subject nucleic acid molecules, if any, comprising a nucleotide sequence that is at least 95% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the group consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is any integer as defined in Table 1;
and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA
Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
The method for diagnosing a pathological condition can comprise a step of detecting nucleic acid moie;cules comprising a nucleotide sequence in a panel of at 1S least two nucleotide sequences, wherein at least one sequence in said panel is at least 9S% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from said group.
Also preferred is a .composition of matter comprising isolated nucleic acid molecules wherein the nucleotide sequences of said nucleic acid molecules comprise a panel of at least two nucleotide sequences, wherein at least one sequence in said panes is at least 9S% identical to a sequence of at least 50 contiguous nucleotides in a sequence selected from the: group consisting of: a nucleotide sequence of SEQ
ID
NO:X wherein X is any inn:eger as defined in Table l; and a nucleotide sequence encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA
clone in Table 1. The nuclieic acid molecules can comprise DNA molecules or RNA
molecules.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the amino acid sequence of SI?Q ID NO:Y wherein Y is any integer as defined in Table i.

Also preferred is a polypeptide~ wherein said sequence of contiguous amino acids is included in the amino acid sequence of SEQ ID NO:Y in the range of positions beginning with the residue at about the position of the First Amino Acid of the Secreted Portion and eroding with the residue at about the Last Amino Acid of the Open Reading Frame as set: forth for SEQ ID NO:Y in Table I.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of SEQ iD NO:Y'.
Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 100 contiguous amino acids in the amino acid sequence of S)_;Q ID NO:Y.
Further preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the complete amino acid sequence of SEQ ID
NO:Y.
Further preferred is an isolated polypeptide comprising an amino acid sequence at least 90% identical to a sequence of at least about 10 contiguous amino acids in the complete amino acid sequence of a secreted protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is a poIypeptide wherein said sequence of contiguous amino acids is included in the amino acid sequence of a secreted portion of the secreted protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown far said cDNA clone in Table 1.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence of at least about 30 contiguous amino acids in the amino acid sequence of the: secreted portion of the protein encoded by a human cDNA
clone identified by a cDN/~ Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 9S% identical to a sequence of at least about I00 contiguous amino acids in WO 00/04140 PCT/US99/15$49 the amino acid sequence of the secreted portion of the protein encoded by a human cDNA clone identified by a. cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is an isolated polypeptide comprising an amino acid sequence at least 95% identical to the; amino acid sequence of the secreted portion of the protein encoded by a human cDNA, clone identified by a cDNA Clone Identifier in Table and contained in the deposit with the ATCC Deposit Number shown for said cDNA
clone in Table I.
Further preferred is an isolated antibody which binds specifically to a IO polypeptide comprising an amino acid sequence that is at least 90%
identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1; and a complete amino acid sequence of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table i.
Further preferred is a method for detecting in a biological sample a polypeptide comprising an amino acidl sequence which is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1; and a complete amino acid sequence of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1; which method comprises a step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group and determining whether the sequence of said polypeptide molecule in said sample is at least 90% identical to said sequence of at. least IO contiguous amino acids.
Also preferred is the above method wherein said step of comparing an amino acid sequence of at least one polypeptide molecule in said sample with a sequence selected from said group comprises determining the extent of specific binding of polypeptides in said sample to an antibody which binds specifically to a polypeptide comprising an amino acid :,equence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of:
an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table l; and a complete amino acid sequence of a protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Also preferred is the above method wherein said step of comparing sequences is performed by comparing; the amino acid sequence determined from a polypeptide molecule in said sample wi~.th said sequence selected from said group.
i0 Also preferred is a 'method for identifying the species, tissue or cell type of a biological sample which method comprises a step of detecting polypeptide molecules in said sample, if any, comprising an amino acid sequence that is at least 90%
identical to a sequence of apt least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y
is any integer as defined in Table 1; and a complete amino acid sequence of a secreted protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said eDNA clone in Table 1.
Also preferred is the above method for identifying the species, tissue or cell type of a biological sample., which method comprises a step of detecting polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least: one sequence in said panel is at least 90%
identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the above group.
Also preferred is a method for diagnosing in a subject a pathological condition associated with abnormal structure or expression of a gene encoding a secreted protein identified in Table l, which method comprises a step of detecting in a biological sample obtained from said subject polypeptide molecules comprising an amino acid sequence in a panel of at least two amino acid sequences, wherein at least one sequence in said panel is at least 90% identical to a sequence of at least contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID 1\(O:Y wherein Y is any integer as defined in Table 1;
and a complete amino acid sequence of a secreted protein encoded by a human cDNA
clone identified by a cDNA Clorne Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
In any of these methods, the step of detecting said polypeptide molecules includes using an antibody.
Also preferred is an isolated nucleic acid molecule comprising a nucleotide sequence which is at least 95% identical to a nucleotide sequence encoding a polyp~ptide wherein said p~olypeptide comprises an amino acid sequence that is at least 90% identical to a sequence of at least 10 contiguous amino acids in a sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y
wherein Y is any integer as defined in Table l; and a complete amino acid sequence of a secreted protein encoded by a human cDNA clone identified by a cDNA Clone identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA cIane in Table 1.
Also preferred is an isolated nucleic acid molecule, wherein said nucleotide sequence encoding a polypeptide has been optimized for expression of said polypeptide in a prokaryotic host.
Also preferred is an isolated nucleic acid molecule, wherein said polypeptide comprises an amino acid sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in Table 1;
and a complete amino acid sequence of a secreted protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA clone in Table 1.
Further preferred is a method of making a recombinant vector comprising inserting any of the above iisolated nucleic acid molecule into a vector. Also preferred is the recombinant vector produced by this method. Also preferred is a method of making a recombinant host: cell comprising introducing the vector into a host cell, as well as the recombinant host cell produced by this method.
Also preferred is a method of making an isolated polypeptide comprising culturing this recombinant host cell under conditions such that said polypeptide is WO 00!04140 PCTIUS99I15849 expressed and recovering said palypeptide. Also preferred is this method of making an isolated polypeptide, wherein said recombinant host cell is a eukaryotic cell and said polypeptide is a secreted. portion of a human secreted protein comprising an amino acid sequence selected from the group consisting of: an amino acid sequence of SEQ ID NO:Y beginning with the residue at the position of the First Amino Acid of the Secreted Portion of SE1~ ID NO:Y wherein Y is an integer set forth in Table 1 and said position of the First Amino Acid of the Secreted Portion of SEQ ID NO:Y
is defined in Table l; and an amino acid sequence of a secreted portion of a protein encoded by a human cDNA clone identified by a cDNA Clone Identifier in Table 1 and contained in the deposit with the ATCC Deposit Number shown for said cDNA
clone in Table 1. The isolated polypeptide produced by this method is also preferred.
Also preferred is a :method of treatment of an individual in need of an increased level of a secreted protein activity, which method comprises administering to such an individual a pharmaceutical composition comprising an amount of an isolated polypeptide, polyrmcleotide, or antibody of the claimed invention effective to increase the level of said protein activity in said individual.
Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as lirr~iting.
xam les Example 1: Isolation of a Selected c:DNA Clone From the Deposited Sample Each cDNA clone :in a cited ATCC deposit is contained in a plasmid vector.
Table 1 identifies the vectors used to construct the cDNA Library from which each clone was isolated. In many cases, the vector used to construct the library is a phage vector from which a plasrroid has been excised. The table immediately below correlates the related plasnnid for each phage vector used in constructing the cDNA
library. For example, where a particular clone is identified in Table 1 as being isolated in the vector "Lambda Zap," the corresponding deposited clone is in "pB Iuescript."

Vector Used to Construct Libra Correspondin~De~posited Plasmid Lambda Zap pBluescript {pBS) Uni-Zap XR pBluescript (pBS) Zap Express pBK
lafmid BA plafmid BA
pSportl pSportl pCMVSport 2.0 pCMVSport 2.0 pCMVSport 3.0 pCMVSport 3.0 pCR~2.1 pCR~2.1 Vectors Lambda Zap (U.S. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap XR (U.S. Patent Nos. 5,12E~, 256 and 5,286,636), Zap Exgress (U.S. Patent Nos.
5,128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res.
16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M., Nucleic Acids Res.
i5 17:9494 {1989)) and pBK {Aping-Mee;s, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Both can be transformed into E. coli strain XL-1 Blue, also available from Stratagene. pBS comes in 4 forms SK+, SK-, KS+
and KS. The S and K refers to the orientation of the polylinker to the T7 and primer sequences which flank the polylinker region {"S" is for Sacl and "K" is for Kpnl which are the first sites on each respective end of the linker). "+" or "-" refer to the orientation of the fl origin of replication ("ori"), such that in one orientation, single stranded rescue initiated from the fl on generates sense strand DNA and in the other, antisense.
Vectors pSportl, pC:MVSport 2.0 and pCMVSport 3.0, were obtained from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All Sport vectors contain an ampicillin resistance gene and may be transformed into E. coli strain DH10B, also available from Life Technologies. (See, for instance, Gruber, C.
E., et al., Focus 15:59 (1993).) Vector lafmid BA (Bento Soares, Columbia University, NY) contains an ampicillin resistance ,gene and can be transformed into E.
coli strain XL-1 Blue. Vector pCR°2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an ampicillin resistance gene and may be transformed into E. coli strain DH10B, available from Life Technologies. (See, for instance, Clark, J. M., Nuc,. Acids Res. 16:9677-9686 (1988} and Mead, D. et al., BiolTechnology 9: (1991).;1 Preferably, a polynucleotide of the present invention does not comprise the phag;e vector sequences identified for the particular clone in Table 1, as well as the corresponding plasmid vector sequences designated above.
The deposited material in the sample assigned the ATCC Deposit Number cited in Table 1 for any given cDNA clone also may contain one or more additional plasmids, each comprising a cDNA clone different from that given clone. Thus, deposits sharing the same ATCC Deposit Number contain at least a plasmid for each cDNA clone identified in 7.'able I. Typically, each ATCC deposit sample cited in Table 1 comprises a mixtm.-e of approximately equal amounts (by weight) of about 50 plasmid DNAs, each containing a different cDNA clone; but such a deposit sample may include plasmids for snore or less than 50 cDNA clones, up to about 500 cDNA
clones.
Two approaches can be used to isolate a particular clone from the deposited sample of plasmid DNAs cited fox that clone in Table 1. First, a plasmid is directly isolated by screening the clones using a polynucleotide probe corresponding to SEQ
ID NO:X.
Particularly, a specific polynuc;leotide with 30..40 nucleotides is synthesized using an Applied Biosystems DNA synthesizer according to the sequence reported.
The oligonucleotide is Iabe:led, for instance, with 3zP-y-ATP using T4 polynucleotide kinase and purified according to routine methods. (E.g., Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring, NY
(1982).) The plasmid mixture is transformed into a suitable host, as indicated above (such as XL-I Blue (Stratagene)) using techniques known to those of skill in the art, such as those provided by the vector supplier or in related publications or patents cited above.
The transformants are plated on 1.5°lo agar plates (containing the appropriate selection agent, e.g., ampicillin} to a~ density of about 150 transformants (colonies) per plate.
These plates are screened using Nylon membranes according to routine methods for bacterial colony screening le.g., Sambrook et al., Molecular Cloning: A
Laboratory Manual, 2nd Edit., ( 1989), Cold Spring Harbor Laboratory Press, pages 1.93 to 1.104), or other techniques known to those of skill in the art.
Alternatively, two primers of 1'7-20 nucleotides derived from both ends of the SEQ ID NO:X (i.e., within the region of SEQ IL7 NO:X bounded by the S' NT and the 3' NT of the clone defined in Table 1) are synthesized and used to amplify the desired cDNA using the deposited cDNA plasmid as a template. The polymerase chain reaction is carried out under routine conditions, for instance, in 2S p.l of reaction mixture with 0.5 ug of the above cDNA template. A convenient reaction mixture is 1.5-S mM MgCl2, 0.01°l0 (w/v) gelatin, 20 p,M each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of 'J~aq polymerase. Thirty five cycles of PCR
(denaturation at 94°C fox 1 min; annealing at SS°C for i min;
elongation at 72°C for 1 min) are performed with a iPerkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis and the DNA band with expected molecular weight is excised and purified. The PCR product is verified to be the selected sequence by su~bcloning and sequencing the DNA product.
Several methods are available for the identification of the 5' or 3' non-coding portions of a gene which may not be present in the deposited clone. These methods include but are not limited to, filter probing, clone enrichment using specific probes, and protocols similar or identical to S' and 3' "RACE" protocols which are well known in the art. For instance, a method similar to S' RACE is available for generating the missing 5' evnd of a desired full-length transcript. (Fromont-Racine et al., Nucleic Acids Res. 21(7):1683-1684 (1993).) Briefly, a specific F~NA oligonucleotide is ligated to the 5' ends of a population of RNA presurr~ably containing full-length gene RNA transcripts. A
primer set containing a primer specific, to the ligated RNA oligonucleotide and a primer specific to a known sequence of the gene of interest is used to PCR
amplify the S' portion of the desired full-length gene. This amplified product may then be sequenced and used to generate the full length gene.
This above method starts with total RNA isolated from the desired source, although poly-A+ RNA can be used. 'The RNA preparation can then be treated with phosphatase if necessary to eliminate 5' phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step. The phosphatase should then be inactivated and the RNA treated with tobacco acid pyraphosphatase in order to remove the cap structure present at the 5' ends of messenger RNAs. This reaction leaves a 5' phosphate group at the 5' end of the cap cleaved RNA which can then be ligated to an RNA aligonucleotide using T4 RNA ligase.
This modified RNA preparation is used as a template for first strand cDNA
synthesis using a gene specific oligonuc:leotide. The first strand synthesis reaction is used as a template for PCR ;amplification of the desired 5' end using a primer specific to the ligated RNA oIigonucleotide and a primer specific to the known sequence of the gene of interest. The resultant product is then sequenced and analyzed to confirm that the 5' end sequence belongs to the desired gene.
Example 2: Isolation of Genomic Clones Corresponding to a Poiynucleotide A human genomic P'1 library (Cienomic Systems, Inc.) is screened by PCR
using primers selected for the cDNA sequence corresponding to SEQ ID NO:X., according to the method de:;cribed in Example 1. (See also, Sambrook.) Example 3: Tissue Distribution of Polvneptide Tissue distribution crf mRNA expression of polynucleotides of the present invention is determined using protocols for Northern blot analysis, described by, among others, Sambrook et al. Far example, a cDNA probe produced by the method described in Example I is habeled with P32 using the rediprimeTM DNA labeling system (Amersham Life Science), according to manufacturer's instructions.
After labeling, the probe is purified using CHROMA SPIN-IOOTM column (Clontech Laboratories, Inc.), according to manufacturer's protocol number PT1200-1. The purified labeled probe is then used to examine various human tissues for mRNA
expression.
Multiple Tissue Na~rthern (MT1V) blots containing various human tissues (H) or human immune system tissues (IM) (Clontech) are examined with the labeled probe using ExpressHybTM hybridization solution (Clontech) according to manufacturer's protocol number PT1190-1. Following hybridization and washing, the blots are mounted and exposed to film at -70°C overnight, and the films developed according to standard procedures.
Example 4: Chromosomal Manning of the Polynucleotides An oligonucleotide primer set is designed according to the sequence at the 5' end of SEQ ID NO:X. This primer preferably spans about i00 nucleotides. This.
primer set is then used in a polymerase chain reaction under the following set of conditions : 30 seconds, 95"C; 1 minute, 56°C; 1 minute, 70°C.
This cycle is repeated 32 times followed by one 5 minute cycle at 70°C. Human, mouse, and hamster DNA is used as template in addition to a somatic cell hybrid panel containing individual chromosomes or chromosome fragments (Bios, Inc). The reactions is analyzed on either 8% polyacrylamide gels or 3.5 % agarose gels. Chromosome mapping is determined by the presence of an approximately 100 by PCR fragment in the particular somatic cell. hybrid.
Example 5: Bacterial Ex~ressian of a Polypentide A polynucleotide encoding a pc>lypeptide of the present invention is amplified using PCR oligonucleotide primers corresponding to the 5' and 3' ends of the DNA
sequence, as outlined in Example 1, to synthesize insertion fragments. The primers used to amplify the cDNA insert should preferably contain restriction sites, such as BamHI and Xbal, at the 5' e;nd of the primers in order to clone the amplified product into the expression vector. For example, BamHI and XbaI correspond to the restriction enzyme sites on vthe bacterial expression vector pQE-9. (Qiagen, Inc., Chatsworth, CA). This plasmid vector encodes antibiotic resistance (Ampr}, a bacterial origin of replication (ori), an IPTG-regulatable promoterloperator (Pl0), a ribosome binding site (RBS'~), a 6-histidine tag (6-His), and restriction enzyme cloning sites.
The pQE-9 vector i~~ digested with BamHI and Xbai and the amplified fragment is ligated into the pQE-9 vector maintaining the reading frame initiated at the bacterial RBS. The ligation mixture is then used to transform the E. coli strain MlSirep4 (Qiagen, Inc.) which contains multiple copies of the plasmid pREP4, which expresses the lacI repressor and also confers kanamycin resistance (Kan~.
Transformants are identified by their ability to grow on LB plates and ampicillin/kanamycin resistant colonies are selected. Plasmid DNA is isolated and confirmed by restriction analysis.
Clones containing the desired constructs are grown overnight (O/N) in liquid culture in LB media supplemented with both Amp (i00 ug/rnl) and Kan (25 ug/mI).
The O/N culture is used to inoculate a large culture at a ratio of 1:100 to 1:250. The cells are grown to an optical density 600 (O.D.''°~ of between 0.4 and 0.6. IPTG
(Isopropyl-B-D-thiogalacto pyranoside) is then added to a final concentration of 1 mM. IPTG induces by inactivating the IacI repressor, clearing the PIO leading to increased gene expression.
Cells are grown for an extxa 3 to 4 hours. Cells are then harvested by centryfugation (20 mins at ~6000Xg). The cell pellet is solubilized in the chaotxopic agent 6 Molar Guanidine HCl by stirring for 3-4 hours at 4°C. The cell debris is removed by centrifugation, and the supernatant containing the polypeptide is loaded onto a nickel-nitrilo-tri-acetic acid ("Ni-NTA") affinity resin coIurnn (available from QIAGEN, Inc., supra). Proteins with a 6 x His tag bind to the Ni-NTA resin with high affinity and can be purified in a simple one-step procedure (for details see: The QIAexpressionist (1995) QIAGEN, Inc., supra).
Briefly, the supernatant is loaded onto the column in 6 M guanidine-HCI, pH
8, the column is first washed with 10 volumes of 6 M guanidine-HCI, pH 8, then washed with 10 volumes of 6 M guanidine-HCI gH 6, and finally the polypeptide is eluted with 6 M guanidine-HCI, pH 5.
The purified protein is then renatured by dialyzing it against phosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus 200 mM NaCI.
Alternatively, the protein can be successfully refolded while immobilized on the Ni NTA column. The recommended conditions are as follows: renature using a linear 6M-1M urea gradient in 5'00 mM NaCI, 20°lo glycerol, 20 mM Tris/HCl pH
7.4, containing protease inhibitors. The renaturation should be performed over a period of 1.5 hours or more. After renaturatian the proteins axe eluted by the addition of 250 WO 00/04140 PCTIUS99/i5849 mM immidazole. Immida~;ole is removed by a final dialyzing step against PBS or mM sodium acetate pH 6 buffer plus 200 mM NaCI. The purified protein is stored at 4° C or frozen at -80° C.
In addition to the above expression vector, the present invention further includes an expression vector comprising phage operator and promoter elements operatively linked to a polynucleotide of the present invention, called pHE4a.
(ATCC
Accession Number 209645, deposited on February 25, 1998.) This vector contains:
1) a neomycinphosphotrarnsferase gene as a selection marker, 2) an E. coli origin of replication, 3) a TS phage promoter sequence, 4) two lac operator sequences, S} a Shine-Delgarno sequence, and 6) the lactose operon repressor gene (IacIq). The origin of replication (oriC) is derived from pUCl9 (LTI, Gaithersburg, MD).
The promoter sequence and operator sequences are made synthetically.
DNA can be inserted into the pHEa by restricting the vector with NdeI and XbaI, BamHI, XhoI, or Asp718, running the restricted product on a gel, and isolating I5 the larger fragment (the stuffer fragment should be about 310 base pairs}.
The DNA
insert is generated according to the PCR protocol described in Example 1, using PCR
primers having restriction ;sites for Ndel (5' primer) and Xbal, BaxnHI, Xhol, or Asp7I8 (3' primer). The F'CR insert is gel purified and restricted with compatible enzymes. The insert and vector are ligated according to standard pratocols.
The engineered vector could easily be substituted in the above protocol to express protein in a bacteriial system.
Examnie 6: Purification of a Polvneutide .from an Inclusion Bod The following alternative method can be used to purify a polypeptide expressed in E coli when it is present in the form of inclusion bodies. Unless otherwise specified, all of the following steps are conducted at 4-10°C.
Upon completion of the production phase of the E. coli fermentation, the cell culture is cooled to 4-10°C: and the cells harvested by continuous centrifugation at 15,000 rpm (Heraeus Sepa~tech). On the basis of the expected yield of protein per unit weight of celi paste and the amount of purified protein required, an appropriate amount of cell paste, by weight, is suspended in a buffer solution containing 100 mM

Tris, 50 mM EDTA, pH 7.4. The cells are dispersed to a homogeneous suspension using a high shear mixer.
The cells are then lysed by passing the solution through a microfluidizer (Microfuidics, Corp. or AP'V Gaulin, inc.) twice at 4000-6000 psi. The homogenate is then mixed with NaCI solution to a final concentration of 0.5 M NaCI, followed by centrifugation at 7000 xg for 15 min. The resultant pellet is washed again using 0.5M
NaCI, 100 mM Tris, 50 mM EDTA, pH 7.4.
The resulting washed inclusiorE bodies are solubilized with I.5 M guanidine hydrochloride (GuHCI) for 2-4 hours. After 7000 xg centrifugation for 15 min., the pellet is discarded and the polypeptide containing supernatant is incubated at 4°C
overnight to allow further GuHCI extraction.
Following high speed centrifugation (30,000 xg) to remove insoluble particles, the GuHCI solubilized protein is refolded by quickly mixing the GuHCI extract with volumes of buffer containing 50 mM sodium, pH 4.5, 150 mM NaCI, 2 mM EDTA
15 by vigorous stirring. The refolded diluted protein solution is kept at 4°C without mixing for 12 hours prior t:o further purification steps.
To clarify the refolded polypeptide solution, a previously prepared tangential filtration unit equipped with 0.i6 p,m membrane filter with appropriate surface area (e.g., Filtron), equilibratedi with 40 mM sodium acetate, pH 6.0 is employed.
The 20 filtered sample is loaded onto a cation exchange resin (e.g., Paros HS-50;
Perseptive Biosystems). The column is washed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and 1500 mM NaCI in the same buffer, in a stepwise manner. The ab:;orbance at 280 nm of the effluent is continuously monitored. Fractions are collected and further analyzed by SDS-PAGE.
Fractions containing the polypeptide are then pooled and mixed with 4 volumes of water. The di iuted sample is then loaded onto a previously prepared set of tandem columns of strong; anion (Poros HQ-50, Perseptive Biosystems) and weak anion (Poros CM-20, Pers,eptive Biosystems) exchange resins. The columns are equilibrated with 40 mM ~~odium acetate, pH 6Ø Both columns are washed with mM sodium acetate, pH b.0, 200 mM NaCI. The CM-20 column is then eluted using a 10 column volume linear gradient ranging from 0.2 M NaCI, 50 mM sodium WO 00/04140 PCTNS99/15$49 acetate, pH 6.0 to 1.0 M NaCI, 50 mNI sodium acetate, pH 6.5. Fractions are collected under constant A,so monitoring of the effluent. Fractions containing the polypeptide (determined, for instance., by 16% SDS-PAGE) are then pooled.
The resultant polyl>eptide should exhibit greater than 95% purity after the S above refolding and purification steps. No major contaminant bands should be observed from Commassie: blue stained 16% SDS-PAGE gel when 5 ~g of purified protein is loaded. The purified protein can also be tested for endotoxin/LPS
contamination, and typically the LPS content is less than 0.1 ng/ml according to LAL
assays.
Example 7: Cloning and Expression of a Pol~~peptide in a Baculovirus Expression Svstem In this example, the plasmid shuttle vector pA2 is used to insert a polynucleotide into a bacu.lovirus to express a polypeptide. This expression vector contains the strong polyhedrin promoter of the Autograplaa californica nuclear polyhedrosis virus (AcMI'TPV} followed by convenient restriction sites such as BamHI, Xba I and Asp71l3. The polyadenylation site of the simian virus 40 ("SV40") is used for efficient polyadenylation. For easy selection of recombinant virus, the plasmid contains the beta-galactosidase gene from E. coli under control of a weak Drosophila promoter in the same orientation, followed by the polyadenylation signal of the polyhedrin gene. The inserted genes are flanked on both sides by viral sequences far cell-mediatt:d homologous recombination with wild-type viral DNA
to generate a viable virus that express tI-~e cloned poiynucleotide.
Many other baculc>virus vectors can be used in place of the vector above, such as pAc373, pVL941, and pAcIMi, as. one skilled in the art would readily appreciate, as long as the construct provides appropriately located signals for transcription, translation, secretion and the like, including a signal peptide and an in-frame AUG as required. Such vectors are described, for instance, in Luckow et al., Virology 170:31-39 ( 1989).
Specifically, the c:DNA sequence contained in the deposited clone, including the AUG initiation codon and the naturally associated leader sequence identified in WO 00104140 PCT/US99/15$49 Table 1, is amplified using the PCR protocol described in Example 1. If the naturally occurnng signal sequence i,s used to produce the secreted protein, the pA2 vector does not need a second signal peptide. Alternatively, the vector can be modified (pA2 GP) to include a baculovirus leader sequence, using the standard methods described in Summers et al., "A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures," Texas Agricultural Experimental Station Bulletin No. 1555 ( 1987).
The amplified fragment is isolated from a 1% agarose gel using a commercially available kit ("Geneclean," BIO l0I Inc., La Jolla, Ca.). The fragment !0 then is digested with appropryate restriction enzymes and again purified on a 1%
agarose gel.
The plasmid is digested with the corresponding restriction enzymes and optionally, can be dephosphorylated using calf intestinal phosphatase, using routine procedures known in the aot. The DNA is then isolated from a 1 % agarose gel using a commercially available kit ("Geneclean" BIO 101 Inc., La Jolla, Ca.).
The fragment and the dephosphorylated plasmid are ligated together with T4 DNA ligase. E. coli HB 101 or other suitable E. coli hosts such as XL-1 Blue (Stratagene Cloning Systems, La Jolla, CA) cells are transformed with the ligation mixture and spread on culture plates. Bacteria containing the plasmid are identified by digesting DNA from individual colonies and analyzing the digestion product by gel electrophoresis. The sequence of the cloned fragment is confirmed by DNA
sequencing.
Five ~.g of a plasmid containing the polynucleotide is co-transfected with 1.0 ~tg of a commercially available Iinearized baculovirus DNA ("BaculoGoldTM
baculovirus DNA", Pharmingen, San Diego, CA), using the lipofection method described by Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417 ( 1987).
One p.g of BaculoGoldz'M virus DNA and 5 ~g of the plasmid are mixed in a sterile well of a microtiter plate containing; 50 pl of serum-free Grace's medium (Life Technologies Inc., Gaithersburg, MD). Afterwards, 10 pl Lipofectin plus 90 ~.1 Grace's medium are added, mixed and incubated for 15 minutes at room temperature. Then the transfection mixture is added drop-wise to Sf9 insect cells (ATCC CRL 1711) seeded in a 35 mm tissue culture plate with i rnl Grace's medium without serum. The plate is then incubated for 5 hours 4~i 2?° C. The transfection solution is then removed from the plate and 1 ml of Grace's insect medium supplemented with 10°lo fetal calf serum is added. Cultivation is they continued at 2?° C for four days.
After four days the supernatant is collected and a plaque assay is performed, as described by Surrimers and Smith, supra. An agarose gel with "Blue Gal"
(Life Technologies Ine., Gaithersburg) is used to allow easy identification and isolation of gal-expressing clones, which produce blue-stained plaques. (A detailed description of a "plaque assay" of this type can also be found in the user's guide for insect cell culture and baculovirology distributed by Life Technologies Inc., Gaithersburg, page 9-10.) After appropriate incubation, blue stained plaques are picked with the tip of a micropipettor (e.g., Eppend.orf). The agar containing the recombinant viruses is then resuspended in a microcentrifuge tube containing 200 p.l of Grace's medium and the suspension containing the recombinant baculovirus is used to infect Sf9 cells seeded in 35 mm dishes. Four days later the supernatants of these culture dishes are harvested and then they are stored at 4° C.
To verify the expression of the polypeptide, S~ cells are grown in Grace's medium supplemented with 10% heat-inactivated FBS. The cells are infected with the recombinant baculovims containing the polynucleotide at a multiplicity of infection ("MOI") of about 2. If radiolabeled proteins are desired, 6 hours later the medium is removed and is replaced with SF900 II medium minus methionine and cysteine (available from Life Technologies Inc., Rockville, MD). After 42 hours, 5 ~Ci of 35S-methionine and 5 pCi 35S-cysteine (available from Amersham) axe added.
The cells are further incubated for 16 hours and then are harvested by centrifugation.
The proteins in the supernatant as well. as the intracellular proteins are analyzed by SDS-PAGE followed by autoradiography (if radiolabeled).
Microsequencing of the amino acid sequence of the amino terminus of purified protein may be used to determine the amino terminal sequence of the produced protein.
Example 8: Expression of a Polype>Dtide in Mammalian Cells The polypeptide of the present invention can be expressed in a mammalian cell. A typical mammalian expression vector contains a promoter element, which mediates the initiation of tr~inscription of mRNA, a protein coding sequence, and signals required for the termination of transcription and polyadenyIation of the transcript. Additional elements include enhancers, Kozak sequences and intervening sequences flanked by donor and acceptor sites for RNA splicing. Highly efficient transcription is achieved with the early and late promoters from SV40, the long terminal repeats (LTRs) from Retroviruses, e.g., RSV, HTLVI, HIVI and the early promoter of the cytomegalcrvirus (CMV). However, cellular elements can also be used (e.g., the human actin promoter).
Suitable expression vectors for use in practicing the present invention include, for example, vectors such as pSVL and pMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146}, pBCI2MI (ATCC 67109), pCMVSport 2.0, and pCM'VSport 3Ø Mammalian host cells that could be used include, human Hela, 293, :EI9 and Jurkat cells, mouse NIH3T3 and C 127 cells, Cos 1, Cos 7 and CV I, quail QC 1-3 cells, mouse L cells and Chinese hamster ovary (CHO}
cells.
Alternatively, the polypeptide c:an be expressed in stable cell lines containing the polynucleotide integrated into a chromosome. The co-transfection with a selectable marker such as dlhfr, gpt, neomycin, hygromycin allows the identification and isolation of the transfected cells.
The transfected gene can also be amplified to express large amounts of the encoded protein. The DHFR (dihydrofolate reductase) marker is useful in developing cell lines that carry several hundred or even several thousand copies of the gene of interest. (See, e.g., Alt, F. 'JV., et al., J. Biol. Chem. 253:1357-1370 (197$); Hamlin, J.
L. and Ma, C., Biochem. e!t Biophys. Acta, 1097:107-143 (1990); Page, M. J.
and Sydenham, M. A., Biotechnology 9:64-68 (1991).} Another useful selection marker is the enzyme glutamine synthase (GS) (Murphy et al., Biochem J. 227:277-279 (1991); Bebbington et al., BioITechnology 10:169-175 (1992). Using these markers, the mammalian cells are grown in sele;etive medium and the cells with the highest resistance are selected. These cell lines contain the amplified genes) integrated into a WO 00/04140 PCTNS99/15849 .

chromosome. Chinese hamster ovary (CHO) and NSO cells are often used for the production of proteins.
Derivatives of the p~lasmid pSV2-dhfr (ATCC Accession No. 37146), the expression vectors pC4 (A'fCC Accession No. 209646) and pC6 (ATCC Accession No.209647) contain the strong promoter (LTR) of the Rous Sarcoma Virus (Cullen et ai., Molecular and Cellular Biology, 4:38-447 (March, 1985)) plus a fragment of the CMV-enhancer (Boshart et. al., Cell 41.:521-530 (1985).) Multiple cloning sites, e.g., with the restriction enzyme; cleavage sites BamHI, XbaI and Asp718, facilitate the cloning of the gene of interest. The vectors also contain the 3' intron, the polyadenylation and termination signal of the rat preproinsulin gene, and the mouse DHF'R gene under control of the SV40 early promoter.
Specifically, the plasmid pC6, for example, is digested with appropriate restriction enzymes and then dephosphorylated using calf intestinal phosphates by procedures known in the art. The vector is then isolated from a 1% agarose gel.
A polynucleotide of the present invention is amplified according to the protocol outlined in Example 1. If the. naturally occurring signal sequence is used. to produce the secreted protein, the vector does not need a second signal peptide.
Alternatively, if the naturally occurnng signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., WO 96134891.) The amplified fragment is isolated from a I% agarose gel using a commercially available kit ("Geneclean," BIO 101 Inc., La Jolla, Ca.). The fragment then is digested with appropriate restriction enzymes and again purified on a 1%
agarose gel.
The amplified fragment is then digested with the same restriction enzyme and purified on a 1% agarose g;eI. The isolated fragment and the dephosphorylated vector are then ligated with T4 DNA ligase. E. coli HB 101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pC6 using, for instance, restriction enzyme analysis.
Chinese hamster ovary cells lacking an active DHFR gene is used for transfection. Five p,g of the expression plasmid pC6 is cotransfected with 0.5 pg of the plasmid pSVneo using iipofectin (Felgner et al., .raepra). The plasmid pSV2-neo contains a dominant setect;able marker, the neo gene from Tn5 encoding an enzyme that confers resistance to a group of antibiotics including G4i8. The cells are seeded in alpha minus MEM supplemented with 1 mg/ml 6418. After 2 days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner> Germany) in alpha minus MEM supplemented with 10, 25, or 50 ng/ml of metothrexate plus 1 mg/mi 6418. After about 10-14 days single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flask:e using different concentrations of methotrexate {50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones growing at the highest concentrations of methotrexate are then transferred to new 6-well plates containing even higher IO concentrations of methotre:xate (1 p,M, 2 p.M, S wM, i0 mM, 20 mM). The same procedure is repeated until clones are obtained which grow at a concentration of 100 -200 ~tM. Expression of th~~ desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reversed phase HPLC analysis.
Example 9: Protein Fusions The polypeptides of the present invention are preferably fused to other proteins. These fusion proteins can be used for a variety of applications. For example, fusion of the present polypeptides to His-tag, HA-tag, protein A, IgG
domains, and maltose binding protein facilitates purification. (See Example 5;
see also EP A 394,827; Traunecker, et al., Nature 331:84-86 (I988).) Similarly, fusion to IgG-1, IgG-3, and albumin increases t:he halflife time in vivo. Nuclear localization signals fused to the polype;ptides of the present invention can target the protein to a specific subcellular locali~:ation, while covalent heterodimer or homodimers can increase or decrease the acaivity of a fusion protein. Fusion proteins can also create chimeric molecules having more than one function. Finally, fusion proteins can increase solubility and/or ;stability of the fused protein compared to the non-fused protein. All of the types of fusion proteins described above can be made by modifying the following protocol, which outlines the fusion of a palypeptide to an IgG molecule, or the protocol described in Example 5.
Briefly, the human Fe portion of the IgG molecule can be PCR amplified, using primers that span th~~ 5' and 3' ends of the sequence described below.
These primers also should have convenient restriction enzyme sites that will facilitate cloning into an expression vector, preferably a mammalian expression vector.
For example, if pC4 (Accession No. 209646} is used, the human Fc portion can be ligated into the BamHI cloning site. Note that the 3' BamHI site should be destroyed. Next, the vector' containing the human Fc portion is re-restricted with BamHI, linearizing the vector, and a polynucleotide of the present invention, isolated by the PCR protocol described in Example l, is ligated into this BamHI site.
Note that the polynucleotide is cloned without a stop colon, otherwise a fusion protein will not be produced.
If the naturally occurring signalL sequence is used to produce the secreted protein, pC4 does not need a second signal peptide. Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. (See, e.g., WO 96/34891.}
Hurnan IgG Fc region:
GGGATCCGGAGCCCA~~ATCTTCTGACAAAACTCACACATGCCCACCGTGC
CCAGCACCTGAATTCGAGGGTGC:ACCGTCAGTCTTCCTCTTCCCCCCAAAA
CCCAAGGACACCCTCA.TGATCTCCCGGACTCCTGAGGTCACATGCGTGGT
GGTGGACGTAAGCCAC'.GAAGACCCTGAGGTCAAGTTCAACTGGTACGTGG
ACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTA
CAACAGCACGTACCGT'GTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT
GGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCA
ACCCCCATCGAGAAAACCATCTC:CAAAGCCAAAGGGCAGCCCCGAGAAC
CACAGGTGTACACCCT'GCCCCCATCCCGGGATGAGCTGACCAAGAACCAG
GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCAAGCGACATCGCCGT
GGAGTGGGAGAGCAA'TGGGCAC;CCGGAGAACAACTACAAGACCACGCCT
CCCGTGCTGGACTCCGACGGCTC:CTTCTTCCTCTACAGCAAGCTCACCGTG
GACAAGAGCAGGTGGCAGCAGC;GGAACGTCTTC"TCATGCTCCGTGATGCA
TGAGGCTCTGCACAAC'.CACTACACGCAGAAGAGCCTCTCCC:TGTC'.TCCGG
GTAAATGAGTGCGACGGCCGCGACTCTAGAGGAT (SEQ ID NO:1}

Example 10: Production ~of an AntikrodX,from a PolYpeptide The antibodies of the present invention can be prepared by a variety of methods. (See, Current Protocols, Chapter 2.) For example, cells expressing a polypeptide of the present invention is administered to an animal to induce the production of sera containing polyclonal antibodies. In a preferred method, a preparation of the secreted protein is prepared and purified to render it substantially free of natural contaminants. Such a preparation is then introduced into an animal in order to produce potyclonal antisera of greater specific activity.
In the most preferred method, the antibodies of the present invention are i0 monoclonal antibodies (or vprotein binding fragments thereof). Such monoclonal antibodies can be prepared using hybridoma technology. (Kohler et al., Nature 256:495 (1975); Kohler et ;al., Eur. J. Immunol. 6:511 (1976); Kohler et al., Eur. J.
Immunol. 6:292 (1976); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. S63-681 (1981).) In general, such procedures involve immunizing an animal (preferably a mouse) with polypeptide or; more preferably, with a secreted polypeptide-expressing cell. Such cells may be cultured in any suitable tissue culture medium; however, it is preferable to culture cells in Earie's modified Eagle's medium supplemented with 10% fetal bovine serum (inactivated at about 56°C)> and supplemented with about 10 g/1 of nonessential amino acids, about 1,000 Ulml of penicillin, and about 100 p.g/ml of streptomycin.
The splenocytes of such mice are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention; howevevr, it is preferable to employ the parent myeloma cell line (SP20), available from then ATCC. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al. (Gastroenterology 80:225-232 {1981).) The hybridoma cells obtained through sucih a selection are then assayed to identify clones which secrete antibodies capable of binding the polypeptide.
Alternatively, additional antibodies capable of binding to the polypeptide can be produced in a two-step procedure using anti-idiotypic antibodies. Such a method makes use of the fact that .antibodies are themselves antigens, and therefore, it is possible to obtain an antibody which binds to a second antibody. In accordance with this method, protein specific; antibodies are used to immunize an animal, preferably a mouse. The splenocytes of such an animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones which produce an antibody whose ability to bind to the protein-specific antibody can be blocked by the polypeptide. Such antibodies comprise anti-idiotypic antibodies to the protein-specific antibody and can bc~ used to irr~munize an animal to induce formation of further protein-specific antilbodies.
It will be appreciated that Fab and F(ab')2 and other fragments of the antibodies of the present invention may be used according to the methods disclosed herein. Such fragments are typically produced by proteoiytic cleavage, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')2 fragments). Alternatively, secreted protein-binding fragments can be produced through the application of recombinant: DNA technology or through synthetic chemistry.
For in vivo use of antibodies in humans, it may be preferable to use "humanized" chimeric monoclonal antibodies. Such antibodies can be produced using genetic constructs derived from lhybridoma cells producing the monoclonal antibodies described above. Methods for producing chimeric antibodies are known in the art. {See, for review, Morrison, Science 229:1202 ( 1985); Oi et al., BioTechniques 4:214 ( 1986); Cabilly et al., U.S. Patent No. 4,816,567;
Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533;
Robinson et al., WO 8702671; Boulianne et al., :f~lature 312:643 (1984); Neuberger et al., Nature 314:268 (i985).}
Example 11: Production Of Secreted Protein For High-Throughput Screening Assavs The following protocol produces a supernatant containing a polypeptide to be tested. This supernatant can then be used in the Screening Assays described in Examples 13-20.

i DEMANDES OU BREV'ETS VOL.UM1NEUX

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'i'H1S SECT10N OF THE APPLlCATIONIPATElIiT CONTAINS MORE
'THAN ONE VOLUME
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Claims (23)

What Is Claimed Is:

1. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence at least 95% identical to a sequence selected from the group consisting of:
(a) a polynucleotide fragment of SEQ ID NO:X or a polynucleotide fragment of the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(b) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(c) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y or a polypeptide domain encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizatrle to SEQ ID NO:X;
(d) a polynucleotide encoding a polypeptide epitope of SEQ ID NO:Y or a polypeptide epitope encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X;
(e) a polynucleotide encoding a polypeptide of SEQ ID NO:Y or the cDNA
sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X, having biological activity;
(f) a polynucleotide which is a variant of SEQ ID NO:X;
(g) a polynucleotide which is an allelic variant of SEQ ID NO:X;
(h) a polynucleotide which encodes a species homologue of the SEQ ID
NO:Y;
(i) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a}-(h), wherein said polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues.

2. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding a secreted protein.

3. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding the sequence identified as SEQ ID NO:Y or the polypeptide encoded by the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X.

4. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises the entire nucleotide sequence of SEQ ID
NO:X
or the cDNA sequence included in ATCC Deposit No:Z, which is hybridizable to SEQ ID NO:X.

5. The isolated nucleic acid molecule of claim 2, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

6. The isolated nucleic acid molecule of claim 3, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

7. A recombinant vector comprising the isolated nucleic acid molecule of claim 1.

8. A method of making a recombinant host cell comprising the isolated nucleic acid molecule of claim 1.

9. A recombinant host cell produced by the method of claim 8.

10. The recombinant host cell of claim 9 comprising vector sequences.

11. An isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence selected from the group consisting of:
{a) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(b) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z, having biological activity;
(c) a polypeptide domain of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(d) a polypeptide epitope of SEQ ID NO;Y or the encoded sequence included in ATCC Deposit No:Z;
(e) a secreted form of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(f) a full length protein of SEQ ID NO:Y or the encoded sequence included in ATCC Deposit No:Z;
(g) a variant of SEQ ID NO:Y;
(h) an allelic variant of SEQ ID NO:Y; or (i) a species homologue of the SEQ ID NO:Y.

12. The isolated polypeptide of claim 11, wherein the secreted form or the full length protein comprises sequential amino acid deletions from either the C-terminus or the N-terminus.

13. An isolated antibody that binds specifically to the isolated polypeptide of claim 11.

14. A recombinant host cell that expresses the isolated polypeptide of claim 11.

15. A method of making an isolated polypeptide comprising:
(a) culturing the recombinant host cell of claim 14 under conditions such that said polypeptide is expressed; and (b) recovering said polypeptide.

16. The polypeptide produced by claim 15.

17. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polypeptide of claim 11 or the polynucleotide of claim 1.

18. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or absence of a mutation in the polynucleotide of claim 1; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or absence of said mutation.

19. A method of diagnosing a pathological condition or a susceptibility to a pathological condition ins a subject comprising:
(a) determining the presence or amount of expression of the polypeptide of claim 11 in a biological sample; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or amount of expression of the polypeptide.

20. A method for identifying a binding partner to the polypeptide of claim 11 comprising:
(a) contacting the polypeptide of claim 11 with a binding partner; and (b) determining whether the binding partner effects an activity of the polypeptide.

21. The gene corresponding to the cDNA sequence of SEQ ID NO:Y.

22. A method of identifying an activity in a biological assay, wherein the method comprises:
(a) expressing SEQ ID NO:X in a cell;
(b) isolating the supernatant;

(c) detecting an activity in a biological assay; and (d) identifying the protein in the supernatant having the activity.

23. The product produced by the method of claim 20.