(12) Patent Application Publication (10) Pub. No.: US 2009/0178153 A1 Gaitanaris Et Al

US 20090178153A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0178153 A1 Gaitanaris et al. (43) Pub. Date: Jul. 9, 2009

(54) GPROTEIN COUPLED RECEPTORS AND Related U.S. Application Data USES THEREOF (63) Continuation of application No. 10/527,265, filed on Jan. 26, 2006, now abandoned, filed as application No. (75) Inventors: George A. Gaitanaris, Seattle, WA PCT/US03/28226 on Sep. 9, 2003. (US); John E. Bergmann, Mercer (60) Provisional application No. 60/409,303, filed on Sep. Island, WA (US); Alexander 9, 2002, provisional application No. 60/461.329, filed Gragerov, Seattle, WA (US); John on Apr. 9, 2003. Hohmann, La Conner, WA (US); Publication Classification Fusheng Li, Seattle, WA (US); (51) Int. Cl. Linda Madisen, Seattle, WA (US); AOIK 67/027 (2006.01) Kellie L. McIlwain, Washington, CI2O I/68 (2006.01) DC (US); Maria N. Pavlova, A63L/7088 (2006.01) Seattle, WA (US); Demitri GOIN 33/53 (2006.01) Vassilatis, Seattle, WA (US); CI2N IS/00 (2006.01) Hongkui Zeng, Shoreline, WA CI2N 5/10 (2006.01) (US) A61R 49/00 (2006.01) (52) U.S. Cl...... 800/18: 530/300: 536/23.1; 435/6; Correspondence Address: 514/44; 435/7.2: 800/21: 435/325; 424/9.2 SEED INTELLECTUAL PROPERTY LAW (57) ABSTRACT GROUP PLLC The present invention provides GPCR polypeptides and poly 701 FIFTHAVE, SUITE 5400 nucleotides, recombinant materials, and transgenic mice, as SEATTLE, WA 98104 (US) well as methods for their production. The polypeptides and polynucleotides are useful, for example, in methods of diag nosis and treatment of diseases and disorders. The invention (73) Assignee: OMEROS CORPORATION, also provides methods for identifying compounds (e.g., ago Seattle, WA (US) nists or antagonists) using the GPCR polypeptides and poly nucleotides of the invention, and for treating conditions asso ciated with GPCR dysfunction with the GPCR polypeptides, (21) Appl. No.: 12/243,731 polynucleotides, or identified compounds. The invention also provides diagnostic assays for detecting diseases or disorders (22) Filed: Oct. 1, 2008 associated with inappropriate GPCR activity or levels. Patent Application Publication Jul. 9, 2009 Sheet 1 of 31 US 2009/0178153 A1

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GPROTEIN COUPLED RECEPTORS AND polypeptide listed in Table 2; (c) polypeptides having at least USES THEREOF 90%.95%,97%.98%, or 99% sequence identity to a polypep tide listed in Table 2; and (d) polypeptides listed in Table 2. REFERENCE TO TABLE SUBMITTED ON 0008 Polypeptides of the present invention also include COMPACT DISC variants of the aforementioned polypeptides, including all 0001 Pursuant to PCT Administrative Instruction S 801 allelic forms and splice variants. Such polypeptides vary from (a), Table 35 is submitted herewith in triplicate on compact the reference polypeptide by insertions, deletions, and Sub disc as “50001.007WO3 Table 35.txt, created on Sep. 8, stitutions that may be conservative or non-conservative, or 2003 and having a size of 1,804 kB, hereby incorporated by any combination thereof. Particularly desirable variants are reference. those in which several, for instance from 50 to 30, from 30 to 20, from 20 to 10, from 10 to 5, from 5 to 3, from 3 to 2, or BACKGROUND OF THE INVENTION from 2 to 1 amino acids are inserted. Substituted, or deleted, in any combination. 0002. The invention relates to the fields of medicine and 0009 Polypeptides of the present invention also include drug discovery. polypeptides that include an amino acid sequence having at 0003 Mammalian G protein coupled receptors (GPCRs) least 30, 50, or 100 contiguous amino acids from any of the constitute a superfamily of diverse proteins with thousands of polypeptides listed in Table 2. Polypeptides of the invention members. GPCRs act as receptors for a multitude of different are desirably biologically active or are antigenic or immuno signals. Chemosensory GPCRs (csGPCR) are receptors for genic in an animal, especially in a human. sensory signals of external origin that are sensed as odors, 0010. The polypeptides of the present invention may be in pheromones, or tastes. Most other GPCRs respond to endog the form of the “mature' polypeptide, or may be a part of a enous signals, such as peptides, lipids, neurotransmitters, or larger polypeptide Such as a precursor or a fusion protein. It is nucleotides. GPCRs falling in the latter group are involved in often advantageous to include an additional amino acid numerous physiological processes, including the regulation sequence that contains secretory or leader sequences, pro of neuronal excitability, metabolism, reproduction, develop sequences, sequences that aid in purification, for instance ment, hormonal homeostasis, and behavior, and are differen multiple histidine residues, or an additional sequence for tially expressed in many cell types in the body. stability during recombinant production. 0004. Of all currently marketed drugs, greater than 30% are modulators of specific GPCRs. Only 10% of GPCRs 0011 Polypeptides of the present invention can be pre (excluding cSGPCRs) are targeted by these drugs, emphasiz pared in any suitable manner, for instance by isolation from ing the potential of the remaining 90% of the gene family for naturally occurring sources, from genetically engineered host the treatment of human disease. cells comprising expression systems, or by chemical synthe 0005. Despite the importance of GPCRs in physiology and sis, using for instance automated peptide synthesizers, or a disease, the size of the GPCR superfamily is still uncertain. combination of Such methods. For example, polypeptides of Analyses of genome sequences have generated markedly var the invention may be produced by expressing in a cell (e.g., a ied estimates (Venter, J. C. et al., Science 291, 1304-51 yeast, bacterial, mammalian, or insect cell) a vector contain (2001); Lander, E. S. et al., Nature 409, 860-921 (2001): ing a polynucleotide that encodes a GPCR of the invention Takeda, S. et al., FEBS Lett 520,97-101 (2002)). In addition, under condition in which the polypeptide (e.g., one listed in while most GPCRs are known to be selectively expressed in Table 2) is expressed. Means for preparing such polypeptides subsets of cells, the expression patterns of most GPCRs are are well understood in the art. incomplete or unknown. Thus, there is a need for GPCR 0012. In another aspect, the invention features substan polypeptides, polynucleotides, antibodies, genetic models, tially pure GPCR polynucleotides. Such polynucleotides and modulating compounds for use in the treatment and diag include: (a) polynucleotides that include a polynucleotide sequence having at least 90%. 95%, 97%, 98%, or 99% nosis of a wide variety of disorders and diseases. sequence identity to a polynucleotide listed in Table 2; (b) SUMMARY OF THE INVENTION polynucleotides that include a polynucleotide sequence hav ing at least 90%, 95%, 97%, 98%, or 99% sequence identity 0006. The present invention provides GPCR polypeptides to the reverse complement of polynucleotide listed in Table 2: and polynucleotides, recombinant materials, and transgenic (c) polynucleotides that include a polynucleotide listed in mice, as well as methods for their production. The polypep Table 2; (d) polynucleotides that are the reverse complement tides and polynucleotides are useful, for example, in methods of polynucleotide listed in Table 2: (e) polynucleotides hav of diagnosis and treatment of diseases and disorders. The ing at least 90%, 95%, 97%, 98%, or 99% sequence identity invention also provides methods for identifying compounds to a polynucleotide listed in Table 2: (f) polynucleotides hav (e.g., agonists or antagonists) using the GPCR polypeptides ing at least 90%, 95%, 97%, 98%, or 99% sequence identity and polynucleotides of the invention, and for treating condi to the reverse complement of polynucleotide listed in Table 2: tions associated with GPCR dysfunction with the GPCR (g) polynucleotides listed in Table 2: (h) reverse complement polypeptides, polynucleotides, or identified compounds. The of polynucleotides listed in Table 2: (i) polynucleotides that invention also provides diagnostic assays for detecting dis include a polynucleotide sequence encoding a polypeptide eases or disorders associated with inappropriate GPCR activ sequence having at least 90%. 95%, 97%, 98%, or 99% iden ity or levels. tity to a polypeptide listed in Table 2: (i) polynucleotides 0007. In one aspect, the invention features a variety of including a nucleotide sequence encoding a polypeptide substantially pure GPCR polypeptides. Such polypeptides listed in Table 2; and (k) polynucleotides encoding a polypep include: (a) polypeptides including a polypeptide sequence tide listed in Table 2. Preferred GPCR polynucleotides of the having at least 90%. 95%, 97%, 98%, or 99% identity to a present invention have at least 15, 30, 50 or 100 contiguous polypeptide listed in Table 2; (b) polypeptides that include a nucleotides from any of the polynucleotides listed in Table 2. US 2009/0178153 A1 Jul. 9, 2009

0013. In one embodiment, the polynucleotide is operably tacted with the compound, indicates that the candidate com linked to a promoter for expression of the polypeptide pound may be useful for the treatment of a neurological encoded by the polynucleotide. In certain embodiments, the disease or disorder. promoter is a constitutive promoter, is inducible by one or 0020 Instill another aspect, the invention features another more external agents, or is cell-type specific. method for determining whether a candidate compound may be useful for the treatment of a neurological disease or disor 0014. In another aspect, the invention features a vector that der. This method includes (a) providing a nucleic acid mol includes a GPCR polynucleotide of the invention, the vector ecule comprising a promoter from a gene encoding a GPCR being capable of directing expression of the polypeptide polypeptide listed in any one of Tables 3-14 and 33, the encoded by the polynucleotide in a vector-containing cell. promoter operably linked to a reporter system; (b) contacting 0015. In another aspect, the invention features a method of the nucleic acid molecule with the candidate compound; and preventing or treating a neurological disease or disorder, (c) measuring reporter activity, wherein altered reporter including introducing into a human an expression vector that activity, relative to a nucleic acid molecule not contacted with includes a nucleic acid molecule encoding a GPCR polypep the compound, indicates that the candidate compound may be tide Substantially identical to a polypeptide listed in any one useful for the treatment of a neurological disease or disorder. of Tables 3-14 and 33, operably linked to a promoter. 0021. In another aspect, the invention features yet another 0016. In still another aspect, the invention features a method for determining whether a candidate compound may method of treating or preventing a neurological disease or be useful for the treatment of a neurological disease or disor disorder, including administering to an animal (e.g., a human) der. a compound that modulates the biological activity of a GPCR 0022. This method includes the steps of: (a) providing a polypeptide Substantially identical to a polypeptide listed in GPCR polypeptide substantially identical to a polypeptide any one of Tables 3-14 and 33. listed in any one of Tables 3-14 and 33; (b) contacting the 0017. In yet another aspect, the invention features a polypeptide with the candidate compound; and (c) measuring method for determining whether a candidate compound is a interaction between the candidate compound and the compound that may be useful for the treatment of a neuro polypeptide. Interaction between the compound and the logical disease or disorder. This method includes the steps of polypeptide indicates that the candidate compound may be (a) providing a GPCR polypeptide substantially identical to a useful for the treatment of a neurological disease or disorder. polypeptide listed in any one of Tables 3-14 and 33; (b) 0023. In still another aspect, the invention features another contacting the GPCR polypeptide with the candidate com method for determining whether a candidate compound may pound; and (c) measuring biological activity of the GPCR be useful for the treatment of a neurological disease or disor polypeptide, wherein altered biological activity, relative to der. This method includes (a) providing a GPCR polypeptide that of the GPCR polypeptide not contacted with the com Substantially identical to a polypeptide listed in any one of pound, indicates that the candidate compound may be useful Tables 3-14 and 33; (b) contacting the polypeptide with the for the treatment of a neurological disease or disorder. The candidate compound; and (c) measuring the half-life of the GPCR polypeptide can be in a cell or may be in a cell-free polypeptide, wherein a change in the half-life of the polypep assay system. tide, relative to that of the polypeptide not contacted with the 0018. In yet another aspect, the invention features another compound, indicates that the candidate compound may be method for determining whether a candidate compound is a useful for the treatment of a neurological disease or disorder. compound that may be useful for the treatment of a neuro Preferably, the GPCR polypeptide is in a cell or a cell free logical disease or disorder. This method includes the steps of assay system. (a) providing a transgenic non-human mammal (e.g., a 0024. In another aspect, the invention features a method knock-out mouse) having a disruption in a nucleic acid mol for determining whether a patient has an increased risk for ecule encoding a GPCR polypeptide substantially identical to developing a neurological disease or disorder. The method a polypeptide listed in any one of Tables 3-14 and 33; (b) includes the step of determining whether the patient has a contacting the transgenic non-human mammal with the can mutation in a gene encoding a polypeptide listed in one of didate compound; and (c) measuring biological activity of the Tables 3-14 and 33, wherein presence of the mutation indi GPCR polypeptide in the transgenic non-human mammal, cates that the patient has an increased risk for developing a wherein altered biological activity, relative to that of the neurological disease or disorder. transgenic non-human mammal not contacted with the com 0025. In a related aspect, the invention features another pound, indicates that the candidate compound may be useful method for determining whether a patient has an increased for the treatment of a neurological disease or disorder. risk for developing a neurological disease or disorder. This 0019. In yet another aspect, the invention features a method includes the step of determining whether the patient method for determining whether a candidate compound is a has a polymorphism in a gene encoding a polypeptide listed in compound that may be useful for the treatment of a neuro any one of Tables 3-14 and 33, wherein presence of the logical disease or disorder. This method includes the steps of polymorphism indicates that the patient has an increased risk (a) providing a transgenic non-human mammal (e.g., a for developing a neurological disease or disorder. mouse) overexpressing a nucleic acid molecule encoding a 0026. In either of these two methods, the mutation or poly GPCR polypeptide substantially identical to a polypeptide morphism is preferably associated with an alteration (for listed in any one of Tables 3-14 and 33; (b) contacting the example, a decrease) in the expression level or biological transgenic non-human mammal with the candidate com activity of the polypeptide. pound; and (c) measuring biological activity of the GPCR 0027. In another aspect, the invention features another polypeptide in the transgenic non-human mammal, wherein method for determining whether a patient has an increased altered biological activity, relative to that of the GPCR risk for developing a neurological disease or disorder. The polypeptide in the transgenic non-human mammal not con method includes measuring biological activity of a GPCR US 2009/0178153 A1 Jul. 9, 2009

polypeptide from the patient that is substantially identical to Arnold-Chiari malformation, arousal disorders, arrhinen a polypeptide listed in any one of Tables 3-14 and 33, wherein cephaly, arsenic poisoning, arteriosclerotic Parkinsonism, increased or decreased levels in the GPCR biological activity, arteriovenous aneurysm, arteriovenous malformations, asep relative to normal levels, indicates that the patient has an tic meningeal reaction, Asperger's syndrome, astereognosis, increased risk for developing a neurological disease or disor asthenia, astrocytomas, asymbolia, asynergia, ataque de der. nervios, ataxia, ataxia telangiectasia, ataxic cerebral palsy, 0028. In still another aspect, the invention features yet ataxic dysarthria, athetosis, atonia, atonic seizures, attention another method for determining whether a patient has an deficit disorder, attention-deficit and disruptive behavior dis increased risk for developing a neurological disease or disor orders, attention-deficit hyperkinetic disorders, atypical der. The method includes the step of measuring the patient's Alzheimer's disease, atypical autism, autism, autism spec expression level of a polypeptide listed in any one of Tables trum disorder, avoidant personality disorder, axial dementias, 3-14 and 33, wherein an alteration in the expression, relative bacterial endocarditis, bacterial infections, Balint's syn to normal, indicates that the patient has an increased risk for drome, ballism, balo disease, basophilic adenoma, Bassen developing a neurological disease or disorder. Preferably, the Knock outrinzweig syndrome, Batten disease, battered expression levels are determined by measuring levels of woman syndrome, Behcet syndrome, Bell palsy, benign polypeptide or mRNA. essential tremor, benign focal epilepsies of childhood, benign 0029 Preferred neurological diseases or disorders that can intracranial hypertension, benxodiazepine dependence, bilat be treated or diagnosed using the methods of the invention or eral cortical dysfunction, Binswanger's disease, bipolar dis for which candidate therapeutic compounds may be identified order, bipolar type I disorder, bipolar type 2 disorder, ble include, without limitation, abetalipoproteinemia, abnormal pharospasm, body dysmorphic disorder, Bogaert-Bertrand Social behaviors, absence (petit mal) epilepsy, absence Sei disease, Bogarad Syndrome, borderline personality disorder, Zures, abulia, acalculia, acidophilic adenoma, acoustic neu botulism, Bouffee Délirante-type reactions, brachial neur roma, acquired aphasia, acquired aphasia with epilepsy (Lan opathy, bradycardia, bradykinesia, brain abscess, brain dau-Kleffner syndrome) specific reading disorder, acquired edema, brain fag, brain stem glioma, brainstem encephalitis, epileptic aphasia, acromegalic neuropathy, acromegaly, brief psychotic disorder, broca's aphasia, brucellosis, action myoclonus-renal insufficiency syndrome, acute auto bulimia, bulimia nervosa, butterfly glioma, cachexia, caffeine nomic neuropathy, acute cerebellar ataxia in children, acute related disorders, california encephalitis, callosal agenesis, depression, acute disseminated encephalomyelitis, acute Canavan's syndrome, cancerpain, cannabis dependence, can idiopathic sensory neuronopathy, acute intermittent porphy nabis flashbacks, cannabis psychosis, cannabis related disor ria, acute mania, acute mixed episode, acute pandysautono ders, carcinoma-associated retinopathy, cardiac arrest, cav mia, acute polymorphic disorder with symptoms of Schizo ernous malformations, cellular (cytotoxic) edema, central phrenia, acute polymorphic psychotic disorder without facial paresis, central herniation syndrome, central neuro symptoms of Schizophrenia, acute purulent meningitis, genic hyperventilation, central pontine myelinolysis, central addiction, Addison syndrome, adenovirus serotypes, adjust post-stroke syndrome (thalamic pain syndrome), cerebellar ment disorders, adrenal hyperfunction, adrenal hypofunction, hemorrhage, cerebellar tonsillar herniation syndrome, cere adrenoleuknock outdystrophy, adrenomyeloneuropathy, bral amyloid (congophilic) angiopathy, cerebral hemorrhage, advanced sleep-phase syndrome, affective disorder Syn cerebral malaria, cerebral palsy, cerebral Subdural empyema, dromes, agenesis of the corpus callosum, agnosia, agorapho cerebrotendinous xanthomatosis, cerebrovascular disorders, bia, agraphia, agyria, agyria-pachygyria, ahylognosia, cervical tumors, cestodes, Charcot-Carie-tooth disease, Che Aicardi syndrome, AIDS, akathisia, akinesia, akinetic mut diak-Cigashi disease, Chemo-oral syndrome, chiari malfor ism, akinetopsia, alcohol abuse, alcohol dependence Syn mation with hydrocephalus, childhood disintegrative disor drome, alcohol neuropathy, alcohol related disorders, alco der, childhood feeding problems, childhood sleep problems, holic amblyopia, alcoholic blacknock oututs, alcoholic cholesteatomas, chordomas, chorea, chorea gravidarum, cerebellar degeneration, alcoholic dementia, alcoholic hallu choreoathetosis, chromophobe adenoma, chromosomal dis cinosis, alcoholic polyneuropathy, alcohol-induced anxiety orders, chronic bipolar major depression, chronic bipolar dis disorders, alcohol-induced dementia, alcohol-induced mood order, chronic demyelinating polyneuritis, chronic depres disorders, alcohol-induced psychosis, alcoholism, Alex Sion, chronic fatigue syndrome, chronic gm2 gangliosidosis, ander's syndrome, alexia, alexia with agraphia, alexia with chronic idiopathic sensory neuropathy, chronic inflammatory out agraphia, alien hand syndrome, Alper's disease, altered demyelinating polyneuropathy, chronic inflammatory demy sexuality syndromes, alternating hemiplagia, Alzheimer's elinating polyradiculoneuropathy, chronic pain, chronic par disease, Alzheimer-like senile dementia, Alzheimer-like oxysmal hemicrania, chronic Sclerosing panencephalitis, juvenile dementia, amenorrea, aminoacidurias, amnesia, chronic traumatic encphalopathy, chronobiological disor amnesia for offences, amok-type reactions, amorphognosia, ders, circadian rhythm disorder, circadian rhythm disorders, amphetamine addiction, amphetamine or amphetamine-like Claude's syndrome, clonic seizures, cluster headache, related disorders, amphetamine withdrawal, amyloid neur cocaine addiction, cocaine withdrawal, cocaine-related dis opathy, amyotrophic lateral sclerosis, anencephaly, aneu orders, Cockayne's syndrome, colloid cysts of the third ven rysms, angioblastic meningiomas, Angleman's syndrome, tricle, colorado tick fever, coma, communicating hydroceph anhidrosis, anisocoria, anomia, anomic aphasia, anorexia alus, communication disorders, complex partial seizures, nervosa, anoSmia, anosognosia, anteriorcingulate syndrome, compression neuropathy, compulsive buying disorder, con anterograde amnesia, antibiotic-induced neuromuscular ceptual apraxia, conduct disorders, conduction aphasia, con blockade, antisocial personality disorder, Anton's syndrome, duction apraxia, congenital analgesia, congenital cytomega anxiety and obsessive-compulsive disorder syndromes, anxi lovirus disease, congenital hydrocephalus, congenital ety disorders, apathy syndromes, aphasia, aphemia, aplasia, hypothyroidism, congenital muscular dystrophy, congenital apnea, apraxia, arachnoid cyst, archicerebellar syndrome, myasthenia, congenital myotonic dystrophy, congenital US 2009/0178153 A1 Jul. 9, 2009 rubella syndrome, congophilic angiopathy, constipation, familial periodic paralysis, familial spastic paraparesis, coprophilia, comedlia de lange syndrome, cortical dementias, familial spastic paraplegias, fear disorders, feeding and eat cortical heteropias, corticobasal degeneration, corticobasal ing disorders of infancy or early childhood, female sexual ganglionic degeneration, coxsackievirus, cranial meningoce arousal disorder, fetal alcohol Syndrome, fetishism, flaccid les, craniopharyngioma, craniorachischisis, craniosynosto dysarthria, floppy infant syndrome, focal inflammatory sis, cranium bifidum, cretinism, Creutzfeldt-Jaknock outb demyelinating lesions with mass effect, focal neonatal bypo disease, Cri-du-Chat syndrome, cruciate hemiplegia, crypto tonia, folie a deux, foramen magnum tumors, Foville's syn coccal granulomas, cryptococcosis, culturally related Syn drome, fragile-X syndrome, Freidrich's ataxia, Frolich syn dromes, culturally stereotyped reactions to extreme environ drome, frontal alexia, frontal convexity syndrome, mental conditions (arctic hysteria), Cushing syndrome, frontotemporal dementia, frontotemporal dementias, frot cyclothymia, cysticercosis, cytomegalovirus, Dandy-Walker teurism, fungal infection, galactocerebroside lipidosis, galac malformation, deafness, defects in the metabolism of amino torrhea, ganglioneuroma, Gaucher disease, gaZe palsy, gen acids, dehydration, Dejerine-Roussy syndrome, Dejerine der identity disorder, generalized anxiety disorder, genital Sottas disease, delayed and advanced sleep phase syndromes, shrinking syndrome (Knock outro, Suo-Yang), germ cell delayed ejaculation, delayed puberty, delayed-sleep-phase tumors, Gerstmann's syndrome, Gerstmann-Stratissler Syn syndrome, delerium due to alcohol, delerium due to intoxi drome, Gerstmann-Straussler-Schenker disease, Gertmann's cation, delerium due to withdrawal, delirium, dementia, and syndrome, gestational Substance abuse syndromes, giant amnestic and other cognitive disorders, delusional disorder, axonal neuropathy, gigantism, Gilles de la Tourette Syn delusional disorder: erotomania Subtype, delusional disorder: drome, glioblastoma multiforme, gliomas, gliomatosis cere grandiose Subtype, delusional disorderjealousy Subtype, bri, global aphasia, glossopharyngeal neuralgia, glycogen delusional misidentification syndromes, dementia due to HIV storage diseases, gm1-gangliosidosis, gm2-gangliosidoses, disease, dementia pugilistica, dementias, dementias associ granular cell tumor, granulocytic brain edema, granulomas, ated with extrapyramidal syndrome, dentatorubral-pallidol granulomatous angiitis of the brain, Grave's disease, growild uysian atrophy, dependent personality disorder, depersonal typeh hormone deficit, growild typeh-hormone secreting ization disorder, depression, depressive personality disorder, adenomas, guam-Parkinson complex dementia, Guillain dermoids, developmental speech and language disorder, Barré syndrome, Hallervorden-Spatz disease, hallucinogen devic syndrome, devivo disease, diabetes, diabetes insipidus, persisting perception disorder, hallucinogen related disor diabetic neuropathy, dialysis demential, dialysis dysequilib ders, hartinup disease, headache, helminthic infections (tri rium syndrome, diencephalic dementias, diencephalic dys chinellosis), hemangioblastomas, hemangiopericytomas, function, diencephalic syndrome of infancy, diencephalic hemiachromatopsia, hemianesthesia, hemianopsia, hemibal vascular dementia, diffuse Sclerosis, digestive disorders, lism, hemibalismus, hemihypacusis, hemihypesthesia, diphtheria, diplopia, disarthria, disassociation apraxia, disor hemiparesis, hemispatial neglect, hemophilus influenza men ders of carbohydrate metabolism, disorders of excessive som ingitis, hemorrhagic cerebrovascular disease, hepatic coma, nolence, disorders of metal metabolism, disorders of purine hepatic encephalopathy, hepatolenticular degeneration (Wil metabolism, disorders of sexual arousal, disorders of sexual son disease), hereditary amyloid neuropathy, hereditary atax aversion, disorders of sexual desire, disorders of the sleep ias, hereditary cerebellar ataxia, hereditary neuropathies, wake schedule, dissociative disorders, dorsolateral tegmental hereditary nonprogressive chorea, hereditary predisposition pontine syndrome, Down syndrome, Down syndrome with to pressure palsies, hereditary sensory autonomic neuropathy, dementia, drug dependence, drug overdose, drug-induced hereditary sensory neuropathy, hereditary spastic paraplegia, myasthenia, Duchenne muscular dystrophy, dwarfism, dys hereditary tyrosinemia, hermichorea, hermifacial spasm, her arthria, dysdiadochokinesia, dysembryoplastic neuroepithe niation syndromes, herpes encephalitis, herpes infections, lial tumor, dysexecutive syndrome, dysgraphia, dyskinesia, herpes Zoster, herpres simplex, heterotopia, hexacarbon neu dyskinetic cerebral palsy, dyslexia, dysmetria, dysomnia, ropathy, histrionic personality disorder, HIV. Holmes-Adie dysosmia, dyspareunia, dysphagia, dysphasia, dysphonia, syndrome, homonymous quadrantaposia, Horner's Syn dysplasia, dyspnea, dysprosody, dyssomnia, dyssynergia, drome, human B-mannosidosis, Hunter's syndrome, Hun dysthesia, dysthymia, dystonia, dystrophinopathies, early tington's chorea, Huntington's disease, Hurler's syndrome, adolescent gender identity disorder, early infantile epileptic Hwa-Byung, hydraencephaly, hydrocephalus, hyperthyroid encephalopathy (Ohtahara syndrome, early myoclonic epi ism, hyperacusis, hyperalgesia, hyperammonemia, hyper leptic encephalopathy, Eaton-Lambert syndrome, echinococ eosinophilic syndrome, hyperglycemia, hyperkalemic peri cus (hydatid cysts), echolalia, echovirus, eclampsia, odic paralysis, hyperkinesia, hyperkinesis, hyperkinetic Edward's syndrome, elimination disorders, embolismintrac dysarthria, hyperosmia, hyperosmolar hyperglygemic nonke erebral hemorrhage, Emery-Dreifuss muscular dystrophy, tonic diabetic coma, hyperparathyroidism, hyperphagia, encephalitis lethargica, encephaloceles, encephalotrigeminal hyperpituitarism, hyperprolactinemia, hypersexuality, hyper angiomatosis, enopthalmos, enterovirus, enuresis, eosino Somnia, hypersomnia secondary to drug intake, hyperSomia philic meningitis, ependymoma, epidural spinal cord com sleep-apnea syndrome, hypersomnolence, hypertension, pression, epilepsy, episodic ataxia, epstein-barr, equine hypertensive encephalopathy, hyperthermia, hyperthyroid encephalomyelitis, erectile dysfunction, essential thromb ism (Graves disease), hypertonia, hypnagogic (predormital) ocythemia, essential tremor, esthesioneuroblastoma, exces hallucinations, hypnogenic paroxysmal dystonia, hypoadren sive daytime Somnolence, excessive secretion of antidiuretic alism, hypoalgesia, hypochondriasis, hypoglycemia, hypoin hormone, excessive sleepiness, exhibitionism, expressive Sulinism, hypokalemic periodic paralysis, hypokinesia, language disorder, extramedullary tumors, extrasylvian hypokinetic dysarthria, hypomania, hypoparathyroidism, aphasias, extratemporal neocortical epilepsy, fabry's disease, hypophagia, hypopituitarism, hypoplasia, hyposmia, hypos facioscapulohumeral muscular dystrophy, factitious disorder, thenuria, hypotension, hypothermia, hypothyroid neuropa factitious disorders, false memories, familial dysautonomia, thy, hypothyroidism, hypotonia, Hyrler syndrome, hysteria, US 2009/0178153 A1 Jul. 9, 2009 ideational apraxia, ideomotor apraxia, idiopathic hyperSom migraine, mild depression, Millard-Gubler syndrome, nia, idiopathic intracranial hypertension, idiopathic orthos Miller-Dieker syndrome, minimal brain dysfunction syn tatic hypotension, immune mediated neuropathies, impersis drome, miosis, mitochondrial encephalopathy with lactic aci tence, impotence, impulse control disorders, impulse dosis and stroke (melas), mixed disorders of scholastic skills, dyscontrol and aggression syndromes, impulse-control dis mixed dysarthrias, mixed transcortical aphasia, Möbius Syn orders, incontinence, incontinentia pigmenti, infantile drome, Mollaret meningitis, monoclonal ganmopathy, encephalopathy with cherry-red spots, infantile neuraxonal mononeuritis nultiplex, monosymptomatic hypochondriacal dystrophy, infantile spasms, infantilism, infarction, infertil psychosis, mood disorders, Moritz Benedikt Syndrome, ity, influenza, inhalant related disorders, insomnias, insuffi Morquio syndrome, Morton's neuroma, motor neuron dis cient sleep syndrome, intention tremor, intermittent explosive ease, motor neurone disease with dementia, motor neuropa disorder, internuclear opthalmoplegia, interstitial (hydro thy with multifocal conduction block, motor skills disorder, cephalic) edema, intoxication, intracranial epidural abscess, mucolipidoses, mucopolysaccharide disorders, muco intracranial hemorrhage, intracranial hypotension, intracra polysaccharidoses, multifocal eosinophilic granuloma, mul nial tumors, intracranial venous-sinus thrombosis, intradural tiple endocrine adenomatosis, multiple myeloma, multiple hematoma, intramedullary tumors, intravascular lymphoma, Sclerosis, multiple system atrophy, multiple systems atrophy, ischemia, ischemic brain edema, ischemic cerebrovascular multisystemic degeneration with dementia, mumps, Mun disease, ischemic neuropathies, isolated inflammatory demy chausen syndrome, Munchausen syndrome by proxy, muscu elinating CNS syndromes, Jackson-Collet syndrome, lar hypertonia, mutism, myasthenia gravis, mycoplasma Jaknock outb-Creutzfeld disease, Japanese encephalitis, jet pneumoniae infection, myoclonic seizures, myoclonic-as lag syndrome, Joseph disease, Joubert's syndrome, juvenile tatic epilepsy (doose syndrome), myoclonus, myotonia con neuroaxonal dystrophy, Kayak-Svimmel, Keams-Sayre Syn genita, myotonic dystrophy, myotonic muscular dystrophy, drome, kinky hair disease (Menkes syndrome), Kleine-Levin nacolepsy, narcissistic personality disorder, narcolepsy, nar syndrome, kleptomania, Klinefelter's syndrome, Kluver colepsy-cataplexy syndrome, necrophilia, nectrotizing Bucy syndrome, Knock outerber-Salus-Elschnig syndrome, encephalomyelopathy, Nelson's syndrome, neocerebellar Knock outrsaknockoutffs syndrome, krabbe disease, krabbe syndrome, neonatal myasthenia, neonatal seizures, nervios, leuknock outdystrophy, Kugelberg-Welander syndrome, nerves, neurasthenia, neuroacanthocytosis, neuroaxonal dys kuru, Lafora's disease, language deficits, language related trophy, neurocutaneous disorders, neurofibroma, neurofibro disorders, latah-type reactions, lateral mass herniation syn matosis, neurogenic orthostatic hypotension, neuroleptic drome, lateropulsation, lathyrism, Laurence-Moon Biedl malignant syndrome, neurologic complications of renal syndrome, Laurence-Moon syndrome, lead poisoning, learn transplantation, neuromyelitis optica, neuromyotonia (Isaacs ing disorders, leber hereditary optic atrophy, left ear extinc syndrome), neuronal ceroid lipofuscinoses, neuro-ophtha tion, legionella pneumophilia infection, Leigh's disease, Len lamic disorders, neuropathic pain, neuropathies associated noc-Gastaut syndrome, Lennox-Gastaut's syndrome, with infections, neuropathy associated with cryoglobulins, leprosy, leptospirosis, Lesch-Nyhan syndrome, leukemia, neuropathy associated with hepatic diseases, neuropathy leuknockoutdystrophies, Levy-Roussy syndrome, lewy body induced by cold, neuropathy produced by chemicals, neur dementia, lewy body disease, limb girdle muscular dystro opathy produced by metals, neurosyphilis, new variant phies, limbic encephalitis, limbic encephalopathy, lissen Creutzfeldt-Jaknock outb disease, nicotine dependence, cephaly, localized hypertrophic neuropathy, locked-in syn nicotine related disorders, nicotine withdrawal, niemann drome, logoclonia, low pressure headache, Lowe syndrome, pick disease, nocturnal dissociative disorders, nocturnal lumbar tumors, lupus anticoagulants, lyme disease, lyme enuresis, nocturnal myoclonus, nocturnal sleep-related eat neuropathy, lymphocytic choriomeningitis, lymphomas, ing disorders, noecerbellar syndrome, non-alzheimer frontal lysosomal and other storage diseases, macroglobinemia, lobe degeneration, nonamyloid polyneuropathies associated major depression with melancholia, major depression with with plasma cell dyscrasia, non-lethal Suicidal behavior, non psychotic features, major depression without melancholia, localizing aphasic syndromes, normal pressure hydroceph major depressive (unipolar) disorder, male orgasmic disorder, alus, Nothnagel's syndrome, nystagmus, obesity, obsessive malformations of septum pellucidum, malignant peripheral compulsive (anankastic) personality disorder, obsessive nerve sheath tumors, malingers, mania, mania with psychotic compulsive disorder, obstetric factitious disorder, obstructive features, mania without psychotic features, maple syrup urine hyrocephalus, obstructive sleep apnea, obstructive sleep disease, Marchiafava-Bignami syndrome, Marcus Gunn syn apnoea syndrome, obstructive sleep hypopnoea syndrome, drome, Marie-Foix syndrome, Marinesco-Sjögren syndrome, occipital dementia, occlusive cerebrovascular disease, oculo Maroteaux-Lamy syndrome, masochism, masturbatory pain, cerebrorenal syndrome of lowe, oculomotor nervepalsy, ocu measles, medial frontal syndrome, medial medullary Syn lopharyngeal muscular dystrophy, oligodendrogliomas, drome, medial tegmental syndrome, medication-induced olivopontocerebellaratrophy, ondine's curse, one and a half movement disorders, medullary dysfunction, medulloblasto syndrome, onychophagia, opiate dependance, opiate over mas, medulloepithelioma, inegalencephaly, melanocytic dose, opiate withdrawal, opioid related disorders, opposi neoplasms, memory disorders, memory disturbances, tional defiant disorder, opSoclonus, orbitofrontal syndrome, meniere syndrome, meningeal carcinomatosis, meningeal orgasmic anhedonia, orgasmic disorders, osteosclerotic sarcoma, meningial gliomatosis, meningiomas, meningism, myeloma, other disorders of infancy, childhood, or adoles meningitis, meningococcal meningitis, mental neuropathy cence, other medication-induced movement disorders, (the numb chin syndrome), mental retardation, mercury poi pachygyria, paedophilia, pain, pain syndromes, painful legs soning, metabolic neuropathies, metachromatic leuknock moving toes syndrome, paleocerebellar syndrome, palilalia, outdystrophy, metastatic neuropathy, metastatic tumors, panhypopituitarism, panic disorder, panic disorders, papillo metazoal infections, microcephaly, microencephaly, mas of the choroid plexus, paraganglioma, paragonimiasis, micropolygyria, midbrain dysfunction, midline syndrome, paralysis, paralysis agitans (shaking palsy), paramyotonia US 2009/0178153 A1 Jul. 9, 2009 congenita, paraneoplastic cerebellar degeneration, paraneo rapid cycling disorder, rapid ejaculation, Raymond-Cestan plastic cerebellar syndrome, paraneoplastic neuropathy, para Chenais syndrome, receptive language disorder, recovered neoplastic syndromes, paranoia, paranoid personality disor memories, recurrent bipolar episodes, recurrent brief depres der, paranoid psychosis, paraphasia, paraphilias, Sion, recurrent hypersomnia, recurrent major depression, ref paraphrenia, parasitic infections, parasomnia, parasomnia Sum disease, reiterative speech disturbances, relational prob overlab disorder, parenchymatous cerebellar degeneration, lems, rem sleep behavior disorder, rem sleep behavioral paresis, paresthesia, parinaud's syndrome, Parkinson's dis disorder, repetitive self-mutilation, repressed memories, res ease, Parkinson-dementia complex of guam, Parkinsonism, piratory dysrhythmia, restless legs syndrome, Rett's Syn Parkinsonism-plus syndromes, Parkinson's disease, paroxyS drome, Reye syndrome, rhythmic movement disorders, rocky mal ataxia, paroxysmal dyskinesia, partial (focal) seizures, mountain spotted fever, rostral basal pontine syndrome, partialism, passive-aggressive (negativistic) personality dis rubella, Rubinstein-Taybi syndrome, sadistic personality dis order, Patau's syndrome, pathological gambling, peduncular order, Salla disease, Sandhoff disease, Sanfilippo syndrome, hallucinosis, Pelizaeus-Merzbacher disease, perineurioma, sarcoid neuropathy, sarcoidosis, Scapuloperoneal syndromes, peripheral neuropathy, perisylvian syndromes, periventricu Schistosomiasis (bilharziasis), Schizencephaly, schizoaffec lar leuknock outmalacia, periventricular white matter disor tive disorder, Schizoid personality disorder, Schizophrenia, der, periventricular-intraventricular hemorrhage, pernicious Schizophrenia and other psychotic disorders, Schizophrenia anemia, peroneal muscular atrophy, peroxisomal diseases, like psychosis, Schizophreniform disorder, Schizotypal per perseveration, persistence of cavum septi pellucidi, persistent Sonality disorder, School-refusal anxiety disorder, Schwan Vegetative state, personality disorders, pervasive develop noma, Scrub typhus, seasonal depression, secondary spinal mental disorders, phencyclidine (or phencyclidine-like) muscular atrophy, secondary thrombosis, sedative hypnotic related disorders, phencyclidine delirium, phencyclidine psy or anxiolytic-related disorders, seizure disorders, selective chosis, phencyclidine-induced psychotic disorder, phenylke mutism, self-defeating (masochistic) personality disorder, tonuria, phobic anxiety disorder, phonic tics, photorecepto semen-loss syndrome (shen-k'uei, dhat, jiryan, Sukra degeneration, pibloktoq, Pick's disease, pineal cell tumors, prameha), senile chorea, senile dementia, sensory perineuri pineoblastoma, pineocytoma, pituitary adenoma, pituitary tis, separation anxiety disorder, septal syndrome, septo-optic apoplexy, pituitary carcinoma, pituitary dwarfism, placebo dysplasia, severe hypoxia, severe myoclonic epilepsy, sexual effect, Plummer's disease, pneumococcal meningitis, and gender identity disorders, sexual disorders, sexual dys poikilolthermia, polio, polycythemia Vera, polydipsia, poly functions, sexual pain disorders, sexual sadism, Shapiro syn glucosan Storage diseases, polymicrogyria, polymyositis, drome, shift work sleep disorder, Shy-Drager syndrome, polyneuropathy with dietary deficiency States, poly Substance sialidosis, sialidosis type 1, sibling rivalry disorder, sickle cell related disorder, polyuria, pontine dysfunction, pontoSubicu anemia, Simmonds disease, simple partial seizures, simul lar neuronal necrosis, porencephaly, porphyric neuropathy, tanagnosia, sleep disorders, sleep paralysis, sleep terrors, portal-systemic encephalopathy, postcoital headaches, post sleep-related enuresis, sleep-related gastroesophageal reflux concussion syndrome, postencephalic Parkinson syndrome, syndrome, sleep-related headaches, sleep-wake disorders, posthemorrhagic hydrocephalus, postinflammatory hydro sleepwalking, Smith-Magenis Syndrome, social anxiety dis cephalus, postpartum depression, postpartum psychoses, order, social phobia, Social relationship syndromes. Somato postpolio syndrome, postpsychotic depression, post-stroke form disorders. Somnambulism, Sotos syndrome, spasmodic hypersomnia, post-traumatic amnesia, post-traumatic epi dysphonia, Spasmodic torticollis (wry neck), spastic cerebral lepsy, post-traumatic hypersomnia, post-traumatic move palsy, spastic dysarthria, specific developmental disorder of ment disorders, post-traumatic stress disorder, post-traumatic motor function, specific developmental disorders of scholas syndromes, Prader-Willi syndrome, precocious puberty, pre tic skills, specific developmental expressive language disor frontal dorsolateral syndrome, prefrontal lobe Syndrome, pre der, specific developmental receptive language disorder, spe menstrual stress disorder, premenstrual syndrome, primary cific disorders of arithmetical skills, specific phobia, specific amebic meningoencephalitis, primary CNS lymphoma, pri speech articulation disorder, specific spelling disorder, mary idiopathic thrombosis, primary lateral Sclerosis, primi speech impairment, spina bifida, spinal epidural abscess, spi tive neuroectodermal tumors, prion disease, problems related nal muscular atrophies, spinocerebellar ataxias, spirochete to abuse or neglect, progressive bulbar palsy, progressive infections, spongiform encephalopathies, spongy degenera frontal lobe dementias, progressive multifocal lueknock out tion of the nervous system, St. Louis encephalitis, Stammer, encephalopathy, progressive muscular atrophy, progressive staphylococcal meningitis, startle syndromes, status marm muscular dystrophies, progressive myoclonic epilepsies, pro oratus, Steele-richardson-olszewski syndrome, Stereotypic gressive myoclonus epilepsies, progressive non-fluent apha movement disorder, Stereotypes, stiff-man syndrome, stiff sia, progressive partial epilepsies, progressive rubella person syndrome, stimulant psychosis, Strachan syndrome encephalitis, progressive Sclerosing poliodystrophy (Alpers (nutritional neuropathy), Streptococcal meningitis, striatoni disease), progressive Subcortical gliosis, progressive Supra gral degeneration, stroke, strongyloidiasis, Sturge-Weber dis nuclear palsy, progressive Supranuclear paralysis, progres ease (Krabbe-Weber-Dimitri disease), stutter, subacute com sive external opthalmoplegia, prolactinemia, prolactin-sec bined degeneration of the spinal cord, Subacute motor treting adenomas, prosopagnosia, protozoan infection, neuronopathy, Subacute necrotic myelopathy, Subacute scle pseudobulbar palsy, pseudocyesis, pseudodementia, psychic rosing panencephalitis, Subacute sensory neuronopathy, Sub blindness, psychogenic excoriation, psychogenic fugue, psy arachniod hemorrhage, Subcortical aphasia, Subfalcine her chogenic pain syndromes, psychological mutism, psychosis niation syndrome, Substance abuse, Substance related after brain injury, psychotic syndromes, ptosis, public mas disorders, Sudanophilic leuknock outdystrophis, Sudden turbation, puerperal panic, pulmonary edema, pure word infant death syndrome, Suicide, Sulfatide lipidosis, Susto, deafness, pyromania, quadrantanopsia, rabies, radiation neu espanto, meido, Sydenham chorea, symmetric neuropathy ropathy, Ramsay Hunt syndrome, rape traume syndrome, associated with carcinoma, sympathotonic orthostatic US 2009/0178153 A1 Jul. 9, 2009 hypotension, Syncope, syndromes related to a cultural nucleic acid molecule encoding a GPCR polypeptide sub emphasis on learnt dissociation, syndromes related to a cul stantially identical to a polypeptide listed in any one of Tables tural emphasis on presenting a physical appearance pleasing 3-14 and 33. to others (taijin-kyofu reactions), syndromes related to accul 0034. In another aspect, the invention features a cell from turative stress, Syringobulbia, Syringomyelia, systemic lupus a non-human mammal having a mutation in a nucleic acid erythematosus, tachycardia, tachypnea, Tangier disease, tar molecule encoding a GPCR polypeptide substantially identi dive dyskinesia, Tay-Sachs disease, telangiectasia, telen cal to a polypeptide listed in any one of Tables 3-14 and 33. cephalic leuknock outencephalopathy, telephone scatologia, 0035. In another aspect, the invention features a method of temporal lobe epilepsy, temporoparietal dementia, tension preventing or treating a disease of the adrenal gland including type headache, teratomas, tetanus, tetany, thalamic syn introducing into a human an expression vector that includes a drome, thallium poisoning, thoracic tumors, thrombotic nucleic acid molecule encoding a GPCR polypeptide sub thrombocytopenic purpura, thyroid disorders, tic disorders, stantially identical to a polypeptide listed in Tables 15 and 33, tick paralysis, tick-borne encephalitis, tinnitis, tomaculous operably linked to a promoter. neuropathy, tonic seizures, tonic-clonic seizures, torticollis, 0036. In still another aspect, the invention features a Tourette syndrome, toxic neuropathies, toxoplasmosis, method of treating or preventing a disease of the adrenal transcortical motor aphasia, transcortical sensory aphasia, gland including administering to an animal (e.g., a human) a transient epileptic amnesia, transient global amnesia, transi compound that modulates the biological activity of a GPCR tional sclerosis, transvestic fetishism, traumatic brain injury, polypeptide Substantially identical to a polypeptide listed in traumatic neuroma, traumatic mutism, tremors, trichinosis, Tables 15 and 33. trichotillomania, trigeminal neuralgia, trochlear nerve palsy, 0037. In yet another aspect, the invention features a tropical ataxic neuropathy, tropical spastic paraparesis, try method for determining whether a candidate compound is a panosomiasis, tuberculomas, tuberculous meningitis, tuber compound that may be useful for the treatment of a disease or ous Sclerosis, tumors, Turner's syndrome, typhus fever, disorder of the adrenal gland. This method includes the steps ulegyria, uncinate fits, Unverricht-Lundborg's disease, upper of (a) providing a GPCR polypeptide substantially identical airway resistance syndrome, upward transtentorial herniation to a polypeptide listed in Tables 15 and 33; (b) contacting the syndrome, uremic encephalopathy, uremic neuropathy, uro GPCR polypeptide with the candidate compound; and (c) philia, Vaccinia, Varicella-Zoster, Vascular dementia, Vascular measuring biological activity of the GPCR polypeptide, malformations, vasculitic neuropathies, vasogenic edema, Velocardiofacial syndrome, venous malformations, ventila wherein altered biological activity, relative to that of the tory arrest, vertigo, Vincristine toxicity, Viral infections, visu GPCR polypeptide not contacted with the compound, indi ospatial impairment, Vogt-Knock outyanagi-Harada Syn cates that the candidate compound may be useful for the drome, Von Hippel-Lindau disease, Von Racklinghousen treatment of a disease or disorder of the adrenal gland. The disease, Voyeurism, Waldenström's macroglobulinemia, GPCR polypeptide can be in a cell or in a cell-free assay Walker-Warburg syndrome, Wallenburg's syndrome, Wall system. eyed syndrome, Weber's syndrome, Wenicke's encephalopa 0038. In yet another aspect, the invention features a thy, Werdnig-Hoffmann disease, Wernicke's encephalopathy, method for determining whether a candidate compound is a Wernicke-Knock outrsaknock outff syndrome, Wernicke's compound that may be useful for the treatment of a disease or aphasia, West's syndrome, whipple disease, Williams syn disorder of the adrenal gland. This method includes the steps drome, Wilson disease, windigo, witiknockout, witigo, with of (a) providing a transgenic non-human mammal (e.g., a drawal with grand mal seizures, withdrawal with perceptual knock-out mouse) having a disruption in a nucleic acid mol disturbances, withdrawal without complications, Wolman ecule encoding a GPCR polypeptide substantially identical to disease, Xeroderma pigmentosum, Xyy syndrome, Zellweger a polypeptide listed in Tables 15 and 33; (b) contacting the syndrome. transgenic non-human mammal with the candidate com pound; and (c) measuring biological activity of the GPCR 0030 Neurological diseases and disorders that are treated polypeptide in the transgenic non-human mammal, wherein or diagnosed by methods of the invention or for which can altered biological activity, relative to that of the transgenic didate therapeutic compounds are identified preferably non-human mammal not contacted with the compound, indi involve at least one of the following neurological tissues: cates that the candidate compound may be useful for the hypothalamus, amygdala, pituitary, nervous system, brain treatment of a disease or disorder of the adrenal gland. stem, cerebellum, cortex, frontal cortex, hippocampus, stria 0039. In yet another aspect, the invention features a tum, and thalamus or other regions of the central or peripheral method for determining whether a candidate compound is a nervous system. compound that may be useful for the treatment of a disease or 0031. In another aspect, the invention features a non-hu disorder of the adrenal gland. This method includes the steps man mammal (e.g., a mouse), having a transgene that of (a) providing a transgenic non-human mammal (e.g., a includes a nucleic acid molecule encoding a GPCR polypep mouse) overexpressing a nucleic acid molecule encoding a tide Substantially identical to a polypeptide listed in any one GPCR polypeptide substantially identical to a polypeptide of Tables 3-14 and 33. listed in Tables 15 and 33; (b) contacting the transgenic non 0032. In yet another aspect, the invention features a non human mammal with the candidate compound; and (c) mea human mammal (e.g., a mouse), having a mutation in a suring biological activity of the GPCR polypeptide in the nucleic acid molecule encoding a GPCR polypeptide sub transgenic non-human mammal, wherein altered biological stantially identical to a polypeptide listed in any one of Tables activity, relative to that of the transgenic non-human mammal 3-14 and 33. not contacted with the compound, indicates that the candidate 0033. In a related aspect, the invention features a cell from compound may be useful for the treatment of a disease or a non-human mammal having a transgene that includes a disorder of the adrenal gland. US 2009/0178153 A1 Jul. 9, 2009

0040. In still another aspect, the invention features another relative to normal levels, indicates that the patient has an method for determining whether a candidate compound may increased risk for developing a disease or disorder of the be useful for the treatment of a disease or disorder of the adrenal gland. adrenal gland. This method includes (a) providing a nucleic 0047. In still another aspect, the invention features yet acid molecule comprising a promoter from a gene encoding a another method for determining whether a patient has an GPCR polypeptide listed in Tables 15 and 33, the promoter increased risk for developing a disease or disorder of the operably linked to a reporter system; (b) contacting the adrenal gland. The method includes the step of measuring the nucleic acid molecule with the candidate compound; and (c) patient's expression levels of a polypeptide listed in Tables 15 measuring reporter activity, wherein altered reporter activity, and 33, wherein altered levels in the expression, relative to relative to a nucleic acid molecule not contacted with the normal, indicate that the patient has an increased risk for compound, indicates that the candidate compound may be developing a disease or disorder of the adrenal gland. Prefer useful for the treatment of a disease or disorder of the adrenal ably, the expression levels are determined by measuring lev gland. els of polypeptide or mRNA. 0041. In another aspect, the invention features yet another 0048 Diseases of the adrenal gland that can be treated or method for determining whether a candidate compound may diagnosed using the methods of the invention or for which be useful for the treatment of a disease or disorder of the candidate therapeutic compounds may be identified include adrenal gland. This method includes the steps of: (a) provid 11-hydroxylase deficiency, 17-hydroxylase deficiency, ing a GPCR polypeptide substantially identical to a polypep 33-dehydrogenase deficiency, acquired immune deficiency tide listed in Tables 15 and 33; (b) contacting the polypeptide syndrome, ACTH-dependent adrenal hyperfunction (Cush with the candidate compound; and (c) measuring interaction ing disease), ACTH-independent adrenal hyperfunction, of the candidate compound to the polypeptide. Interaction of acute adrenal insufficiency, adrenal abscess, adrenal the compound to the polypeptide indicates that the candidate adenoma, adrenal calcification, adrenal cysts, adrenal compound may be useful for the treatment of a disease or cytomegaly, adrenal dysfunction in glycerol kinase defi disorder of the adrenal gland. ciency, adrenal hematoma, adrenal hemorrhage, adrenal his 0042. In still another aspect, the invention features another toplasmosis, adrenal hyperfunction, adrenal hyperplasia, method for determining whether a candidate compound may adrenal medullary hyperplasia, adrenal myelolipoma, adre be useful for the treatment of a disease or disorder of the nal tuberculosis, adrenocortical adenoma, adrenocortical adrenal gland. This method includes (a) providing a GPCR adenoma with primary hyperaldosteronism (Conn's Syn polypeptide substantially identical to a polypeptide listed in drome), adrenocortical carcinoma, adrenocortical carcinoma Tables 15 and 33; (b) contacting the polypeptide with the with Cushing's syndrome, adrenocortical hyperfunction, candidate compound; and (c) measuring the half-life of the adrenocortical insufficiency, adrenocortical neoplasms, adre polypeptide, wherein an alteration in the half-life of the noleuknock outdystrophy, amyloidosis, anencephaly, polypeptide, relative to that of the polypeptide not contacted autoimmune Addison's disease, Beckwith-Wiedemann syn with the compound, indicates that the candidate compound drome, bilateral adrenal hyperplasia, chronic insufficiency of may be useful for the treatment of a disease or disorder of the adrenocortical hormone synthesis, complete 21-hydroxylase adrenal gland. Preferably the GPCR polypeptide is in a cell or deficiency, congenital adrenal hyperplasia, congenital adre a cell free assay system. nal hypoplasia, cortical hyperplasia, desmolase deficiency, 0043. In another aspect, the invention features a method ectopic ACTH syndrome, excess aldosterone secretion, for determining whether a patient has an increased risk for excess cortisol secretion (Cushing's syndrome), excess secre developing a disease or disorder of the adrenal gland. The tion of adrenocortical hormones, excess sex hormone secre method includes the step of determining whether the patient tion, familial glucocorticoid deficiency, functional “black” has a mutation in a gene encoding a polypeptide listed in adenomas, ganglioneuroblastoma, ganglioneuroma, gluco Tables 15 and 33, wherein presence of the mutation indicates corticoid remediable hyperaldosteronism, herpetic adrenali that the patient has an increased risk for developing a disease tis, hyperaldosteronism, idiopathic Addison's disease, idio or disorder of the adrenal gland. pathic hyperaldosteronism with bilateral hyperplasia of Zona 0044. In a related aspect, the invention features another glomerulosa, latrogenic hypercortisolism, lysosomal storage method for determining whether a patient has an increased diseases, macronodular hyperplasia, macronodular hyperpla risk for developing a disease or disorder of the adrenal gland. sia with marked adrenal enlargement, malignant lymphoma, This method includes the step of determining whether the malignant melanoma, metastatic carcinoma, metastatic patient has a polymorphism in a gene encoding a polypeptide tumors, micronocular hyperplasia, multiple endocrine neo listed in Tables 15 and 33, wherein presence of the polymor plasia syndromes, multiple endocrine neoplasia type I phism indicates that the patient may have an increased risk for (Wermer syndrome), multiple endocrine neoplasia type 2a developing a disease or disorder of the adrenal gland. (Sipple syndrome), multiple endocrine neoplasia type 2b, 0045. In either of these two methods, the mutation or poly neuroblastoma, Niemann-Pick disease, ovarian thecal meta morphism is preferably associated with an alteration (for plasia, paraganglioma, partial 21-hydroxylase deficiency, example, a decrease) in the biological activity of the polypep pheochromocytoma, primary aldosteronism (Conn's Syn tide. drome), primary chronic adrenal insufficiency (Addison's 0046. In another aspect, the invention features another disease), primary hyperaldosteronism, primary mesenchy method for determining whether a patient has an increased mal tumors, primary pigmented nodular adrenocortical dis risk for developing a disease or disorder of the adrenal gland. ease, salt-wasting congenital adrenal hyperplasia, secondary The method includes measuring biological activity of a Addison's disease, secondary hyperaldosteronsim, selective GPCR polypeptide from the patient that is substantially iden hypoaldosteronism, simple virilizing congenital adrenal tical to a polypeptide listed in Tables 15 and 33, wherein hyperplasia, Waterhouse-Friderichsen syndrome, and Wol increased or decreased levels in the GPCR biological activity, man's disease. US 2009/0178153 A1 Jul. 9, 2009

0049. In another aspect, the invention features a non-hu the candidate compound; and (c) measuring biological activ man mammal (e.g., a mouse), having a transgene that ity of the GPCR polypeptide in the transgenic non-human includes a nucleic acid molecule encoding a GPCR polypep mammal, wherein altered biological activity, relative to that tide substantially identical to a polypeptide listed in Table 15. of the transgenic non-human mammal not contacted with the 0050. In yet another aspect, the invention features a non compound, indicates that the candidate compound may be human mammal (e.g., a mouse), having a mutation in a useful for the treatment of a disease or disorder of the colon. nucleic acid molecule encoding a GPCR polypeptide sub 0.058 Instill another aspect, the invention features another stantially identical to a polypeptide listed in Table 15. method for determining whether a candidate compound may 0051. In a related aspect, the invention features a cell from be useful for the treatment of a disease or disorder of the a non-human mammal having a transgene that includes a colon. This method includes (a) providing a nucleic acid nucleic acid molecule encoding a GPCR polypeptide sub molecule comprising a promoter from a gene encoding a stantially identical to a polypeptide listed in Table 15. GPCR polypeptide listed in Tables 16 and 33, the promoter 0052. In another aspect, the invention features a cell from operably linked to a reporter system; (b) contacting the a non-human mammal having a mutation in a nucleic acid nucleic acid molecule with the candidate compound; and (c) molecule encoding a GPCR polypeptide substantially identi measuring reporter activity, wherein altered reporter activity, cal to a polypeptide listed in Table 15. relative to a nucleic acid molecule not contacted with the 0053. In another aspect, the invention features a method of compound, indicates that the candidate compound may be preventing or treating a disease of the colon including intro useful for the treatment of a disease or disorder of the colon. ducing into a human an expression vector that includes a 0059. In another aspect, the invention features yet another nucleic acid molecule encoding a GPCR polypeptide sub method for determining whether a candidate compound may stantially identical to a polypeptide listed in Tables 16 and 33, be useful for the treatment of a disease or disorder of the operably linked to a promoter. colon. This method includes the steps of: (a) providing a 0054. In still another aspect, the invention features a GPCR polypeptide substantially identical to a polypeptide method of treating or preventing a disease of the colon includ listed in Tables 16 and 33; (b) contacting the polypeptide with ing administering to an animal (e.g., a human) a compound the candidate compound; and (c) measuring interaction of the that modulates the biological activity of a GPCR polypeptide candidate compound to the polypeptide. Interaction of the substantially identical to a polypeptide listed in Tables 16 and compound to the polypeptide indicates that the candidate 33. compound may be useful for the treatment of a disease or 0055. In yet another aspect, the invention features a disorder of the colon. method for determining whether a candidate compound is a 0060 Instill another aspect, the invention features another compound that may be useful for the treatment of a disease or method for determining whether a candidate compound may disorder of the colon. This method includes the steps of (a) be useful for the treatment of a disease or disorder of the providing a GPCR polypeptide substantially identical to a colon. This method includes (a) providing a GPCR polypep polypeptide listed in Tables 16 and 33; (b) contacting the tide substantially identical to a polypeptide listed in Tables 16 GPCR polypeptide with the candidate compound; and (c) and 33; (b) contacting the polypeptide with the candidate measuring biological activity of the GPCR polypeptide, compound; and (c) measuring the half-life of the polypeptide, wherein altered biological activity, relative to that of the wherein an alteration in the half-life of the polypeptide, rela GPCR polypeptide not contacted with the compound, indi tive to that of the polypeptide not contacted with the com cates that the candidate compound may be useful for the pound, indicates that the candidate compound may be useful treatment of a disease or disorder of the colon. The GPCR for the treatment of a disease or disorder of the colon. Pref polypeptide can be in a cell or in a cell-free assay System. erably the GPCR polypeptide is in a cell or a cell free assay 0056. In yet another aspect, the invention features a system. method for determining whether a candidate compound is a 0061. In another aspect, the invention features a method compound that may be useful for the treatment of a disease or for determining whether a patient has an increased risk for disorder of the colon. This method includes the steps of (a) developing a disease or disorder of the colon. The method providing a transgenic non-human mammal (e.g., a knock includes the step of determining whether the patient has a out mouse) having a disruption in a nucleic acid molecule mutation in a gene encoding a polypeptide listed in Tables 16 encoding a GPCR polypeptide substantially identical to a and 33, wherein presence of the mutation indicates that the polypeptide listed in Tables 16 and 33; (b) contacting the patient has an increased risk for developing a disease or transgenic non-human mammal with the candidate com disorder of the colon. pound; and (c) measuring biological activity of the GPCR 0062. In a related aspect, the invention features another polypeptide in the transgenic non-human mammal, wherein method for determining whether a patient has an increased altered biological activity, relative to that of the transgenic risk for developing a disease or disorder of the colon. This non-human mammal not contacted with the compound, indi method includes the step of determining whether the patient cates that the candidate compound may be useful for the has a polymorphism in a gene encoding a polypeptide listed in treatment of a disease or disorder of the colon. Tables 16 and 33, wherein presence of the polymorphism 0057. In yet another aspect, the invention features a indicates that the patient may have an increased risk for method for determining whether a candidate compound is a developing a disease or disorder of the colon. compound that may be useful for the treatment of a disease or 0063. In either of these two methods, the mutation or poly disorder of the colon. This method includes the steps of (a) morphism is preferably associated with an alteration (for providing a transgenic non-human mammal (e.g., a mouse) example, a decrease) in the biological activity of the polypep overexpressing a nucleic acid molecule encoding a GPCR tide. polypeptide Substantially identical to a polypeptide listed in 0064. In another aspect, the invention features another Tables 16 and 33; (b) contacting the GPCR polypeptide with method for determining whether a patient has an increased US 2009/0178153 A1 Jul. 9, 2009

risk for developing a disease or disorder of the colon. The 0067. In another aspect, the invention features a non-hu method includes measuring biological activity of a GPCR man mammal (e.g., a mouse), having a transgene that polypeptide from the patient that is substantially identical to includes a nucleic acid molecule encoding a GPCR polypep a polypeptide listed in Tables 16 and 33, wherein increased or tide substantially identical to a polypeptide listed in Table 16. decreased levels in the GPCR biological activity, relative to 0068. In yet another aspect, the invention features a non normal levels, indicate that the patient may have an increased human mammal (e.g., a mouse), having a mutation in a risk for developing a disease or disorder of the colon. nucleic acid molecule encoding a GPCR polypeptide sub stantially identical to a polypeptide listed in Table 16. 0065. In still another aspect, the invention features yet 0069. In a related aspect, the invention features a cell from another method for determining whether a patient has an a non-human mammal having a transgene that includes a increased risk for developing a disease or disorder of the nucleic acid molecule encoding a GPCR polypeptide sub colon. The method includes the step of measuring the stantially identical to a polypeptide listed in Table 6. patient's expression levels of a polypeptide listed in Tables 16 0070. In another aspect, the invention features a cell from and 33, wherein altered levels in the expression, relative to a non-human mammal having a mutation in a nucleic acid normal, indicate that the patient has an increased risk for molecule encoding a GPCR polypeptide substantially identi developing a disease or disorder of the colon. Preferably, the cal to a polypeptide listed in Table 16. expression levels are determined by measuring levels of 0071. In another aspect, the invention features a method of polypeptide or mRNA. preventing or treating cardiovascular disease, including intro 0066 Diseases of the colon that can be treated or diag ducing into a human an expression vector that includes a nosed using the methods of the invention or for which candi nucleic acid molecule encoding a GPCR polypeptide sub date therapeutic compounds may be identified include acute stantially identical to a polypeptide listed in Tables 17 and 33, self-limited infectious colitis, adenocarcinoma, adenoma, operably linked to a promoter. adenoma-carcinoma sequence, adenomatous polyposis coli, 0072. In still another aspect, the invention features a adenosquamous carcinomas, allergic (eosinophilic) proctitis method of treating or preventing cardiovascular disease, and colitis, amebiasis, amyloidosis, angiodysplasia, anorec including administering to an animal (e.g., a human) a com tal malformations, blue rubber bleb nevus syndrome, brown pound that modulates the biological activity of a GPCR bowel syndrome, Campylobacter fetus infection, carcinoid polypeptide Substantially identical to a polypeptide listed in tumors, carcinoma of the anal canal, carcinoma of the colon Tables 17 and 33. and rectum, chlamidial proctitis, Crohn's disease, clear cell 0073. In yet another aspect, the invention features a carcinomas, Clostridium difficile pseudomembranous entero method for determining whether a candidate compound is a colitis, collagenous colitis, colonic adenoma, colonic diver compound that may be useful for the treatment of a cardio ticulosis, colonic inertia, colonic ischemia, congenital atresia, vascular disease or disorder. This method includes the steps of congenital megacolon (Hirschsprung's disease), congenital (a) providing a GPCR polypeptide substantially identical to a Stenosis, constipation, Cowden's syndrome, cystic fibrosis, polypeptide listed in Tables 17 and 33; (b) contacting the cytomegalovirus colitis, diarrhea, dieulafor lesion, diversion GPCR polypeptide with the candidate compound; and (c) colitis, diverticulitis, diverticulosis, drug-induced diseases, measuring biological activity of the GPCR polypeptide, dysplasia and malignancy in inflammatory bowel disease, wherein altered biological activity, relative to that of the Ehlers-Danlos syndromes, enterobiasis, familial adenoma GPCR polypeptide not contacted with the compound, indi tous polyposis, familial polyposis syndromes, Gardner's Syn cates that the candidate compound may be useful for the drome, gastrointestinal Stromal neoplasms, hemangiomas treatment of a cardiovascular disease or disorder. The GPCR and vascular anomalies, hemorrhoids, hereditary hemor polypeptide can be in a cell or in a cell-free assay System. rhagic telangiectasia, herpes colitis, hyperplastic polyps, 0074. In yet another aspect, the invention features a idiopathic inflammatory bowel disease, incontinence, inflam method for determining whether a candidate compound is a matory bowel syndrome, inflammatory polyps, inherited compound that may be useful for the treatment of a cardio adenomatous polyposis syndromes, intestinal hamartomas, vascular disease or disorder. This method includes the steps of intestinal pseudo-obstruction, irritable bowel syndrome, (a) providing a transgenic non-human mammal (e.g., a ischemic colitis,juvenile polyposis,juvenile polyps, Klippel knock-out mouse) having a disruption in a nucleic acid mol Trénaunay-Weber syndrome, leiomyomas, lipomas, lympho ecule encoding a GPCR polypeptide substantially identical to cytic (microscopic) colitis, lymphoid hyperplasia and lym a polypeptide listed in Tables 17 and 33; (b) contacting the phoma, malaknock outplakia, malignant lymphoma, transgenic non-human mammal with the candidate com malignant neoplasms, malrotation, metastatic neoplasms, pound; and (c) measuring biological activity of the GPCR mixed hyperplastic and adenomatous polyps, mucosal pro polypeptide in the transgenic non-human mammal, wherein lapse syndrome, neonatal necrotizing enterocolitis, neuroen altered biological activity, relative to that of the transgenic docrine cell tumors, neurogenic tumors, neutropenic entero non-human mammal not contacted with the compound, indi colitis, non-neoplastic polyps, Peutz-Jeghers syndrome, cates that the candidate compound may be useful for the pneumatosis cystoides intestinalis, polyposis coli, treatment of a cardiovascular disease or disorder. pseudomembranous colitis, pseudoxanthoma elasticum, pure 0075. In yet another aspect, the invention features a squamous carcinomas, radiation colitis, Schistosomiasis, Shi method for determining whether a candidate compound is a gella colitis (bacilliary dysentery), spindle cell carcinomas, compound that may be useful for the treatment of a cardio spirochetosis, Stercolar ulcers, stromal tumors, systemic scle vascular disease or disorder. This method includes the steps of rosis and CREST syndrome, trichuriasis, tubular adenoma (a) providing a transgenic non-human mammal (e.g., a (adenomatous polyp, polypoid adenoma), Turcot's Syn mouse) overexpressing a nucleic acid molecule encoding a drome, Turner's syndrome, ulcerative colitis, villous GPCR polypeptide substantially identical to a polypeptide adenoma, and Volvulus. listed in Tables 17 and 33; (b) contacting the transgenic non US 2009/0178153 A1 Jul. 9, 2009

human mammal with the candidate compound; and (c) mea I0082 In another aspect, the invention features another suring biological activity of the GPCR polypeptide in the method for determining whether a patient has an increased transgenic non-human mammal, wherein altered biological risk for developing a cardiovascular disease or disorder. The activity, relative to that of the transgenic non-human mammal method includes measuring biological activity of a GPCR not contacted with the compound, indicates that the candidate polypeptide from the patient that is substantially identical to compound may be useful for the treatment of a cardiovascular a polypeptide listed in Tables 17 and 33, wherein increased or disease or disorder. decreased levels in the GPCR biological activity, relative to 0076. In still another aspect, the invention features another normal levels, indicate that the patient may have an increased method for determining whether a candidate compound may risk for developing a cardiovascular disease or disorder. be useful for the treatment of a cardiovascular disease or I0083. In still another aspect, the invention features yet disorder. This method includes (a) providing a nucleic acid another method for determining whether a patient has an molecule comprising a promoter from a gene encoding a increased risk for developing a cardiovascular disease or dis GPCR polypeptide listed in Tables 17 and 33, the promoter order. The method includes the step of measuring the patient's operably linked to a reporter system; (b) contacting the expression levels of a polypeptide listed in Tables 17 and 33, nucleic acid molecule with the candidate compound; and (c) wherein altered levels in the expression, relative to normal, measuring reporter activity, wherein altered reporter activity, indicate that the patient has an increased risk for developing a relative to a nucleic acid molecule not contacted with the cardiovascular disease or disorder. Preferably, the expression compound, indicates that the candidate compound may be levels are determined by measuring levels of polypeptide or useful for the treatment of a cardiovascular disease or disor mRNA. der. I0084. One preferred cardiovascular disease that can be 0077. In another aspect, the invention features yet another treated or diagnosed using the methods of the invention or for method for determining whether a candidate compound may which candidate therapeutic compounds may be identified is be useful for the treatment of a cardiovascular disease or coronary artery disease. Others include acute coronary Syn disorder. This method includes the steps of: (a) providing a drome, acute idiopathic pericarditis, acute rheumatic fever, GPCR polypeptide substantially identical to a polypeptide American trypanosomiasis (Chagas disease), angina pecto listed in Tables 17 and 33; (b) contacting the polypeptide with ris, ankylosing spondylitis, anomalous pulmonary venous the candidate compound; and (c) measuring interaction of the connection, anomalous pulmonary venous drainage, aortic candidate compound to the polypeptide. Interaction of the atresia, aortic regurgitation, aortic Stenosis, aortic valve insuf compound to the polypeptide indicates that the candidate ficiency, aortopulmonary septal defect, asymmetric septal compound may be useful for the treatment of a cardiovascular hypertrophy, asystole, atrial fibrillation, atrial flutter, atrial disease or disorder. septal defect, atrioventricular septal defect, autoimmune 0078. In still another aspect, the invention features another myocarditis, bacterial endocarditis, calcific aortic Stenosis, method for determining whether a candidate compound may calcification of the central valve, calcification of the valve be useful for the treatment of a cardiovascular disease or ring, carcinoid heart disease, cardiac amyloidosis, cardiac disorder. This method includes (a) providing a GPCR arrest, cardiac arrhythmia, cardiac failure, cardiac myxoma, polypeptide Substantially identical to a polypeptide listed in cardiac rejection, cardiac tamponade, cardiogenic shock, car Tables 17 and 33; (b) contacting the polypeptide with the diomyopathy of pregnancy, chronic adhesive pericarditis, candidate compound; and (c) measuring the half-life of the chronic constrictive pericarditis, chronic left ventricular fail polypeptide, wherein an alteration in the half-life of the ure, coarctation of the aorta, complete heart block, complete polypeptide, relative to that of the polypeptide not contacted transposition of the great vessels, congenital bicuspid aortic with the compound, indicates that the candidate compound valves, congenital narrowing of the left ventricular outflow may be useful for the treatment of a cardiovascular disease or tract, congenital pulmonary valve Stenosis, congenitally cor disorder. Preferably the GPCR polypeptide is in a cellor a cell rected transposition of the great arteries, congestive heart free assay system. failure, constrictive pericarditis, cor pulmonale, coronary 0079. In another aspect, the invention features a method artery origin from pulmonary artery, coronary atherosclero for determining whether a patient has an increased risk for sis, dilated (congestive) cardiomyopathy, diphtheria, double developing a cardiovascular disease or disorder. The method inlet left ventricle, double outlet right ventricle, Ebstein's includes the step of determining whether the patient has a malformation, endocardial fibroelastosis, endocarditis, mutation in a gene encoding a polypeptide listed in Tables 17 endomyocardial fibrosis, eosinophilic endomyocardial dis and 33, wherein presence of the mutation indicates that the ease (Loffler endocarditis), fibroma, glycogen storage dis patient may have an increased risk for developing a cardio eases, hemochromatosis, hypertensive heart disease, hyper vascular disease or disorder. thyroid heart disease, hypertrophic cardiomyopathy, 0080. In a related aspect, the invention features another hypothyroid heart disease, idiopathic dilated cardiomyopa method for determining whether a patient has an increased thy, idiopathic myocarditis, infectious myocarditis, infective risk for developing a cardiovascular disease or disorder. This endocarditis, ischemic heart disease, left ventricular failure, method includes the step of determining whether the patient Libman-Sachs endocarditis, lupus erythematosus, lyme dis has a polymorphism in a gene encoding a polypeptide listed in ease, marantic endocarditis, metastatic tumors, mitral insuf Tables 17 and 33, wherein presence of the polymorphism ficiency, mitral regurgitation, mitral Stenosis, mitral valve indicates that the patient may have an increased risk for prolapse, mucopolysaccharidoses, multifocal atrial tachycar developing a cardiovascular disease or disorder. dia, myocardial infarction, myocardial ischemia, myocardial 0081. In either of these two methods, the mutation or poly rupture, myocarditis, myxomatuos degeneration, nonathero morphism is preferably associated with an alteration (for matous coronary artery disease, nonbacterial thrombotic example, a decrease) in the biological activity of the polypep endocarditis, noninfectious acute pericarditis, nonviral infec tide. tious pericarditis, obliterative cardiomyopathy, patent ductus US 2009/0178153 A1 Jul. 9, 2009

arteriosus, pericardial effusion, pericardial tumors, pericardi 0092. In yet another aspect, the invention features a tis, persistent truncus arteriosis, premature ventricular con method for determining whether a candidate compound is a traction, progressive infarction, pulmonary atresia with intact compound that may be useful for the treatment of a disease or Ventricular septum, pulmonary atresia with Ventricular septal disorder of the intestine. This method includes the steps of (a) defect, pulmonary insufficiency, pulmonary regurgitation, providing a transgenic non-human mammal (e.g., a knock pulmonary Stenosis, pulmonary valve lesions, pulmonary out mouse) having a disruption in a nucleic acid molecule valve Stenosis, pyogenic pericarditis, Q fever, radiations myo encoding a GPCR polypeptide substantially identical to a carditis, restrictive cardiomyopathy, rhabdomyoma, rheu polypeptide listed in Tables 18 and 33; (b) contacting the matic aortic Stenosis, rheumatic heart disease, rocky moun transgenic non-human mammal with the candidate com tain spotted fever, rupture of the aortic valve, sarcoid pound; and (c) measuring biological activity of the GPCR myocarditis, Scleroderma, shingolipidoses, sinus brachycar polypeptide in the transgenic non-human mammal, wherein dia, Sudden death syndrome, syphilis, Systemic embolism altered biological activity, relative to that of the transgenic from mural thrombi, Systemic lupus erythematosus, tetralogy non-human mammal not contacted with the compound, indi of fallot, thiamine deficiency (Beriberi) heart disease, tho cates that the candidate compound may be useful for the racic outlet syndrome, Torsade de Pointes, toxic cardiomy treatment of a disease or disorder of the intestine. opathy, toxic myocarditis, toxoplasmosis, trichinosis, tricus 0093. In yet another aspect, the invention features a pid atresia, tricuspid insufficiency, tricuspid regurgitation, method for determining whether a candidate compound is a tricuspid Stenosis, tricuspid valve lesions, tuberculosis peri compound that may be useful for the treatment of a disease or carditis, typhus, Ventricular aneurysm, Ventricular fibrilla disorder of the intestine. This method includes the steps of (a) tion, Ventricular septal defect, Ventricular tachycardia, Ven providing a transgenic non-human mammal (e.g., a mouse) triculoarterial septal defect, viral pericarditis, and Wolff overexpressing a nucleic acid molecule encoding a GPCR Parkinson-White syndrome. polypeptide Substantially identical to a polypeptide listed in 0085. In another aspect, the invention features a non-hu Tables 18 and 33; (b) contacting the transgenic non-human man mammal (e.g., a mouse), having a transgene that mammal with the candidate compound; and (c) measuring includes a nucleic acid molecule encoding a GPCR polypep biological activity of the GPCR polypeptide in the transgenic tide substantially identical to a polypeptide listed in Table 17. non-human mammal, wherein altered biological activity, I0086. In yet another aspect, the invention features a non relative to that of the transgenic non-human mammal not human mammal (e.g., a mouse), having a mutation in a contacted with the compound, indicates that the candidate nucleic acid molecule encoding a GPCR polypeptide sub compound may be useful for the treatment of a disease or stantially identical to a polypeptide listed in Table 17. disorder of the intestine. 0094. In still another aspect, the invention features another 0087. In a related aspect, the invention features a cell from method for determining whether a candidate compound may a non-human mammal having a transgene that includes a be useful for the treatment of a disease or disorder of the nucleic acid molecule encoding a GPCR polypeptide sub intestine. This method includes (a) providing a nucleic acid stantially identical to a polypeptide listed in Table 17. molecule comprising a promoter from a gene encoding a 0088. In another aspect, the invention features a cell from GPCR polypeptide listed in Tables 18 and 33, the promoter a non-human mammal having a mutation in a nucleic acid operably linked to a reporter system; (b) contacting the molecule encoding a GPCR polypeptide substantially identi nucleic acid molecule with the candidate compound; and (c) cal to a polypeptide listed in Table 17. measuring reporter activity, wherein altered reporter activity, 0089. In another aspect, the invention features a method of relative to a nucleic acid molecule not contacted with the preventing or treating a disease of the intestine including compound, indicates that the candidate compound may be introducing into a human an expression vector that includes a useful for the treatment of a disease or disorder of the intes nucleic acid molecule encoding a GPCR polypeptide sub tine. stantially identical to a polypeptide listed in Tables 18 and 33, 0095. In another aspect, the invention features yet another operably linked to a promoter. method for determining whether a candidate compound may 0090. In still another aspect, the invention features a be useful for the treatment of a disease or disorder of the method of treating or preventing a disease of the intestine intestine. This method includes the steps of: (a) providing a including administering to an animal (e.g., a human) a com GPCR polypeptide substantially identical to a polypeptide pound that modulates the biological activity of a GPCR listed in Tables 18 and 33; (b) contacting the polypeptide with polypeptide Substantially identical to a polypeptide listed in the candidate compound; and (c) measuring interaction of the Tables 18 and 33. candidate compound to the polypeptide. Interaction of the 0091. In yet another aspect, the invention features a compound to the polypeptide indicates that the candidate method for determining whether a candidate compound is a compound may be useful for the treatment of a disease or compound that may be useful for the treatment of a disease or disorder of the intestine. disorder of the intestine. This method includes the steps of (a) 0096. In still another aspect, the invention features another providing a GPCR polypeptide substantially identical to a method for determining whether a candidate compound may polypeptide listed in Tables 18 and 33; (b) contacting the be useful for the treatment of a disease or disorder of the GPCR polypeptide with the candidate compound; and (c) intestine. This method includes (a) providing a GPCR measuring biological activity of the GPCR polypeptide, polypeptide Substantially identical to a polypeptide listed in wherein altered biological activity, relative to that of the Tables 18 and 33; (b) contacting the polypeptide with the GPCR polypeptide not contacted with the compound, indi candidate compound; and (c) measuring the half-life of the cates that the candidate compound may be useful for the polypeptide, wherein an alteration in the half-life of the treatment of a disease or disorder of the intestine. The GPCR polypeptide, relative to that of the polypeptide not contacted polypeptide can be in a cell or in a cell-free assay System. with the compound, indicates that the candidate compound US 2009/0178153 A1 Jul. 9, 2009

may be useful for the treatment of a disease or disorder of the polyps, idiopathic inflammatory bowel disease, ileus, imper intestine. Preferably the GPCR polypeptide is in a cell or a forate anus, intestinal (abdominal ischemia), intestinal atre cell free assay system. sia, intestinal cryptosporidiosis, microsporidiosis & isospo 0097. In another aspect, the invention features a method riasis in AIDS, intestinal hamartomas, intestinal for determining whether a patient has an increased risk for helminthiasis, intestinal hemorrhage, intestinal infiltrative developing a disease or disorder of the intestine. The method disorders, intestinal lymphangiectasia, intestinal obstruction, includes the step of determining whether the patient has a intestinal perforation, intestinal reduplication, intestinal mutation in a gene encoding a polypeptide listed in Tables 18 Stenosis, intestinal tuberculosis, intussusception, jejunal and 33, wherein presence of the mutation indicates that the diverticulosis, juvenile polyposis, juvenile retention polyps, patient may have an increased risk for developing a disease or lactase deficiency, lymphomas, malabsorption syndrome, disorder of the intestine. malignant lymphoma, malignant neoplasms, malrotations, 0098. In a related aspect, the invention features another mechanical obstruction, Meckel's diverticulum, meconium method for determining whether a patient has an increased illeus, mediterranean lymphoma, mesenchymal tumors, risk for developing a disease or disorder of the intestine. This mesenteric vasculitis, mesenteric vein thrombosis, metastatic method includes the step of determining whether the patient neoplasms, microVillus inclusion disease, mixed hyperplastic has a polymorphism in a gene encoding a polypeptide listed in and adenomatous polyps, neonatal necrotizing enterocolitis, Tables 18 and 33, wherein presence of the polymorphism nodular duodenum, nonocclusive intestinal ischemia, non indicates that the patient may have an increased risk for specific duodenitis, nontyphoidal salmonellosis, omphalo developing a disease or disorder of the intestine. cele, parasitic infections, peptic ulcer disease, Peutz-Jeghers 0099. In either of these two methods, the mutation or poly syndrome, pneumatosis cystoides intestinalis, poorly differ morphism is preferably associated with an alteration (for entiated neuroendocrine carcinomas, primary lymphoma, example, a decrease) in the biological activity of the polypep protein-losing enteropathy, Salmonella gastroenteritis, Sar tide. coidosis, sarcomas, Shigellosis, staphlococcal food poison 0100. In another aspect, the invention features another ing, steatorrhea, Sugar intolerance, thrombosis of the mesen method for determining whether a patient has an increased teric veins, toxigenic diarrhea, toxigenic Escherichia coli risk for developing a disease or disorder of the intestine. The infection, tropical sprue, tubular adenoma (adenomatous method includes measuring biological activity of a GPCR polyp, polypoid adenoma), typhoid fever, ulcers, vascular polypeptide from the patient that is substantially identical to malformations, villous adenoma, viral enteritis, viral gastro enteritis, visceral myopathy, visceral neuropathy, Vitelline a polypeptide listed in Tables 18 and 33, wherein increased or duct remnants, Volvulus, Western-type intestinal lymphoma, decreased levels in the GPCR biological activity, relative to Whipple's disease (intestinal lipopy strophy), Yersinia entero normal levels, indicate that the patient may have an increased colitica & Yersinia pseudotuberculosis infection, and risk for developing a disease or disorder of the intestine. Zollinger-Ellison syndrome. 0101. In still another aspect, the invention features yet another method for determining whether a patient has an 0103) In another aspect, the invention features a non-hu increased risk for developing a disease or disorder of the man mammal (e.g., a mouse), having a transgene that intestine. The method includes the step of measuring the includes a nucleic acid molecule encoding a GPCR polypep patient's expression levels of a polypeptide listed in Tables 18 tide substantially identical to a polypeptide listed in Table 18. and 33, wherein altered levels in the expression, relative to 0104. In yet another aspect, the invention features a non normal, indicate that the patient has an increased risk for human mammal (e.g., a mouse), having a mutation in a developing a disease or disorder of the intestine. Preferably, nucleic acid molecule encoding a GPCR polypeptide sub the expression levels are determined by measuring levels of stantially identical to a polypeptide listed in Table 18. polypeptide or mRNA. 0105. In a related aspect, the invention features a cell from 0102 Diseases of the intestine that can be treated or diag a non-human mammal having a transgene that includes a nosed using the methods of the invention or for which candi nucleic acid molecule encoding a GPCR polypeptide sub date therapeutic compounds may be identified include stantially identical to a polypeptide listed in Table 18. abdominal hernia, abetalipoproteinemia, abnormal rotation, 0106. In another aspect, the invention features a cell from acute hypotensive hypoperfusion, acute intestinal ischemia, a non-human mammal having a mutation in a nucleic acid acute Small intestinal infarction, adenocarcinoma, adenoma, molecule encoding a GPCR polypeptide substantially identi adhesions, amebiasis, anemia, arterial occlusion, atypical cal to a polypeptide listed in Table 18. mycobacteriosis, bacterial diarrhea, bacterial overgrowild 0107. In another aspect, the invention features a method of typeh Syndromes, botulism, Campylobacter fetus infection, preventing or treating a disease of the kidney including intro Campylobacter jejuni, carbohydrate absorption defects, car ducing into a human an expression vector that includes a cinoid tumors, celiac disease (nontropical sprue, gluten-in nucleic acid molecule encoding a GPCR polypeptide sub duced enteropathy), cholera, Chrohn's disease, chronic intes stantially identical to a polypeptide listed in Tables 19 and 33, tinal ischemia, Clostridium difficile pseudomembranous operably linked to a promoter. enterocolitis, Clostridium perfiringens, congenital umbilical 0108. In still another aspect, the invention features a hernia, Cronkhite-Canada syndrome, cytomegalovirus method of treating or preventing a disease of the kidney enterocolitis, diarrhea, diarrhea caused by invasive bacteria, including administering to an animal (e.g., a human) a com diverticulitis, diverticulosis, dysentery, enteroinvasive and pound that modulates the biological activity of a GPCR enterohemorrhagic Escherichia coli infection, eosinophilic polypeptide Substantially identical to a polypeptide listed in gastroenteritis, failure of peristalsis, familial polyposis Syn Tables 19 and 33. dromes, food poisoning, fungal enteritis, gangliocytic 0109. In yet another aspect, the invention features a paragangliomas, Gardner's syndrome, gastrointestinal stro method for determining whether a candidate compound is a mal neoplasms, giardiasis, hemorrhoids, hernia, hyperplastic compound that may be useful for the treatment of a disease or US 2009/0178153 A1 Jul. 9, 2009

disorder of the kidney. This method includes the steps of (a) 0114 Instill another aspect, the invention features another providing a GPCR polypeptide substantially identical to a method for determining whether a candidate compound may polypeptide listed in Tables 19 and 33; (b) contacting the be useful for the treatment of a disease or disorder of the GPCR polypeptide with the candidate compound; and (c) kidney. This method includes (a) providing a GPCR polypep measuring biological activity of the GPCR polypeptide, tide substantially identical to a polypeptide listed in Tables 19 wherein altered biological activity, relative to that of the and 33; (b) contacting the polypeptide with the candidate GPCR polypeptide not contacted with the compound, indi compound; and (c) measuring the half-life of the polypeptide, cates that the candidate compound may be useful for the wherein an alteration in the half-life of the polypeptide, rela treatment of a disease or disorder of the kidney. The GPCR tive to that of the polypeptide not contacted with the com polypeptide can be in a cell or in a cell-free assay System. pound, indicates that the candidate compound may be useful for the treatment of a disease or disorder of the kidney. Pref 0110. In yet another aspect, the invention features a erably the GPCR polypeptide is in a cell or a cell free assay method for determining whether a candidate compound is a system. compound that may be useful for the treatment of a disease or 0.115. In another aspect, the invention features a method disorder of the kidney. This method includes the steps of (a) for determining whether a patient has an increased risk for providing a transgenic non-human mammal (e.g., a knock developing a disease or disorder of the kidney. The method out mouse) having a disruption in a nucleic acid molecule includes the step of determining whether the patient has a encoding a GPCR polypeptide substantially identical to a mutation in a gene encoding a polypeptide listed in Tables 19 polypeptide listed in Tables 19 and 33; (b) contacting the and 33, wherein presence of the mutation indicates that the transgenic non-human mammal with the candidate com patient may have an increased risk for developing a disease or pound; and (c) measuring biological activity of the GPCR disorder of the kidney. polypeptide in the transgenic non-human mammal, wherein 0116. In a related aspect, the invention features another altered biological activity, relative to that of the transgenic method for determining whether a patient has an increased non-human mammal not contacted with the compound, indi risk for developing a disease or disorder of the kidney. This cates that the candidate compound may be useful for the method includes the step of determining whether the patient treatment of a disease or disorder of the kidney. has a polymorphism in a gene encoding a polypeptide listed in 0111. In yet another aspect, the invention features a Tables 19 and 33, wherein presence of the polymorphism method for determining whether a candidate compound is a indicates that the patient may have an increased risk for compound that may be useful for the treatment of a disease or developing a disease or disorder of the kidney. disorder of the kidney. This method includes the steps of (a) 0117. In either of these two methods, the mutation or poly providing a transgenic non-human mammal (e.g., a mouse) morphism is preferably associated with an alteration (for overexpressing a nucleic acid molecule encoding a GPCR example, a decrease) in the biological activity of the polypep polypeptide Substantially identical to a polypeptide listed in tide. Tables 19 and 33; (b) contacting the transgenic non-human 0118. In another aspect, the invention features another mammal with the candidate compound; and (c) measuring method for determining whether a patient has an increased biological activity of the GPCR polypeptide in the transgenic risk for developing a disease or disorder of the kidney. The non-human mammal, wherein altered biological activity, method includes measuring biological activity of a GPCR relative to that of the transgenic non-human mammal not polypeptide from the patient that is substantially identical to contacted with the compound, indicates that the candidate a polypeptide listed in Tables 19 and 33, wherein increased or compound may be useful for the treatment of a disease or decreased levels in the GPCR biological activity, relative to disorder of the kidney. normal levels, indicate that the patient may have an increased 0112 Instill another aspect, the invention features another risk for developing a disease or disorder of the kidney. method for determining whether a candidate compound may 0119. In still another aspect, the invention features yet be useful for the treatment of a disease or disorder of the another method for determining whether a patient has an kidney. This method includes (a) providing a nucleic acid increased risk for developing a disease or disorder of the molecule comprising a promoter from a gene encoding a kidney. The method includes the step of measuring the GPCR polypeptide listed in Tables 19 and 33, the promoter patient's expression levels of a polypeptide listed in Tables 19 operably linked to a reporter system; (b) contacting the and 33, wherein altered levels in the expression, relative to nucleic acid molecule with the candidate compound; and (c) normal, indicate that the patient has an increased risk for measuring reporter activity, wherein altered reporter activity, developing a disease or disorder of the kidney. Preferably, the relative to a nucleic acid molecule not contacted with the expression levels are determined by measuring levels of compound, indicates that the candidate compound may be polypeptide or mRNA. useful for the treatment of a disease or disorder of the kidney. I0120 Diseases of the kidney that can be treated or diag 0113. In another aspect, the invention features yet another nosed using the methods of the invention or for which candi method for determining whether a candidate compound may date therapeutic compounds may be identified include be useful for the treatment of a disease or disorder of the acquired cystic disease, acute (postinfectious) glomerulone kidney. This method includes the steps of: (a) providing a phritis, acute infectious interstitial nephritis, acute interstitial GPCR polypeptide substantially identical to a polypeptide nephritis, acute pyelonephritis, acute renal failure, acute listed in Tables 19 and 33; (b) contacting the polypeptide with transplant failure, acute tubular necrosis, adult polycystic the candidate compound; and (c) measuring interaction of the kidney disease, AL amyloid, analgesic nephropathy, anti candidate compound to the polypeptide. Interaction of the glomerular basement membrane disease (Goodpasture's compound to the polypeptide indicates that the candidate Syndrome), asymptomatic hematuria, asymptomatic pro compound may be useful for the treatment of a disease or teinuria, autosomal dominant polycystic kidney disease, disorder of the kidney. autosomal recessive polycystic kidney disease, Bence Jones US 2009/0178153 A1 Jul. 9, 2009 cast nephropathy, benign familial hematuria, benign nephro ing administering to an animal (e.g., a human) a compound Sclerosis and atheromatous embolization, bilateral cortical that modulates the biological activity of a GPCR polypeptide necrosis, chronic glomerulonephritis, chronic interstitial substantially identical to a polypeptide listed in Tables 20 and nephritis, chronic pyelonephritis, chronic renal failure, 33. chronic transplant failure, circulating immune complex I0127. In yet another aspect, the invention features a nephritis, crescentic glomerulonephritis, cryoglobulinemia; method for determining whether a candidate compound is a cystic renal dysplasia, diabetic glomerulosclerosis, diabetic compound that may be useful for the treatment of a disease or nephropathy, dialysis cystic disease, drug induced (allergic) disorder of the liver. This method includes the steps of (a) acute interstitial nephritis, ectopic kidney, Fabry's disease, providing a GPCR polypeptide substantially identical to a familial juvenile nephronophthisis-medullary cystic disease polypeptide listed in Tables 20 and 33; (b) contacting the complex, focal glomerulosclerosis (segmental hyalinosis), GPCR polypeptide with the candidate compound; and (c) glomerulocystic disease, glomerulonephritis, glomerulone measuring biological activity of the GPCR polypeptide, phritis associated with bacterial endocarditis, glomeruloscle wherein altered biological activity, relative to that of the rosis, hemolytic-uremic syndrome, Henoch-Schönlein pur GPCR polypeptide not contacted with the compound, indi pura, hepatitis-associated glomerulonephritis, hereditary cates that the candidate compound may be useful for the nephritis (Alport syndrome), horseshoe kidney, hydroneph treatment of a disease or disorder of the liver. The GPCR rosis, IgA nephropathy, infantile polycystic kidney disease, polypeptide can be in a cell or in a cell-free assay System. ischemic acute tubular necrosis, light-chain deposit disease, I0128. In yet another aspect, the invention features a malignant nephrosclerosis, medullary cystic disease, mem method for determining whether a candidate compound is a branoproliferative (mesangiocapillary) glomerulonephritis, compound that may be useful for the treatment of a disease or membranous glomerulonephritis, membranous nephropathy, disorder of the liver. This method includes the steps of (a) mesangial proliferative glomerulonephritis (includes Berg providing a transgenic non-human mammal (e.g., a knock er's Disease), minimal change glomerular disease, minimal out mouse) having a disruption in a nucleic acid molecule change nephrotic syndrome, nephritic syndrome, nephro encoding a GPCR polypeptide substantially identical to a blastoma (Wilms tumor), nephronophthisis (medullary cystic polypeptide listed in Tables 20 and 33; (b) contacting the disease complex), nephrotic syndrome, plasma cell dyscra transgenic non-human mammal with the candidate com sias (monoclonal immunoglobulin-induced renal damage), pound; and (c) measuring biological activity of the GPCR polyarteritis nodosa, proteinuria, pyelonephritis, rapidly pro polypeptide in the transgenic non-human mammal, wherein gressive (crescentic) glomerulonephritis, renal agenesis, altered biological activity, relative to that of the transgenic renal amyloidosis, renal cell carcinoma, renal dysgenesis, non-human mammal not contacted with the compound, indi renal dysplasia, renal hypoplasia, renal infection, renal cates that the candidate compound may be useful for the osteodystrophy, renal stones (urolithiasis), renal tubular aci treatment of a disease or disorder of the liver. dosis, renal vasculitis, renovascular hypertension, Sclero I0129. In yet another aspect, the invention features a derma (progressive systemic Sclerosis), secondary acquired method for determining whether a candidate compound is a glomerulonephritis, simple renal cysts, systemic lupus compound that may be useful for the treatment of a disease or erythematosus, thin basement membrane nephropathy, disorder of the liver. This method includes the steps of (a) thrombotic microangiopathy, thrombotic thrombocytopenic providing a transgenic non-human mammal (e.g., a mouse) purpura, toxic acute tubular necrosis, tubular defects, tubu overexpressing a nucleic acid molecule encoding a GPCR lointerstitial disease in multiple myeloma, urate nephropathy, polypeptide Substantially identical to a polypeptide listed in urinary obstruction, and vasculitis. Tables 20 and 33; (b) contacting the transgenic non-human 0121. In another aspect, the invention features a non-hu mammal with the candidate compound; and (c) measuring man mammal (e.g., a mouse), having a transgene that biological activity of the GPCR polypeptide in the transgenic includes a nucleic acid molecule encoding a GPCR polypep non-human mammal, wherein altered biological activity, tide substantially identical to a polypeptide listed in Table 19. relative to that of the transgenic non-human mammal not 0122. In yet another aspect, the invention features a non contacted with the compound, indicates that the candidate human mammal (e.g., a mouse), having a mutation in a compound may be useful for the treatment of a disease or nucleic acid molecule encoding a GPCR polypeptide sub disorder of the liver. stantially identical to a polypeptide listed in Table 19. 0.130 Instill another aspect, the invention features another 0123. In a related aspect, the invention features a cell from method for determining whether a candidate compound may a non-human mammal having a transgene that includes a be useful for the treatment of a disease or disorder of the liver. nucleic acid molecule encoding a GPCR polypeptide sub This method includes (a) providing a nucleic acid molecule stantially identical to a polypeptide listed in Table 19. comprising a promoter from a gene encoding a GPCR 0.124. In another aspect, the invention features a cell from polypeptide listed in Tables 20 and 33, the promoter operably a non-human mammal having a mutation in a nucleic acid linked to a reporter system; (b) contacting the nucleic acid molecule encoding a GPCR polypeptide substantially identi molecule with the candidate compound; and (c) measuring cal to a polypeptide listed in Table 19. reporter activity, wherein altered reporter activity, relative to 0.125. In another aspect, the invention features a method of a nucleic acid molecule not contacted with the compound, preventing or treating a disease of the liver including intro indicates that the candidate compound may be useful for the ducing into a human an expression vector that includes a treatment of a disease or disorder of the liver. nucleic acid molecule encoding a GPCR polypeptide sub I0131. In another aspect, the invention features yet another stantially identical to a polypeptide listed in Tables 20 and 33, method for determining whether a candidate compound may operably linked to a promoter. be useful for the treatment of a disease or disorder of the liver. 0126. In still another aspect, the invention features a This method includes the steps of: (a) providing a GPCR method of treating or preventing a disease of the liver includ polypeptide Substantially identical to a polypeptide listed in US 2009/0178153 A1 Jul. 9, 2009

Tables 20 and 33; (b) contacting the polypeptide with the viral hepatitis, acute liver failure, acute viral hepatitis, aden candidate compound; and (c) measuring interaction of the ovirus hepatitis, Alagile syndrome, alcoholic cirrhosis, alco candidate compound to the polypeptide. Interaction of the holic hepatitis, alcoholic liver disease, alpha 1-antitrypsin compound to the polypeptide indicates that the candidate deficiency, amebic abscess, angiolmyolipoma, angiosar compound may be useful for the treatment of a disease or coma, ascending cholangitis, autoimmune chronic active disorder of the liver. hepatitis (lupoid hepatitis), bile duct adenoma, bile duct cys 0.132. In still another aspect, the invention features another tadenocarcinoma, bile duct cystadenoma, biliary atresia, bil method for determining whether a candidate compound may iary cirrhosis, biliary papillomatosis, bridging necrosis, be useful for the treatment of a disease or disorder of the liver. Budd-Chiari syndrome, Byler disease, cardiac fibrosis of the This method includes (a) providing a GPCR polypeptide substantially identical to a polypeptide listed in Tables 20 and liver, Caroli disease, cavernous hemangioma, cholangiocar 33; (b) contacting the polypeptide with the candidate com cinoma, cholangitic abcess, choleostasis, cholestatic viral pound; and (c) measuring the half-life of the polypeptide, hepatitis, chronic active hepatitis, chronic alcoholic liver dis wherein an alteration in the half-life of the polypeptide, rela ease, chronic graft-Versus-host disease, chronic hepatic tive to that of the polypeptide not contacted with the com venous congestion, chronic hepatitis, chronic liver failure, pound, indicates that the candidate compound may be useful chronic passive congestion, chronic viral hepatitis, cirrhosis, for the treatment of a disease or disorder of the liver. Prefer combined hepatocellular and cholangiocarcinoma, confluent ably the GPCR polypeptide is in a cell or a cell free assay hepatic necrosis, congenital hepatic fibrosis, Crigler-Najjar system. syndrome, cryptogenic cirrhosis, cystic fibrosis, defects of 0133. In another aspect, the invention features a method coagulation, delta hepatitis, Dubin-Johnson syndrome, epi for determining whether a patient has an increased risk for thelioid hemangioendothelioma, erythrohepatic protopor developing a disease or disorder of the liver. The method phyria, extrahepatic biliary obstruction (primary biliary cir includes the step of determining whether the patient has a rhosis), fatty change, fatty liver, focal necrosis, focal nodular mutation in a gene encoding a polypeptide listed in Tables 20 hyperplasia, fulminant viral hepatitis, galactosemia, Gilbert's and 33, wherein presence of the mutation indicates that the syndrome, glycogen storage diseases, graft-Versus-host dis patient may have an increased risk for developing a disease or ease, granulomatous hepatitis, hemangioma, hemangiosar disorder of the liver. coma, hemochromatosis, hepatic adenoma, hepatic amebia 0134. In a related aspect, the invention features another sis, hepatic encephalopathy, hepatic failure, hepatic method for determining whether a patient has an increased schistosomiasis, hepatic veno-occlusive disease, hepatitis A, risk for developing a disease or disorder of the liver. This hepatitis B, hepatitis C, hepatitis D, hepatitis E. hepatoblas method includes the step of determining whether the patient toma, hepatocellular adenoma, hepatocellular carcinoma, has a polymorphism in a gene encoding a polypeptide listed in hepatocellular necrosis, hepatorenal syndrome, hereditary Tables 20 and 33, wherein presence of the polymorphism fructose intolerance, hereditary hemochromatosis, herpesvi indicates that the patient may have an increased risk for rus hepatitis, hydatid cust, hyperplastic lesions, hypoalbu developing a disease or disorder of the liver. minenia, infantile hemangioendothelioma, infarction of the 0135) In either of these two methods, the mutation or poly liver, infectious mononucleosis hepatitis, inflammatory morphism is preferably associated with an alteration (for pseudotumor of the liver, intrahepatic cholangiocarcinoma, example, a decrease) in the biological activity of the polypep intrahepatic cholestasis, intrahepatic protal hypertension, tide. ischemic necrosis (ischemic hepatitis), isoniazid-induced 0136. In another aspect, the invention features another necrosis, jaundice, leptospirosis, liver cell adenoma, liver method for determining whether a patient has an increased manifestations of Rocky Mountain spotted fever, macronodu risk for developing a disease or disorder of the liver. The lar cirrhosis, macrovesicular Steatosis, malignant vascular method includes measuring biological activity of a GPCR neoplasts, mass lesions, massive hepatocellular necrosis, polypeptide from the patient that is substantially identical to massive necrosis, mesenchymal hamartoma, metastatic a polypeptide listed in Tables 20 and 33, wherein increased or tumors, micronodular cirrhosis, microvesicular Steatosis, decreased levels in the GPCR biological activity, relative to neonatal (physiologic) jaundice, neonatal hepatitis, neoplas normal levels, indicate that the patient may have an increased tic lesions, nodular transformation (nodular regenerative risk for developing a disease or disorder of the liver. hyperplasia, nonSuppurative infections, nutritional cirrhosis, 0.137 In still another aspect, the invention features yet nutritional liver disease, oriental cholangiohepatitis, parasitic another method for determining whether a patient has an infestation of the liver, peliosis hepatis, porphyria cutaneo increased risk for developing a disease or disorder of the liver. tarda, portal hypertension, portal vein thrombosis, posthe The method includes the step of measuring the patient's patic portal hypertension, predictable (dose-related) toxicity, expression levels of a polypeptide listed in Tables 20 and 33, prehepatic portal hypertension, primary biliary cirrhosis, pri wherein altered levels in the expression, relative to normal, mary Sclerosing cholangitis, pyogenic liver abcess, Q-fever indicate that the patient has an increased risk for developing a hepatitis, Rotor's syndrome, Sclerosing bile duct adenoma, disease or disorder of the liver. Preferably, the expression Sclerosing cholangitis, secondary hemochromatosis, Submas levels are determined by measuring levels of polypeptide or sive necrosis, syphilis, toxic liver injury, tyrosinemia, undif mRNA. ferentiated sarcoma, unpredictable (idiosyncratic) toxicity, 0.138. Diseases of the liver that can be treated or diagnosed vascular lesions, virus-induced cirrhosis, Wilson's disease, using the methods of the invention or for which candidate and Zonal necrosis. therapeutic compounds may be identified include acute alco 0.139. In another aspect, the invention features a non-hu holic hepatitis (acute Sclerosing hyaline necrosis of the liver), man mammal (e.g., a mouse), having a transgene that acute graft-Versus-host disease, acute hepatitis, acute hepato includes a nucleic acid molecule encoding a GPCR polypep cellular injury associated with infectious diseases other than tide substantially identical to a polypeptide listed in Table 20. US 2009/0178153 A1 Jul. 9, 2009

0140. In yet another aspect, the invention features a non pound, indicates that the candidate compound may be useful human mammal (e.g., a mouse), having a mutation in a for the treatment of a disease or disorder of the lung. nucleic acid molecule encoding a GPCR polypeptide sub 0.148. In still another aspect, the invention features another stantially identical to a polypeptide listed in Table 20. method for determining whether a candidate compound may 0141. In a related aspect, the invention features a cell from be useful for the treatment of a lung disease or disorder. This a non-human mammal having a transgene that includes a method includes (a) providing a nucleic acid molecule com nucleic acid molecule encoding a GPCR polypeptide sub prising a promoter from a gene encoding a GPCR polypeptide stantially identical to a polypeptide listed in Table 20. listed in Tables 21 and 33, the promoter operably linked to a 0142. In another aspect, the invention features a cell from reporter system; (b) contacting the nucleic acid molecule with a non-human mammal having a mutation in a nucleic acid the candidate compound; and (c) measuring reporter activity, molecule encoding a GPCR polypeptide substantially identi wherein altered reporter activity, relative to a nucleic acid cal to a polypeptide listed in Table 20. molecule not contacted with the compound, indicates that the 0143. In another aspect, the invention features a method of candidate compound may be useful for the treatment of a lung preventing or treating lung disease, including introducing disease or disorder. into a human an expression vector that includes a nucleic acid 0149. In another aspect, the invention features yet another molecule encoding a GPCR polypeptide substantially identi method for determining whether a candidate compound may cal to a polypeptide listed in Tables 21 and 33, operably linked be useful for the treatment of a lung disease or disorder. This to a promoter. method includes the steps of: (a) providing a GPCR polypep 0144. In still another aspect, the invention features a tide substantially identical to a polypeptide listed in Tables 21 method of treating or preventing lung disease, including and 33; (b) contacting the polypeptide with the candidate administering to an animal (e.g., a human) a compound that compound; and (c) measuring interaction of the candidate modulates the biological activity of a GPCR polypeptide compound to the polypeptide. Interaction of the compound to substantially identical to a polypeptide listed in Tables 21 and the polypeptide indicates that the candidate compound may 33. be useful for the treatment of a lung disease or disorder. 0145. In yet another aspect, the invention features a 0150. In still another aspect, the invention features another method for determining whether a candidate compound is a method for determining whether a candidate compound may compound that may be useful for the treatment of a lung be useful for the treatment of a lung disease or disorder. This disease or disorder. This method includes the steps of (a) method includes (a) providing a GPCR polypeptide substan providing a GPCR polypeptide substantially identical to a tially identical to a polypeptide listed in Tables 21 and 33; (b) polypeptide listed in Tables 21 and 33; (b) contacting the contacting the polypeptide with the candidate compound; and GPCR polypeptide with the candidate compound; and (c) (c) measuring the half-life of the polypeptide, wherein an measuring biological activity of the GPCR polypeptide, alteration in the half-life of the polypeptide, relative to that of wherein altered biological activity, relative to that of the the polypeptide not contacted with the compound, indicates GPCR polypeptide not contacted with the compound, indi that the candidate compound may be useful for the treatment cates that the candidate compound may be useful for the of a lung disease or disorder. Preferably, the GPCR polypep treatment of a lung disease or disorder. The GPCR polypep tide can be in a cell or in a cell-free assay system. tide is in a cell or a cell free assay system. 0146 In yet another aspect, the invention features a 0151. In another aspect, the invention features a method method for determining whether a candidate compound is a for determining whether a patient has an increased risk for compound that may be useful for the treatment of a disease or developing a lung disease or disorder. The method includes disorder of the lung. This method includes the steps of (a) the step of determining whether the patient has a mutation in providing a transgenic non-human mammal (e.g., a knock a gene encoding a polypeptide listed in Tables 21 and 33. out mouse) having a disruption in a nucleic acid molecule wherein presence of the mutation indicates that the patient encoding a GPCR polypeptide substantially identical to a may have an increased risk for developing a lung disease or polypeptide listed in Tables 21 and 33; (b) contacting the disorder. transgenic non-human mammal with the candidate com 0152. In a related aspect, the invention features another pound; and (c) measuring biological activity of the transgenic method for determining whether a patient has an increased non-human mammal, wherein altered biological activity, risk for developing a lung disease or disorder. This method relative to that of the transgenic non-human mammal not includes the step of determining whether the patient has a contacted with the compound, indicates that the candidate polymorphism in a gene encoding a polypeptide listed in compound may be useful for the treatment of a disease or Tables 21 and 33, wherein presence of the polymorphism disorder of the lung. indicates that the patient may have an increased risk for 0147 In yet another aspect, the invention features a developing a lung disease or disorder. method for determining whether a candidate compound is a 0153. In either of these two methods, the mutation or poly compound that may be useful for the treatment of a disease or morphism is preferably associated with an alteration (for disorder of the lung. This method includes the steps of (a) example, a decrease) in the biological activity of the polypep providing a transgenic non-human mammal (e.g., a mouse) tide. overexpressing a nucleic acid molecule encoding a GPCR 0154) In another aspect, the invention features another polypeptide Substantially identical to a polypeptide listed in method for determining whether a patient has an increased Tables 21 and 33; (b) contacting the transgenic non-human risk for developing a lung disease or disorder. The method mammal with the candidate compound; and (c) measuring includes measuring biological activity of a GPCR polypep biological activity of the transgenic non-human mammal, tide from the patient that is substantially identical to a wherein altered biological activity, relative to that of the polypeptide listed in Tables 21 and 33, wherein increased or transgenic non-human mammal not contacted with the com decreased levels in the GPCR biological activity, relative to US 2009/0178153 A1 Jul. 9, 2009

normal levels, indicate that the patient may have an increased (paraceptal) emphysema, drug-induced asthma, drug-in risk for developing a lung disease or disorder. duced diffuse alveolar damage, dyspnea, ectopic hormone 0155. In still another aspect, the invention features yet syndromes, emphysema, empyemma, eosinophilic pneumo another method for determining whether a patient has an nias, exercise-induced asthma, extralobar sequestration, increased risk for developing a lung disease or disorder. The extrinsic allergic asthma, fat emboli, focal dust emphysema, method includes the step of measuring the patient's expres follicular bronchiolitis, follicular bronchitis, foreign-body sion levels of a polypeptide listed in Tables 21 and 33, embolism, Fuller's earth pneumoconiosis, functional resis wherein altered levels in the expression, relative to normal, tance to arterial flow (vasoconstriction), fungal granulomas indicate that the patient has an increased risk for developing a of the lung, fungal infections, Goodpasture's syndrome, lung disease or disorder. Preferably, the expression levels are graphite pneumoconiosis, gray hepatization, hamartomas, determined by measuring levels of polypeptide or mRNA. hard metal disease, hemoptysis, hemothorax, herniation of 0156 Preferred lung diseases (including those of the tra lung tissue, herpes simplex, heterotopic tissues, high-altitude ches) that can be treated or diagnosed using the methods of pulmonary edema, histoplasmosis, horseshoe lung, humidi the invention or for which candidate therapeutic compounds fier fever, hyaline membrane disease, hydatid cysts, may be identified include abnormal diffusion, abnormal per hydrothorax, hypersensitivity pneumonitis (extrinsic allergic fusion, abnormal ventilation, accelerated silicosis, actinomy alveolitis), hypoxic vascular remodeling, iatrogenic drug cosis, acute air space pneumonia (acute bacterial pneumo chemical-, or radiation-induced interstitial fibrosis, idio nia), acute bronchiolitis, acute congestion, acute infections of pathic interstitial pneumonia, idiopathic organizing pneumo the lung, acute interstitial pneumonia, acute necrotizing viral nia, idiopathic pulmonary fibrosis (fibrosing alveolitis, Ham pneumonia, acute organic dust toxic syndrome, acute pneu man-Rich syndrome, acute interstitial pneumonia), monia, acute radiation pneumonitis, acute rheumatic fever, idiopathic pulmonary hemosiderosis, immunologic intersti acute silicosis, acute tracheobronchitis, adenocarcinoma, tial fibrosis, immunologic interstitial pneumonitis, immuno adenoid cystic carcinoma, adenosquamous carcinoma, aden logic lung disease, infections causing chronic granulomatous ovirus, adult respiratory distress syndrome (shock lung), inflammation, infections causing chronic Suppurative inflam agenesis, AIDS, air embolism, allergic bronchopulmonary mation, infections of the air passages, infiltrative lung dis mycosis, allergic granulomatosis and angiitis (Churg ease, inflammatory lesions, inflammatory pseudotumors, Strauss), allograft rejection, aluminum pneumoconiosis, influenza, interstitial diseases of uncertain etiology, intersti alveolar microlithiasis, alveolar proteinosis, amebic lung tial lung disease, interstitial pneumonitis in connective tissue abscess, amniotic fluid embolism, amyloidosis of the lung, diseases, intralobar sequestration of the lung (congenital), anomalies of pulmonary vasculature, anomalous pulmonary intrinsic (nonallergic) asthma, invasive pulmonary venous return, aspiration pneumonia, aplasia, asbestosis, aspergillosis, kaolin pneumoconiosis, Kartagner's syndrome, asbestos-related diseases, aspergillosis, asthma, atelectasis, Klebsiella pneumonia, Langerhans cell histiocytosis (histio atriovenous fistulas, atypical mycobacterial infection, bacte cytosis X), large cell undifferentiated carcinoma, larval remia, bacterial pneumonia, benign clear cell tumor, benign migration of Ascaris lumbricoides, larval migration of epithelial tumors, benign fibrous mesothelioma, berylliosis, Strongyloides stercoralis, left pulmonary artery 'sling. blastomycosis, bronchialatresia, bronchial asthma, bronchial Legionella pneumonia, lipid pneumonia, lobar pneumonia, carcinoid tumor, bronchial isomerism, bronchial obstruction, localized emphysema, long-standing bronchial obstruction, bronchial Stenosis, bronchiectasis, bronchioalveolar carci lung abscess, lung collapse, lung fluke, lung transplantation noma, bronchiolitis, bronchiolitis obliterans-organizing implantation response, lymphangiomyomatosis, lympho pneumonia, bronchocentric granulomatosis, bronchogenic cytic interstitial pneumonitis (pseudolymphoma, lymphoma, cyst, bronchopneumonia, bronchopulmonary dysplasia, lymphomatoid granulomatosis, malignant mesothelioma, bronchopulmonary sequestration, bullae, bullous emphy massive pulmonary hemorrhage in the newborn, measles, sema, cancer, carcinoid tumors, carcinoma of the lung (bron meconium aspiration syndrome, mesenchymal cystic hama chogenic carcinoma), central (bronchogenic) carcinoma, rtomas, mesenchymal tumors, mesothelioma, metal-induced central cyanosis, centriacinar emphysema, cetrilobular lung diseases, metastatic calcification, metastatic neoplasms, emphysema, chest pain, Chlamydial pneumonia, chondroid metastatic ossification, mica pneumoconiosis, mixed dust hamartoma, chronic airflow obstruction, chronic bronchitis, fibrosis, mixed epithelial-mesenchymal tumors, mixed type chronic diffuse interstitial lung disease, chronic idiopathic neoplasms, mucoepidermoid tumor, mucoviscidosis (fibro pulmonary fibrosis, chronic lung abscess, chronic obstructive cystic disease of the pancreas), mycoplasma pneumoniae, pulmonary diseases, chronic radiation pneumonitis, chronic necrotizing bacterial pneumonia, necrotizing sarcoid granu silicosis, chylothorax, ciliary dyskinesia, coal worker's pneu lomatosis, neonatal respiratory distress syndrome, neoplasms moconiosis (anthracosis), coccidioidomycosis, collagen-vas of the pleura, neuromuscular syndromes, nocardiosis, nonde cular diseases, common cold, compensatory emphysema, structive lung disease, North American blastomycosis, occu congenital acinar dysplasia, congenital alveolar capillary pational asthma, organic dust disease, panacinar emphysema, dysplasia, congenital bronchobiliary fistula, congenital bron Pancoast's syndrome, paracoccidioidomycosis, parainflu choesophageal fistula, congenital cystic adenomatoid malfor enza, paraneoplastic syndromes, paraseptal emphysema mation, congenital pulmonary lymphangiectasis, congenital (paracicatricial), parasilicosis syndromes, parasitic infec pulmonary overinflation (congenital emphysema), conges tions of the lung, peripheral cyanosis, peripheral lung carci tion, cough, cryptococcosis, cyanosis, cystic fibrosis, cys noma, persistent pulmonary hypertension of the newborn, ticercosis, cytomegalovirus, descquamative interstitial pneu pleural diseases, pleural effusion, pleural plaques, pneumo monitis, destructive lung disease, diatomaceous earth coccal pneumonia, pneumoconioses (inorganic dust dis pneumoconiosis, diffuse alveolar damage, diffuse pulmonary eases), Pneumocystis carinii pneumonia, pneumocystosis, hemorrhage, diffuse septal amyloidosis, diffuse panbronchi pneumonitis, pneumothorax, precapillary pulmonary hyper olitis, Dirofilaria immitis, diseases of the pleura, distalacinar tension, primary (childhood) tuberculosis, primary (idio US 2009/0178153 A1 Jul. 9, 2009 pathic) pulmonary hypertension, primary mesothelial neo modulates the biological activity of a GPCR polypeptide plasms, primary pulmonary hypertensions, progressive substantially identical to a polypeptide listed in Tables 22 and massive fibrosis, psittacosis, pulmonary actinomycosis, pull 33. monary air-leak syndromes, pulmonary alveolar proteinosis, 0163. In yet another aspect, the invention features a pulmonary arteriovenous malformation, pulmonary blas method for determining whether a candidate compound is a toma, pulmonary capillary hemangiomatosis, pulmonary car compound that may be useful for the treatment of a muscular cinosarcoma, pulmonary edema, pulmonary embolism, pull disease or disorder. This method includes the steps of (a) monary eosinophilia, pulmonary fibrosis, pulmonary providing a GPCR polypeptide substantially identical to a hypertension, pulmonary hypoplasia, pulmonary infarction, polypeptide listed in Tables 22 and 33; (b) contacting the pulmonary infiltration and eosinophilia, pulmonary intersti GPCR polypeptide with the candidate compound; and (c) tial air (pulmonary interstitial emphysema), pulmonary measuring biological activity of the GPCR polypeptide, wherein altered biological activity, relative to that of the lesions, pulmonary nocardiosis, pulmonary parenchymal GPCR polypeptide not contacted with the compound, indi anomalies, pulmonary thromboembolism, pulmonary tuber cates that the candidate compound may be useful for the culosis, pulmonary vascular disorders, pulmonary vasculiti treatment of a muscular disease or disorder. The GPCR des, pulmonary veno-occlusive disease, pyothorax, radiation polypeptide can be in a cell or in a cell-free assay System. pneumonitis, recurrent pulmonary emboli, red hepatization, 0164. In yet another aspect, the invention features a respiration failure, respiratory syncytial virus, Reye's Syn method for determining whether a candidate compound is a drome, rheumatoid lung disease, Rickettsial pneumonia, rup compound that may be useful for the treatment of a muscular ture of pulmonary arteries, sarcoidosis, scar cancer, Scimitar disease or disorder. This method includes the steps of (a) syndrome, Scleroderma, Sclerosing hemangioma, secondary providing a transgenic non-human mammal (e.g., a knock (adult) tuberculosis, secondary bacterial pneumonia, second out mouse) having a disruption in a nucleic acid molecule ary pleural neoplasms, secondary pulmonary hypertension, encoding a GPCR polypeptide substantially identical to a senile emphysema, siderosis, silicate pneumoconiosis asbes polypeptide listed in Tables 22 and 33; (b) contacting the tosis, silicatosis, silicosis, simple nodular silicosis, Sjögren's transgenic non-human mammal with the candidate com syndrome, Small airway lesions, Small cell carcinoma, Small pound; and (c) measuring biological activity of the GPCR cell undifferentiated (oat cell) carcinoma, spontaneous pneu polypeptide in the transgenic non-human mammal, wherein mothorax, sporotrichosis, sputum production, Squamous altered biological activity, relative to that of the transgenic (epidermoid) carcinoma, Stannosis, Staphlococcal pneumo non-human mammal not contacted with the compound, indi nia, Suppuration (abscess formation), Systemic lupus erythe cates that the candidate compound may be useful for the matosus, talcosis, tension pneumothorax, tracheal agenesis, treatment of a muscular disease or disorder. tracheal Stenosis, tracheobronchial amyloidosis, tracheo 0.165. In yet another aspect, the invention features a bronchomegaly, tracheoesophageal fistula, transient tachyp method for determining whether a candidate compound is a nea of the newborn (neonatal wet lung), tungsten carbide compound that may be useful for the treatment of a muscular pneumoconiosis, usual interstitial pneumonia, usual intersti disease or disorder. This method includes the steps of (a) tial pneumonitis, varicella, viral pneumonia, visceral pleural providing a transgenic non-human mammal (e.g., a mouse) thickening, Wegener's granulomatosis, and whooping cough overexpressing a nucleic acid molecule encoding a GPCR (pertussis). polypeptide Substantially identical to a polypeptide listed in 0157. In another aspect, the invention features a non-hu Tables 22 and 33; (b) contacting the transgenic non-human man mammal (e.g., a mouse), having a transgene that mammal with the candidate compound; and (c) measuring includes a nucleic acid molecule encoding a GPCR polypep biological activity of the GPCR polypeptide in the transgenic tide substantially identical to a polypeptide listed in Table 21. non-human mammal, wherein altered biological activity, 0158. In yet another aspect, the invention features a non relative to that of the transgenic non-human mammal not human mammal (e.g., a mouse), having a mutation in a contacted with the compound, indicates that the candidate nucleic acid molecule encoding a GPCR polypeptide sub compound may be useful for the treatment of a muscular stantially identical to a polypeptide listed in Table 21. disease or disorder. 0166 Instill another aspect, the invention features another 0159. In a related aspect, the invention features a cell from method for determining whether a candidate compound may a non-human mammal having a transgene that includes a be useful for the treatment of a muscular disease or disorder. nucleic acid molecule encoding a GPCR polypeptide sub This method includes (a) providing a nucleic acid molecule stantially identical to a polypeptide listed in Table 21. comprising a promoter from a gene encoding a GPCR 0160. In another aspect, the invention features a cell from polypeptide listed in Tables 22 and 33, the promoter operably a non-human mammal having a mutation in a nucleic acid linked to a reporter system; (b) contacting the nucleic acid molecule encoding a GPCR polypeptide substantially identi molecule with the candidate compound; and (c) measuring cal to a polypeptide listed in Table 21. reporter activity, wherein altered reporter activity, relative to 0161 In another aspect, the invention features a method of a nucleic acid molecule not contacted with the compound, preventing or treating muscular disease, including introduc indicates that the candidate compound may be useful for the ing into a human an expression vector that includes a nucleic treatment of a muscular disease or disorder. acid molecule encoding a GPCR polypeptide substantially 0167. In another aspect, the invention features yet another identical to a polypeptide listed in Tables 22 and 33, operably method for determining whether a candidate compound may linked to a promoter. be useful for the treatment of a muscular disease or disorder. 0162. In still another aspect, the invention features a This method includes the steps of: (a) providing a GPCR method of treating or preventing muscular disease, including polypeptide Substantially identical to a polypeptide listed in administering to an animal (e.g., a human) a compound that Tables 22 and 33; (b) contacting the polypeptide with the US 2009/0178153 A1 Jul. 9, 2009 20 candidate compound; and (c) measuring interaction of the trophic lateral Sclerosis, antimyelin antibodies, bacteremic candidate compound to the polypeptide. Interaction of the myositis, Batten's disease (neuronal ceroid lipofuscinoses), compound to the polypeptide indicates that the candidate Becker's muscular dystrophy, benign neoplasms, Bornholm compound may be useful for the treatment of a muscular disease, botulism, branching enzyme deficiency (type 4 gly disease or disorder. cogenosis), carbohydrate storage diseases, carnitine deficien 0.168. In still another aspect, the invention features another cies, carnitine palmitoyltransferase deficiency, central core method for determining whether a candidate compound may disease, centronuclear (myotubular) myopathy, Chagas dis be useful for the treatment of a muscular disease or disorder. ease, chondrodystrophic myotonia, chronic renal disease, This method includes (a) providing a GPCR polypeptide congenital fibertype disproportion, congenital muscular dys substantially identical to a polypeptide listed in Tables 22 and trophy, congenital myopathies, congenital myotonic dystro 33; (b) contacting the polypeptide with the candidate com phy, congenital paucity of synaptic clefts, cysticercosis, cyto pound; and (c) measuring the half-life of the polypeptide, plasmic body myopathy, debranching enzyme deficiency wherein an alteration in the half-life of the polypeptide, rela tive to that of the polypeptide not contacted with the com (type 3 glycogenosis), defect in acetylcholine synthesis, den pound, indicates that the candidate compound may be useful ervation, dermatomyositis, diabetes mellitus, diphtheria, dis for the treatment of a muscular disease or disorder. Preferably orders of glycolysis, disorders of neuromuscular junction, the GPCR polypeptide is in a cell or a cell free assay system. distal muscular dystrophy, drug induced inflammatory 0169. In another aspect, the invention features a method myopathy, Duchenne muscular dystrophy, embryonal rhab for determining whether a patient has an increased risk for domyosarcoma, Emery-Dreifuss muscular dystrophy, exo developing a muscular disease or disorder. The method toxic bacterial infections, facioscapulohumeral muscular includes the step of determining whether the patient has a dystrophy, failure of neuromuscular transmission, fiber mutation in a gene encoding a polypeptide listed in Tables 22 necrosis, fibromyalgia, fingerprint body myopathy, Forbe's and 33, wherein presence of the mutation indicates that the disease, gas gangrene, Guillain-Barré syndrome, inclusion patient may have an increased risk for developing a muscular body myositis, infantile spinal muscularatrophies, infectious disease or disorder. myositis, inflammatory myopathies, influenza, Isaac's Syn 0170 In a related aspect, the invention features another drome, ischemia, Kearns-Sayre syndrome, lactase dehydro method for determining whether a patient has an increased genase deficiency, Lambert-Eaton syndrome, Leigh's dis risk for developing a muscular disease or disorder. This ease, leuknock outdystrophies, limb girdle muscular method includes the step of determining whether the patient dystrophy, lipid storage myopathies, Luft's disease, lysoso has a polymorphism in a gene encoding a polypeptide listed in mal glycogen storage disease with normal acid maltase activ Tables 22 and 33, wherein presence of the polymorphism ity, maignant neoplasms, malignant hyperthermia, McAr indicates that the patient may have an increased risk for dle's disease, MELAS syndrome (mitochondrial myopathy, developing a muscular disease or disorder. encephalopathy, lacticacidosis, and strokes), MERRF syn 0171 In either of these two methods, the mutation or poly drome (myoclonus epilepsy with ragged-red fibers), meta morphism is preferably associated with an alteration (for bolic myopathies, microfiber myopathy, mitochondrial myo example, a decrease) in the biological activity of the polypep pathies, multicore disease (minicore disease), multisystem tide. triglyceride storage disease, muscle wasting from diabetes, 0172. In another aspect, the invention features another muscular dystrophies, myasthenia gravis, myasthenic Syn method for determining whether a patient has an increased drome (Eaton-Lambert syndrome), myoadenylate deaminase risk for developing a muscular disease or disorder. The deficiency, myoglobinuria, myopathies, myophosphorylase method includes measuring biological activity of a GPCR deficiency (type 5 glycogenosis), myositis, myositis ossifi polypeptide from the patient that is substantially identical to cans, myotonia congenita, myotonic muscular dystrophy, a polypeptide listed in Tables 22 and 33, wherein increased or nemaline myopathy, ocular muscular dystrophy, oculopha decreased levels in the GPCR biological activity, relative to ryngeal muscular dystrophy, paramyotonia, parasytic myo normal levels, indicate that the patient may have an increased pathies, periodic paralysis, peripheral neuropathies, phos risk for developing a muscular disease or disorder. phofructokinase deficiency (type 7 glycogenosis), 0173. In still another aspect, the invention features yet phosphoglycerate kinase deficiency, phosphoglycerate another method for determining whether a patient has an mutase deficiency, pleomorphic rhabdomyosarcoma, poly increased risk for developing a muscular disease or disorder. myositis, Pompe's disease, progressive muscular atrophy, The method includes the step of measuring the patient's progressive systemic sclerosis, reducing body myopathy, expression levels of a polypeptide listed in Tables 22 and 33, RefSum's disease, rhabdomyolysis, rhabdomyoma, rhab wherein altered levels in the expression, relative to normal, domyosarcoma, sarcoidosis, sarcoma botryoides, sarcotubu indicate that the patient has an increased risk for developing a lar myopathy, secondary congenital myopathies, slow chan muscular disease or disorder. Preferably, the expression lev nel syndrome, spasmodic torticollis, spheroid body els are determined by measuring levels of polypeptide or myopathy, spinal muscular atrophy, Steroid myopathy, stiff mRNA. person syndrome, systemic lupus erythematosus, Tauri's dis 0174 Preferred muscular diseases that can be treated or ease, tick paralysis, toxic myopathies, toxoplasmosis, trichi diagnosed using the methods of the invention or for which nosis, trilaminar fiber myopathy, type 2 myofiber atrophy, candidate therapeutic compounds may be identified include typhoid fever, vasculitis, viral myositis, and Zebra body abnormalities of ion channel closure, acetylcholine receptor myopathy. deficiency, acetylcholinesterase deficiency, acid maltase defi 0.175. In another aspect, the invention features a non-hu ciencies (type 2 glycogenosis), acquired myopathies, man mammal (e.g., a mouse), having a transgene that acquired myotonia, adult myotonic dystrophy, alveolar rhab includes a nucleic acid molecule encoding a G3PCR polypep domyosarcoma, aminoglycoside drugs, amyloidosis, amyo tide substantially identical to a polypeptide listed in Table 22. US 2009/0178153 A1 Jul. 9, 2009

0176). In yet another aspect, the invention features a non contacted with the compound, indicates that the candidate human mammal (e.g., a mouse), having a mutation in a compound may be useful for the treatment of a disease or nucleic acid molecule encoding a GPCR polypeptide sub disorder of the ovary. stantially identical to a polypeptide listed in Table 22. 0.184 Instill another aspect, the invention features another 0177. In a related aspect, the invention features a cell from method for determining whether a candidate compound may a non-human mammal having a transgene that includes a be useful for the treatment of a disease or disorder of the nucleic acid molecule encoding a GPCR polypeptide sub ovary. This method includes (a) providing a nucleic acid stantially identical to a polypeptide listed in Table 22. molecule comprising a promoter from a gene encoding a 0178. In another aspect, the invention features a cell from GPCR polypeptide listed in Tables 23 and 33, the promoter a non-human mammal having a mutation in a nucleic acid operably linked to a reporter system; (b) contacting the molecule encoding a GPCR polypeptide substantially identi nucleic acid molecule with the candidate compound; and (c) cal to a polypeptide listed in Table 22. measuring reporter activity, wherein altered reporter activity, 0179. In another aspect, the invention features a method of relative to a nucleic acid molecule not contacted with the preventing or treating a disease of the ovary including intro compound, indicates that the candidate compound may be ducing into a human an expression vector that includes a useful for the treatment of a disease or disorder of the ovary. nucleic acid molecule encoding a GPCR polypeptide sub 0185. In another aspect, the invention features yet another stantially identical to a polypeptide listed in Tables 23 and 33, method for determining whether a candidate compound may operably linked to a promoter. be useful for the treatment of a disease or disorder of the 0180. In still another aspect, the invention features a ovary. This method includes the steps of: (a) providing a method of treating or preventing a disease of the ovary includ GPCR polypeptide substantially identical to a polypeptide ing administering to an animal (e.g., a human) a compound listed in Tables 23 and 33; (b) contacting the polypeptide with that modulates the biological activity of a GPCR polypeptide the candidate compound; and (c) measuring interaction of the substantially identical to a polypeptide listed in Tables 23 and candidate compound to the polypeptide. Interaction of the 33. compound to the polypeptide indicates that the candidate 0181. In yet another aspect, the invention features a compound may be useful for the treatment of a disease or method for determining whether a candidate compound is a disorder of the ovary. compound that may be useful for the treatment of a disease or 0186 Instill another aspect, the invention features another disorder of the ovary. This method includes the steps of (a) method for determining whether a candidate compound may providing a GPCR polypeptide substantially identical to a be useful for the treatment of a disease or disorder of the polypeptide listed in Tables 23 and 33; (b) contacting the ovary. This method includes (a) providing a GPCR polypep GPCR polypeptide with the candidate compound; and (c) tide substantially identical to a polypeptide listed in Tables 23 measuring biological activity of the GPCR polypeptide, and 33; (b) contacting the polypeptide with the candidate wherein altered biological activity, relative to that of the compound; and (c) measuring the half-life of the polypeptide, GPCR polypeptide not contacted with the compound, indi wherein an alteration in the half-life of the polypeptide, rela cates that the candidate compound may be useful for the tive to that of the polypeptide not contacted with the com treatment of a disease or disorder of the ovary. The GPCR pound, indicates that the candidate compound may be useful polypeptide can be in a cell or in a cell-free assay System. for the treatment of a disease or disorder of the ovary. Pref 0182. In yet another aspect, the invention features a erably the GPCR polypeptide is in a cell or a cell free assay method for determining whether a candidate compound is a system. compound that may be useful for the treatment of disease or 0187. In another aspect, the invention features a method disorder of the ovary. This method includes the steps of (a) for determining whether a patient has an increased risk for providing a transgenic non-human mammal (e.g., a knock developing a disease or disorder of the ovary. The method out mouse) having a disruption in a nucleic acid molecule includes the step of determining whether the patient has a encoding a GPCR polypeptide substantially identical to a mutation in a gene encoding a polypeptide listed in Tables 23 polypeptide listed in Tables 23 and 33; (b) contacting the and 33, wherein presence of the mutation indicates that the transgenic non-human mammal with the candidate com patient may have an increased risk for developing a disease or pound; and (c) measuring biological activity of the GPCR disorder of the ovary. polypeptide in the transgenic non-human mammal, wherein 0188 In a related aspect, the invention features another altered biological activity, relative to that of the transgenic method for determining whether a patient has an increased non-human mammal not contacted with the compound, indi risk for developing a disease or disorder of the ovary. This cates that the candidate compound may be useful for the method includes the step of determining whether the patient treatment of a disease or disorder of the ovary. has a polymorphism in a gene encoding a polypeptide listed in 0183 In yet another aspect, the invention features a Tables 23 and 33, wherein presence of the polymorphism method for determining whether a candidate compound is a indicates that the patient may have an increased risk for compound that may be useful for the treatment of a disease or developing a disease or disorder of the ovary. disorder of the ovary. This method includes the steps of (a) 0189 In either of these two methods, the mutation or poly providing a transgenic non-human mammal (e.g., a mouse) morphism is preferably associated with an alteration (for overexpressing a nucleic acid molecule encoding a GPCR example, a decrease) in the biological activity of the polypep polypeptide Substantially identical to a polypeptide listed in tide. Tables 23 and 33; (b) contacting the transgenic non-human 0190. In another aspect, the invention features another mammal with the candidate compound; and (c) measuring method for determining whether a patient has an increased biological activity of the GPCR polypeptide in the transgenic risk for developing a disease or disorder of the ovary. The non-human mammal, wherein altered biological activity, method includes measuring biological activity of a GPCR relative to that of the transgenic non-human mammal not polypeptide from the patient that is substantially identical to US 2009/0178153 A1 Jul. 9, 2009 22 a polypeptide listed in Tables 23 and 33, wherein increased or 0199. In yet another aspect, the invention features a decreased levels in the GPCR biological activity, relative to method for determining whether a candidate compound is a normal levels, indicate that the patient may have an increased compound that may be useful for the treatment of a blood risk for developing a disease or disorder of the ovary. disease or disorder. This method includes the steps of (a) 0191 In still another aspect, the invention features yet providing a GPCR polypeptide substantially identical to a another method for determining whether a patient has an polypeptide listed in Tables 24 and 33; (b) contacting the increased risk for developing a disease or disorder of the GPCR polypeptide with the candidate compound; and (c) ovary. The method includes the step of measuring the measuring biological activity of the GPCR polypeptide, patient's expression levels of a polypeptide listed in Tables 23 wherein altered biological activity, relative to that of the and 33, wherein altered levels in the expression, relative to GPCR polypeptide not contacted with the compound, indi normal, indicate that the patient has an increased risk for developing a disease or disorder of the ovary. Preferably, the cates that the candidate compound may be useful for the expression levels are determined by measuring levels of treatment of a blood disease or disorder. The GPCR polypep polypeptide or mRNA. tide can be in a cell or in a cell-free assay system. 0.192 Diseases of the ovary that can be treated or diag 0200. In yet another aspect, the invention features a nosed using the methods of the invention or for which candi method for determining whether a candidate compound is a date therapeutic compounds may be identified include compound that may be useful for the treatment of a blood autoimmune oophoritis, brenner tumors, choriocarcinoma, disease or disorder. This method includes the steps of (a) clear cell adenocarcinoma, clear cell carcinoma, corpus luteal providing a transgenic non-human mammal (e.g., a knock cysts, decidual reaction, dysgerminoma, embryonal carci out mouse) having a disruption in a nucleic acid molecule noma, endometrioid tumors, endometriosis, endometriotic encoding a GPCR polypeptide substantially identical to a cysts, epithelial inclusion cysts, fibrothecoma, follicular polypeptide listed in Tables 24 and 33; (b) contacting the cysts, gonadoblastoma, granulosa-stroma cell tumors, granu transgenic non-human mammal with the candidate com losa-theca cell tumor, gynandroblastoma, hilum cell hyper pound; and (c) measuring biological activity of the GPCR plasia, luteal cysts, luteal hematomas, luteoma of pregnancy, polypeptide in the transgenic non-human mammal, wherein massive ovarian edema, metastatic neoplasm, mixed germ altered biological activity, relative to that of the transgenic cell tumors, monodermal tumors, mucinous tumors, neoplas non-human mammal not contacted with the compound, indi tic cysts, ovarian changes secondary to cytotoxic drugs and cates that the candidate compound may be useful for the radiation, ovarian fibroma, polycystic ovary syndrome, preg treatment of a blood disease or disorder nancy luteoma, premature follicle depletion, pseudomyxoma 0201 In yet another aspect, the invention features a peritonei, resistant ovary, serous tumors, Sertoli-Leydig cell method for determining whether a candidate compound is a tumor, sex-cord tumor with annular tubules, steroid (lipid) compound that may be useful for the treatment of a blood cell tumor, stromal hyperplasia, Stromal hyperthecosis, ter disease or disorder. This method includes the steps of (a) atoma, theca lutein cysts, thecomas, transitional cell carci providing a transgenic non-human mammal (e.g., a mouse) noma, undifferentiated carcinoma, and yolk sac carcinoma overexpressing a nucleic acid molecule encoding a GPCR (endodermal sinus tumor). polypeptide Substantially identical to a polypeptide listed in 0193 In another aspect, the invention features a non-hu Tables 24 and 33; (b) contacting the transgenic non-human man mammal (e.g., a mouse), having a transgene that mammal with the candidate compound; and (c) measuring includes a nucleic acid molecule encoding a GPCR polypep biological activity of the GPCR polypeptide in the transgenic tide substantially identical to a polypeptide listed in Table 23. non-human mammal, wherein altered biological activity, 0194 In yet another aspect, the invention features a non relative to that of the transgenic non-human mammal not human mammal (e.g., a mouse), having a mutation in a contacted with the compound, indicates that the candidate nucleic acid molecule encoding a GPCR polypeptide sub compound may be useful for the treatment of a blood disease stantially identical to a polypeptide listed in Table 23. or disorder. 0.195. In a related aspect, the invention features a cell from 0202 Instill another aspect, the invention features another a non-human mammal having a transgene that includes a method for determining whether a candidate compound may nucleic acid molecule encoding a GPCR polypeptide sub be useful for the treatment of a blood disease or disorder. This stantially identical to a polypeptide listed in Table 23. method includes (a) providing a nucleic acid molecule com 0196. In another aspect, the invention features a cell from prising a promoter from a gene encoding a GPCR polypeptide a non-human mammal having a mutation in a nucleic acid listed in Tables 24 and 33, the promoter operably linked to a molecule encoding a GPCR polypeptide substantially identi reporter system; (b) contacting the nucleic acid molecule with cal to a polypeptide listed in Table 23. the candidate compound; and (c) measuring reporter activity, 0197) In another aspect, the invention features a method of wherein altered reporter activity, relative to a nucleic acid preventing or treating blood disease, including introducing molecule not contacted with the compound, indicates that the into a human an expression vector that includes a nucleic acid candidate compound may be useful for the treatment of a molecule encoding a GPCR polypeptide substantially identi blood disease or disorder. cal to a polypeptide listed in Tables 24 and 33, operably linked 0203. In another aspect, the invention features yet another to a promoter. method for determining whether a candidate compound may 0198 In still another aspect, the invention features a be useful for the treatment of a blood disease or disorder. This method of treating or preventing blood disease, including method includes the steps of: (a) providing a GPCR polypep administering to an animal (e.g., a human) a compound that tide substantially identical to a polypeptide listed in Tables 24 modulates the biological activity of a GPCR polypeptide and 33; (b) contacting the polypeptide with the candidate substantially identical to a polypeptide listed in Tables 24 and compound; and (c) measuring interaction of the candidate 33. compound to the polypeptide. Interaction of the compound to US 2009/0178153 A1 Jul. 9, 2009 the polypeptide indicates that the candidate compound may response to endotoxin, adult T-cell leukemial/lymphoma, afi be useful for the treatment of a blood disease or disorder. brinogenemia, alphathalassemia, altered affinity of hemoglo 0204 Instill another aspect, the invention features another bin for oxygen, amyloidosis, anemia, anemia due to acute method for determining whether a candidate compound may blood loss, anemia due to chronic blood loss, anemia of be useful for the treatment of a blood disease or disorder. This chronic disease, anemia of chronic renal failure, anemias method includes (a) providing a GPCR polypeptide substan associated with enzyme deficiencies, anemias associated tially identical to a polypeptide listed in Tables 24 and 33; (b) with erythrocyte cytoskeletal defects, anemias caused by contacting the polypeptide with the candidate compound; and inherited disorders of hemoglobin synthesis, angiogenic (c) measuring the half-life of the polypeptide, wherein an myeloid metaplasia, aplastic anemia, ataxia-telangiectasia, alteration in the half-life of the polypeptide, relative to that of Auer rods, autoimmune hemolytic anemias, B-cell chronic the polypeptide not contacted with the compound, indicates lymphocytic leukemia, B-cell chronic lymphoproliferative that the candidate compound may be useful for the treatment disorders, Bernard-Soulier disease, beta thalassemia, Black of a blood disease or disorder. Preferably the GPCR polypep fan-Diamond disease, brucellosis, Burkitt's lymphoma, Ché tide is in a cell or a cell free assay system. diak-Higashi syndrome, cholera, chronic acquired pure red 0205. In another aspect, the invention features a method cell aplasia, chronic granulocytic leukemia, chronic granulo for determining whether a patient has an increased risk for matous disease, chronic idiopathic myelofibrosis, chronic developing a blood disease or disorder. The method includes idiopathic thrombocytopenic purpura, chronic lymphocytic the step of determining whether the patient has a mutation in leukemia, chronic lymphoproliferative disorders, chronic a gene encoding a polypeptide listed in Tables 24 and 33. myelocytic leukemia, chronic myelogenous leukemia, wherein presence of the mutation indicates that the patient chronic myeloid leukemia, chronic myeloproliferative disor may have an increased risk for developing a blood disease or ders, congenital dyserythropoietic anemias, congenital dys disorder. fibrinogenemia, congenital neutropenia, corticosteriods, 0206. In a related aspect, the invention features another cyclic neutropenia, cytoplasmic maturation defect, defi method for determining whether a patient has an increased ciency of coagulation factors, delta-beta thalassemia, diph risk for developing a blood disease or disorder. This method theria, disorders of blood coagulation, disseminated intravas includes the step of determining whether the patient has a cular coagulation & fibrinolysis, Döhle bodies, drug & polymorphism in a gene encoding a polypeptide listed in chemical-induced hemolysis, drug-induced thrombocytope Tables 24 and 33, wherein presence of the polymorphism nia, drugs that Suppress granulopoiesis, E. coli, early preleu indicates that the patient may have an increased risk for kemic myeloid leukemia, eosinophilia, eosinophilic granu developing a blood disease or disorder. loma, erythrocute enzyme deficiency, erythrocyte membrane 0207. In either of these two methods, the mutation or poly defects, essential thrombocythemia, factor 7 deficiency, morphism is preferably associated with an alteration (for familial cyclic neutropenia, Felty's syndrome, fibrinolytic example, a decrease) in the biological activity of the polypep activity, folate antagonists, folic acid deficiency, Gaucher tide. disease, Glanzmann's thrombasthenia, glucose-6-phosphate 0208. In another aspect, the invention features another dehydrogenase deficiency, granulated T-cell lymphocyte leu method for determining whether a patient has an increased kemia, granulocytic sarcoma, granulocytosis, Hageman trait, risk for developing a blood disease or disorder. The method hairy cell leukemia (leukemic reticuloendotheliosis), Hand includes measuring biological activity of a GPCR polypep Schiller-Christian disease, heavy-chain disease, hemoglobin tide from the patient that is substantially identical to a C disease, hemoglobin constant spring, hemoglobin S, hemo polypeptide listed in Tables 24 and 33, wherein increased or globinopathies, hemolysis caused by infectious agents, decreased levels in the GPCR biological activity, relative to hemolytic anemia, hemolytic anemia secondary to mechani normal levels, indicate that the patient may have an increased cal erythrocyte destruction, hemolytic blood transfusion risk for developing a blood disease or disorder. reactions, hemolytic disease of the newborn, hemophago 0209. In still another aspect, the invention features yet cytic disorders, hemophilia A, hemophilia B (Christmas dis another method for determining whether a patient has an ease, factor 9 deficiency, hepatitis, hereditary elliptocytosis, increased risk for developing a blood disease or disorder. The hereditary spherocytosis, heterozygous beta thalassemia method includes the step of measuring the patient's expres (Cooley's trait), homozygous betathalassemia (Cooley's ane sion levels of a polypeptide listed in Tables 24 and 33, mia), hypereosinophilic syndrome, hypoxia, idiopathic cold wherein altered levels in the expression, relative to normal, hemagglutinin disease, idiopathic thrombocytopenic pur indicate that the patient has an increased risk for developing a pura, idiopathic warm autoimmune hemolytic anemia, blood disease or disorder. Preferably, the expression levels immune drug induced hemolysis, immune-mediated are determined by measuring levels of polypeptide or mRNA. hemolytic anemias, immunodeficiency disease, infantile neu 0210 Preferred blood diseases that can be treated or diag tropenia (Knock outstmann), instability of the hemoglobin nosed using the methods of the invention or for which candi molecule, iron deficiency anemia, isoimmune hemolytic ane date therapeutic compounds may be identified include abnor mia,juvenile chronic myeloid leukemia, Langerhans cell his mal hemoglobins, abnormalities in granulocyte count, tiocytosis, large granular lymphocyte leukemia, lazy leu abnormalities in lymphocyte count, abnormalities in mono knock outcyte syndrome, Letterer-Siwe disease, leukemias, cyte count, abnormalities of blood platelets, abnormalities of leukemoid reaction, leuknock outerythroblastic anemia, lipid platelet function, acanthocytosis, acquired neutropenia, acute storage diseases, lymphoblastosis, lymphocytopenia, lym granulocytic leukemia, acute idiopathic thrombocytopenic phocytosis, lymphoma, lymphopenia, macroangiopathic purpura, acute infections, acute lymphoblastic leukemia, hemolytic anemia, malaria, marrow aplasia, May-Hegglin acute lymphocytic leukemia, acute myeloblastic leukemia, anomaly, measles, megaloblastic anemia, metabolic diseases, acute myelocytic leukemia, acute myeloid leukemia, acute microangiopathic hemolytic anemia, microcytic anemia, mil pyogenic bacterial infections, acute red cell aplasia, acute iary tuberculosis, mixed phenotupe acute leukemia, mono US 2009/0178153 A1 Jul. 9, 2009 24 clonal gammopathy of undetermined significance, monocytic polypeptide listed in Tables 25 and 33; (b) contacting the leukemia, monocytosis, mucopolysaccharidosis, multiple GPCR polypeptide with the candidate compound; and (c) myeloma, myeloblastic luekemia, myelodysplastic Syn measuring biological activity of the GPCR polypeptide, dromes, myelofibrosis (agnogenic myeloid metaplasia), wherein altered biological activity, relative to that of the myeloproliferative diseases, myelosclerosis, neonatal throm GPCR polypeptide not contacted with the compound, indi bocytopenic purpura, neoplasms of hematopoietic cells, neu cates that the candidate compound may be useful for the tropenia, neutrophil dysfunction syndromes, neutrophil leu treatment of a disease or disorder of the prostate. The GPCR knock outcytosis, neutrophilia, Niemann-Pick disease, polypeptide can be in a cell or in a cell-free assay System. nonimmune drug-induced hemolysis, normocytic anemia, 0218. In yet another aspect, the invention features a nuclear maturation defects, parahemophilia, paroxysmal cold method for determining whether a candidate compound is a hemoglominuria, paroxysmal nocturnal hemoglobinuria, compound that may be useful for the treatment of a disease or Pelger-Hiet anomaly, pernicious (Addisonian) anemia, disorder of the prostate. This method includes the steps of (a) plasma cell leukemia, plasma cell neoplasia, polycythemia, providing a transgenic non-human mammal (e.g., a knock polycythemia rubra Vera, presence of circulating anticoagul out mouse) having a disruption in a nucleic acid molecule lants, primary (idiopathic) thrombocythemia, primary neo encoding a GPCR polypeptide substantially identical to a plasms, prolymphocytic leukemia, Proteus, Pseudomonas, polypeptide listed in Tables 25 and 33; (b) contacting the pure red cell aplasia, pyogenic bacterial infection, pyruvate transgenic non-human mammal with the candidate com kinase deficiency, radiation, red cell aplasia, refractory ane pound; and (c) measuring biological activity of the transgenic mias, ricketsial infections, Rosenthal's syndrome, secondary non-human mammal, wherein altered biological activity, absolute polycythemia, septicemia, severe combined immu relative to that of the transgenic non-human mammal not nodeficiency disease, Sézary syndrome, sickle cell disease, contacted with the compound, indicates that the candidate sickle cell-beta thalassemia, sideroblastic anemia, Solitary compound may be useful for the treatment of a disease or plasmacytoma, storage pool disease, stress, structural hemo disorder of the prostate. globin variants, systemic lupus erythematosus, systemic mas 0219. In yet another aspect, the invention features a tocytosis, tart cell, T-cell chronic lymphoproliferative disor method for determining whether a candidate compound is a ders, T-cell prolymphocytic leukemia, thalassemias, compound that may be useful for the treatment of a blood thrombocytopenia, thrombotic thrombocytopenic purpura, disease or disorder of the prostate. This method includes the toxic granulation, toxic granules in severe infection, typhus, steps of (a) providing a transgenic non-human mammal (e.g., vitamin B12 deficiency, vitamin K deficiency, Von Will a mouse) overexpressing a nucleic acid molecule encoding a ebrand's disease, Waldenstrom macroglobulinemia, and Wis GPCR polypeptide substantially identical to a polypeptide knock outtt-aldrich syndrome. listed in Tables 25 and 33; (b) contacting the transgenic non 0211. In another aspect, the invention features a non-hu human mammal with the candidate compound; and (c) mea man mammal (e.g., a mouse), having a transgene that suring biological activity of the GPCR polypeptide in the includes a nucleic acid molecule encoding a GPCR polypep transgenic non-human mammal, wherein altered biological tide substantially identical to a polypeptide listed in Table 24. activity, relative to that of the transgenic non-human mammal 0212. In yet another aspect, the invention features a non not contacted with the compound, indicates that the candidate human mammal (e.g., a mouse), having a mutation in a compound may be useful for the treatment of a disease or nucleic acid molecule encoding a GPCR polypeptide sub disorder of the prostate. stantially identical to a polypeptide listed in Table 24. 0220 Instill another aspect, the invention features another 0213. In a related aspect, the invention features a cell from method for determining whether a candidate compound may a non-human mammal having a transgene that includes a be useful for the treatment of a disease or disorder of the nucleic acid molecule encoding a GPCR polypeptide sub prostate. This method includes (a) providing a nucleic acid stantially identical to a polypeptide listed in Table 24. molecule comprising a promoter from a gene encoding a 0214. In another aspect, the invention features a cell from GPCR polypeptide listed in Tables 25 and 33, the promoter a non-human mammal having a mutation in a nucleic acid operably linked to a reporter system; (b) contacting the molecule encoding a GPCR polypeptide substantially identi nucleic acid molecule with the candidate compound; and (c) cal to a polypeptide listed in Table 24. measuring reporter activity, wherein altered reporter activity, 0215. In another aspect, the invention features a method of relative to a nucleic acid molecule not contacted with the preventing or treating a disease of the prostate including compound, indicates that the candidate compound may be introducing into a human an expression vector that includes a useful for the treatment of a disease or disorder of the prostate. nucleic acid molecule encoding a GPCR polypeptide sub 0221. In another aspect, the invention features yet another stantially identical to a polypeptide listed in Tables 25 and 33, method for determining whether a candidate compound may operably linked to a promoter. be useful for the treatment of a disease or disorder of the 0216. In still another aspect, the invention features a prostate. This method includes the steps of: (a) providing a method of treating or preventing a disease of the prostate GPCR polypeptide substantially identical to a polypeptide including administering to an animal (e.g., a human) a com listed in Tables 25 and 33; (b) contacting the polypeptide with pound that modulates the biological activity of a GPCR the candidate compound; and (c) measuring interaction of the polypeptide Substantially identical to a polypeptide listed in candidate compound to the polypeptide. Interaction of the Tables 25 and 33. compound to the polypeptide indicates that the candidate 0217. In yet another aspect, the invention features a compound may be useful for the treatment of a disease or method for determining whether a candidate compound is a disorder of the prostate. compound that may be useful for the treatment of a disease or 0222 Instill another aspect, the invention features another disorder of the prostate. This method includes the steps of (a) method for determining whether a candidate compound may providing a GPCR polypeptide substantially identical to a be useful for the treatment of a disease or disorder of the US 2009/0178153 A1 Jul. 9, 2009 prostate. This method includes (a) providing a GPCR pseudotumor, leiomyosarcoma, leukemia, lymphoepithe polypeptide Substantially identical to a polypeptide listed in lioma-like carcinoma, malaknock outplakia, malignant lym Tables 25 and 33; (b) contacting the polypeptide with the phoma, mucinous (colloid) carcinoma, nodular hyperplasia candidate compound; and (c) measuring the half-life of the (benign prostatic hyperplasia), nonbacterial prostatitis, polypeptide, wherein an alteration in the half-life of the obstruction of urinary outflow, phyllodes tumor, postatrophic polypeptide, relative to that of the polypeptide not contacted hyperplasia, postirradiation granulomatous prostatitis, post with the compound, indicates that the candidate compound operative spindle cell nodules, postSurgical granulomatous may be useful for the treatment of a disease or disorder of the prostatitis, prostatic adenocarcinoma, prostatic carcinoma, prostate. Preferably the GPCR polypeptide is in a cellor a cell prostatic intraepithelial neoplasia, prostatic melanosis, pros free assay system. tatic neoplasm, prostatitis, rhabdomyosarcoma, sarcomatoid 0223) In another aspect, the invention features a method carcinoma of the prostate, Sclerosing adenosis, signet ring for determining whether a patient has an increased risk for cell carcinoma, Small-cell, undifferentiated carcinoma (high developing a disease or disorder of the prostate. The method grade neuroendocrine carcinoma), Squamous cell carcinoma includes the step of determining whether the patient has a of the prostate, Stromal hyperplasia with atypia, transitional mutation in a gene encoding a polypeptide listed in Tables 25 cell carcinoma of the prostate, Xanthogranulomatous prostati and 33, wherein presence of the mutation indicates that the tis, and Xanthoma. patient may have an increased risk for developing a disease or 0229. In another aspect, the invention features a non-hu disorder of the prostate. man mammal (e.g., a mouse), having a transgene that 0224. In a related aspect, the invention features another includes a nucleic acid molecule encoding a GPCR polypep method for determining whether a patient has an increased tide substantially identical to a polypeptide listed in Table 25. risk for developing a disease or disorder of the prostate. This 0230. In yet another aspect, the invention features a non method includes the step of determining whether the patient human mammal (e.g., a mouse), having a mutation in a has a polymorphism in a gene encoding a polypeptide listed in nucleic acid molecule encoding a GPCR polypeptide sub Tables 25 and 33, wherein presence of the polymorphism stantially identical to a polypeptide listed in Table 25. indicates that the patient may have an increased risk for 0231. In a related aspect, the invention features a cell from developing a disease or disorder of the prostate. a non-human mammal having a transgene that includes a 0225. In either of these two methods, the mutation or poly nucleic acid molecule encoding a GPCR polypeptide sub morphism is preferably associated with an alteration (for stantially identical to a polypeptide listed in Table 25. example, a decrease) in the biological activity of the polypep 0232. In another aspect, the invention features a cell from tide. a non-human mammal having a mutation in a nucleic acid 0226. In another aspect, the invention features another molecule encoding a GPCR polypeptide substantially identi method for determining whether a patient has an increased cal to a polypeptide listed in Table 25. risk for developing a disease or disorder of the prostate. The 0233. In another aspect, the invention features a method of method includes measuring biological activity of a GPCR preventing or treating skin disease, including introducing into polypeptide from the patient that is substantially identical to a human an expression vector that includes a nucleic acid a polypeptide listed in Tables 25 and 33, wherein increased or molecule encoding a GPCR polypeptide substantially identi decreased levels in the GPCR biological activity, relative to cal to a polypeptide listed in Tables 26 and 33, operably linked normal levels, indicate that the patient may have an increased to a promoter. risk for developing a disease or disorder of the prostate. 0234. In still another aspect, the invention features a 0227. In still another aspect, the invention features yet method of treating or preventing skin disease, including another method for determining whether a patient has an administering to an animal (e.g., a human) a compound that increased risk for developing a disease or disorder of the modulates the biological activity of a GPCR polypeptide prostate. The method includes the step of measuring the substantially identical to a polypeptide listed in Tables 26 and patient's expression levels of a polypeptide listed in Tables 25 33. and 33, wherein altered levels in the expression, relative to 0235. In yet another aspect, the invention features a normal, indicate that the patient has an increased risk for method for determining whether a candidate compound is a developing a disease or disorder of the prostate. Preferably, compound that may be useful for the treatment of a skin the expression levels are determined by measuring levels of disease or disorder. This method includes the steps of (a) polypeptide or mRNA. providing a GPCR polypeptide substantially identical to a 0228 Diseases of the prostate that can be treated or diag polypeptide listed in Tables 26 and 33; (b) contacting the nosed using the methods of the invention or for which candi GPCR polypeptide with the candidate compound; and (c) date therapeutic compounds may be identified include acute measuring biological activity of the GPCR polypeptide, bacterial prostatitis, acute prostatitis, adenoid basal cell wherein altered biological activity, relative to that of the tumor (adenoid cystic-like tumor), allergic (eosinophilic) GPCR polypeptide not contacted with the compound, indi granulomatous prostatitis, atrophy, atypical adenomatous cates that the candidate compound may be useful for the hyperplasia, atypical basal cell hyperplasia, basal cell treatment of a skin disease or disorder. The GPCR polypep adenoma, basal cell hyperplasia, BCG-induced granuloma tide can be in a cell or in a cell-free assay system. tous prostatitis, benign prostatic hyperplasia, benign prostatic 0236. In yet another aspect, the invention features a hypertrophy, blue nevus, carcinosarcoma, chronic abacterial method for determining whether a candidate compound is a prostatitis, chronic bacterial prostatitis, cribriform hyperpla compound that may be useful for the treatment of a skin sia, ductal (endometrioid) adenocarcinoma, granulomatous disease or disorder. This method includes the steps of (a) prostatitis, hematuria, iatrogenic granulomatous prostatitis, providing a transgenic non-human mammal (e.g., a knock idiopathic (nonspecific) granulous prostatitis, impotence, out mouse) having a disruption in a nucleic acid molecule infectious granulomatous prostatitis, inflammatory encoding a GPCR polypeptide substantially identical to a US 2009/0178153 A1 Jul. 9, 2009 26 polypeptide listed in Tables 26 and 33; (b) contacting the wherein presence of the mutation indicates that the patient transgenic non-human mammal with the candidate com may have an increased risk for developing a skin disease or pound; and (c) measuring biological activity of the GPCR disorder. polypeptide in the transgenic non-human mammal, wherein 0242. In a related aspect, the invention features another altered biological activity, relative to that of the transgenic method for determining whether a patient has an increased non-human mammal not contacted with the compound, indi risk for developing a skin disease or disorder. This method cates that the candidate compound may be useful for the includes the step of determining whether the patient has a treatment of a skin disease or disorder polymorphism in a gene encoding a polypeptide listed in Tables 26 and 33, wherein presence of the polymorphism 0237. In yet another aspect, the invention features a indicates that the patient may have an increased risk for method for determining whether a candidate compound is a developing a skin disease or disorder. compound that may be useful for the treatment of a skin 0243 In either of these two methods, the mutation or poly disease or disorder. This method includes the steps of (a) morphism is preferably associated with an alteration (for providing a transgenic non-human mammal (e.g., a mouse) example, a decrease) in the biological activity of the polypep overexpressing a nucleic acid molecule encoding a GPCR tide. polypeptide Substantially identical to a polypeptide listed in 0244. In another aspect, the invention features another Tables 26 and 33; (b) contacting the transgenic non-human method for determining whether a patient has an increased mammal with the candidate compound; and (c) measuring risk for developing a skin disease or disorder. The method biological activity of the GPCR polypeptide in the transgenic includes measuring biological activity of a GPCR polypep non-human mammal, wherein altered biological activity, tide from the patient that is substantially identical to a relative to that of the transgenic non-human mammal not polypeptide listed in Tables 26 and 33, wherein increased or contacted with the compound, indicates that the candidate decreased levels in the GPCR biological activity, relative to compound may be useful for the treatment of a disease skin normal levels, indicate that the patient may have an increased disease or disorder. risk for developing a skin disease or disorder. 0238. In still another aspect, the invention features another 0245. In still another aspect, the invention features yet method for determining whether a candidate compound may another method for determining whether a patient has an be useful for the treatment of a skin disease or disorder. This increased risk for developing a skin disease or disorder. The method includes (a) providing a nucleic acid molecule com method includes the step of measuring the patient's expres prising a promoter from a gene encoding a GPCR polypeptide sion levels of a polypeptide listed in Tables 26 and 33, listed in Tables 26 and 33, the promoter operably linked to a wherein altered levels in the expression, relative to normal, reporter system; (b) contacting the nucleic acid molecule with indicate that the patient has an increased risk for developing a the candidate compound; and (c) measuring reporter activity, skin disease or disorder. Preferably, the expression levels are wherein altered reporter activity, relative to a nucleic acid determined by measuring levels of polypeptide or mRNA. molecule not contacted with the compound, indicates that the 0246 Preferred skin diseases that can be treated or diag nosed using the methods of the invention or for which candi candidate compound may be useful for the treatment of a skin date therapeutic compounds may be identified include acan disease or disorder. thosis nigricans, acne Vulgaris, acquired epidermolysis 0239. In another aspect, the invention features yet another bullosa, acrochordons, acrodermatitis enteropathica, acro method for determining whether a candidate compound may pustulosis, actinic keratosis, acute cutaneous lupus erythema be useful for the treatment of a skin disease or disorder. This tosus, age spots, allergic dermatitis, alopecia areata, method includes the steps of: (a) providing a GPCR polypep angioedema, angiokeratoma, angioma, anthrax, apocrine tide substantially identical to a polypeptide listed in Tables 26 tumors, arthropid-bite reactions, atopic dermatitis, atypical and 33; (b) contacting the polypeptide with the candidate fibroXanthoma, Bart's syndrome, basal cell carcinoma (basal compound; and (c) measuring interaction of the candidate cell epithelioma), Bateman's purpura, benign familial pem compound to the polypeptide. Interaction of the compound to phigus (Hailey-Hailey disease), benign keratoses, Berloque the polypeptide indicates that the candidate compound may dermatitis, blue nevus, borderline leprosy, Borrelia infection be useful for the treatment of a skin disease or disorder. (lyme disease), Bowen's disease (carcinoma in situ), bullous 0240. In still another aspect, the invention features another pemphigoid, Café-au-lait spot, calcification, cellular blue method for determining whether a candidate compound may nevus, cellulitis, Chagas disease, chickenpox (varicella), be useful for the treatment of a skin disease or disorder. This chloasma, chondrodermatitis nodularis helicis, chondroid method includes (a) providing a GPCR polypeptide substan Syringoma, chronic actinic dermatitis, chronic cutaneous tially identical to a polypeptide listed in Tables 26 and 33; (b) lupus erythematosus, chronic discoid lesions, cicatricial pem contacting the polypeptide with the candidate compound; and phigoid, collagen abnormalities, compount melanocytic (c) measuring the half-life of the polypeptide, wherein an nevus, congenital melanocytic nevus, connective tissue alteration in the half-life of the polypeptide, relative to that of nevus, contact dermatitis, cutaneous leishmaniasis, cutis the polypeptide not contacted with the compound, indicates laxa, cysts of the skin, dandruff, Darier's disease (keratosis that the candidate compound may be useful for the treatment follicularis), deep fungal infections, delayed-hypersensitivity of a skin disease or disorder. Preferably the GPCR polypep reaction, dermal Spitz's nevus, dermatitis, dermatitis herpe tide is in a cell or a cell free assay system. tiformis, dermatofibroma (cutaneous fibrous histiocytoma), 0241. In another aspect, the invention features a method dermatofibrosarcoma protuberans, dermatomyositis, der for determining whether a patient has an increased risk for matophyte infections, dermatophytid reactions, dermoid developing a skin disease or disorder. The method includes cyst, dermotropic ricketsial infections, dermotropic viral the step of determining whether the patient has a mutation in infections, desmoplastic melanoma, discoid lupus erythema a gene encoding a polypeptide listed in Tables 26 and 33. tosus, dominant dystrophic epidermolysis bullosa, Dowling US 2009/0178153 A1 Jul. 9, 2009 27

Meara epidermolysis bullosa, dyshidrotic dermatitis, dys sia, sebaceous tumors, seborrheic dermatitis, seborrheic plastic nevi, eccrine tumors, ecthyma, eczema, elastic tissue keratosis, Sezary syndrome, skin manifestations of systemic abnormalities, elastosis perforans serpiginosa, eosinophilic diseases, Small plaque parapsoriasis, Smallpox (variola), Soli fasciitis, eosinophilic folliculitis, ephelides (freckles), epi tary mastocytoma, Spirochetal infections, Spitz's nevus, dermal cysts, epidermolysis bullosa, epidermolysis bullosa Spitz's nevus junctional type, squamous cell carcinoma, sta simplex, epidermotropic T-cell lymphoma, epidermotropic sis dermatitis, Stevens-Johnson syndrome, Subacute cutane viruses, erysipelas, erythema multiforme, erythema ous lupus erythematosus, Subcorneal pustular dermatosis, Superficial fungal infections, Superficial spreading melanoma nodosum, erythema nodosum leprosum, fibrotic disorders, in situ, Syphilis, Syringoma, systemic lupus erythematosus, fibrous tumors, follicular mucinosis, Fordyce's condition, systemic mastocytosis, tinea (dermatophytosis, tinea versi fungal infections, genodermatoses, graft-Versus-host disease, color, toxic epidermal necrolysis, transient acantholytic der granuloma annulare, granulomatous vasculitis, Grover's dis matosis, tuberculoid leprosy, tuberculosis, urticaria, urticaria ease, hair follicle infections, hair follicle tumors, hair loss, pigmentosa, urticarial vasculitis, vascular tumors, Verruca halo nevus, herpes simplex, herpes Zoster (shingles), hidrad Vulgaris (common wart), vertical growild typeh phase mela enitis Suppurativa, histiocytic lesions, HIV infections, hives, noma, visceral leishmaniasis, vitiligo, warty dyskeratoma, human papillomavirus, hyperhydrosis, ichthyosis, idiopathic Weber-Cockayne epidermolysis bullosa, Woringer-Knock skin diseases, impetigo, incontinentia pigmenti, intraepider mal spongiotic vesicles and bullae, invasive malignant mela outlopp disease, Xanthomas, Xeroderma pigmentosum, Xero noma, invasive squamous cell carcinoma, junctional epider sis, and yaws. molysis bullosa, junctional melanocytic nevus, juvenile 0247. In another aspect, the invention features a non-hu Xanthogranuloma, Kaposi's sarcoma, keloids, keratinocytic man mammal (e.g., a mouse), having a transgene that lesions; keratinocytic tumors, keratoacanthoma, keratoderma includes a nucleic acid molecule encoding a GPCR polypep blennorrhagicum, ketatosis pilaris, leiomyoma, lentigo, len tide substantially identical to a polypeptide listed in Table 26. tigo maligna (Hutchinson's freckle), lepromatous leprosy, 0248. In yet another aspect, the invention features a non leprosy (Hansen's disease), leuknock outcytoclastic vasculi human mammal (e.g., a mouse), having a mutation in a tis, lichen planus, lichen Sclerosus et atrophicus, lichen sim nucleic acid molecule encoding a GPCR polypeptide sub plex chronicus, lichen striatus, lichenoid disorders, lichenoid stantially identical to a polypeptide listed in Table 26. drug reactions, light eruptions, linear bullous IgA dermatitis, 0249. In a related aspect, the invention features a cell from lipoma, Lucio's phenomenon, lupus erythematosus, lym a non-human mammal having a transgene that includes a phatic filariasis, lymphocytic vasculitis, lymphocytomacutis, nucleic acid molecule encoding a GPCR polypeptide sub lymphoid lesions, lymphomatoid papulosis, malignant blue stantially identical to a polypeptide listed in Table 26. nevus, malignant lymphomas, malignant melanoma, malig 0250 In another aspect, the invention features a cell from nant melanoma in situ (noninvasive malignant melanoma), a non-human mammal having a mutation in a nucleic acid mast cell neoplasms, mastocytosis, measles, melanocyte dis molecule encoding a GPCR polypeptide substantially identi orders, melanocytic lesions, melanocytic neoplasms, mel cal to a polypeptide listed in Table 26. anocytic nevus, melanocytic nevus with dysplasia, melanotic 0251. In another aspect, the invention features a method of macule, reactive type, melasma, merkel cell (neuroendo preventing or treating a disease of the spleen including intro crine) carcinoma, metastatic melanoma, miliara, mixed con ducing into a human an expression vector that includes a nective tissue disease, molluscum contagiosum, morphea, nucleic acid molecule encoding a GPCR polypeptide sub mucin deposition, mucocutaneous leishmaniasis, mycetoma, stantially identical to a polypeptide listed in Tables 27 and 33, mycobacterial infection, Mycobacterium marinum, Myco operably linked to a promoter. bacterium ulcerans, mycosis fungoides (cutaneous T cell 0252. In still another aspect, the invention features a lymphoma), myxoid cyst, necrobiosis lipoidica, necrobiosis method of treating or preventing a disease of the spleen lipoidica diabeticorum, necrolytic migratory erythema, including administering to an animal (e.g., a human) a com necrotizing fasciitis, neoplasms of dermal mesenchymal pound that modulates the biological activity of a GPCR cells, neoplasms of keratinocytes, neoplasms of skin append polypeptide Substantially identical to a polypeptide listed in ages, neoplasms of the epidermis, neural tumors, neuroendo Tables 27 and 33. crine carcinoma of the skin, neurothekeoma, nevocellular 0253) In yet another aspect, the invention features a nevus (melanocytic nevus), nummular dermatitis, oblitera method for determining whether a candidate compound is a tive vasculitis, onchocerciasis, Paget's disease, pale cellacan compound that may be useful for the treatment of a disease or thoma of Degos, palisaded encapsulated neuroma, papillo disorder of the spleen. This method includes the steps of (a) mavirus infections, paraneoplastic pemphigus, parasitic providing a GPCR polypeptide substantially identical to a infections, pemphigoid gestationis, pemphigus, pemphigus polypeptide listed in Tables 27 and 33; (b) contacting the foliaceus, pemphigus Vulgaris, perivascular infiltrates, pilar GPCR polypeptide with the candidate compound; and (c) cysts, pinta, pityriasis alba, pityriasis lichenoides chronica (of measuring biological activity of the GPCR polypeptide, Juliusberg), pityriasis lichenoides et varioliformis acuta, wherein altered biological activity, relative to that of the pityriasis rosea, pityriasis rubra pilaris, plantar warts, poro GPCR polypeptide not contacted with the compound, indi keratosis, pressure necrosis, progressive systemic sclerosis, cates that the candidate compound may be useful for the protozoal infections, pruritic urticarial papules and plasques treatment of a disease or disorder of the spleen. The GPCR of pregnancy, pruritisani, pseudofolliculitis barbae, pseudox polypeptide can be in a cell or in a cell-free assay System. anthoma elasticum, psoriasis Vulgaris, pyogenic granuloma, 0254. In yet another aspect, the invention features a radial growild typeh phase melanoma, recessive dystrophic method for determining whether a candidate compound is a epidermolysis bullosa, Reiter's syndrome, ringworm, Roch compound that may be useful for the treatment of a disease or alimaea hemselae infection, rosacea, rubella, Sarcoidosis, Sca disorder of the spleen. This method includes the steps of (a) bies, Schamberg's disease, Scleroderma, sebaceous hyperpla providing a transgenic non-human mammal (e.g., a knock US 2009/0178153 A1 Jul. 9, 2009 28 out mouse) having a disruption in a nucleic acid molecule includes the step of determining whether the patient has a encoding a GPCR polypeptide substantially identical to a mutation in a gene encoding a polypeptide listed in Tables 27 polypeptide listed in Tables 27 and 33; (b) contacting the and 33, wherein presence of the mutation indicates that the transgenic non-human mammal with the candidate com patient may have an increased risk for developing a disease or pound; and (c) measuring biological activity of the GPCR disorder of the spleen. polypeptide in the transgenic non-human mammal, wherein 0260. In a related aspect, the invention features another altered biological activity, relative to that of the transgenic method for determining whether a patient has an increased non-human mammal not contacted with the compound, indi risk for developing a disease or disorder of the spleen. This cates that the candidate compound may be useful for the method includes the step of determining whether the patient treatment of a disease or disorder of the spleen. has a polymorphism in a gene encoding a polypeptide listed in 0255. In yet another aspect, the invention features a Tables 27 and 33, wherein presence of the polymorphism method for determining whether a candidate compound is a indicates that the patient may have an increased risk for compound that may be useful for the treatment of a disease or developing a disease or disorder of the spleen. disorder of the spleen. This method includes the steps of (a) 0261. In either of these two methods, the mutation or poly providing a transgenic non-human mammal (e.g., a mouse) morphism is preferably associated with an alteration (for overexpressing a nucleic acid molecule encoding a GPCR example, a decrease) in the biological activity of the polypep polypeptide Substantially identical to a polypeptide listed in tide. Tables 27 and 33; (b) contacting the transgenic non-human 0262. In another aspect, the invention features another mammal with the candidate compound; and (c) measuring method for determining whether a patient has an increased biological activity of the GPCR polypeptide in the transgenic risk for developing a disease or disorder of the spleen. The non-human mammal, wherein altered biological activity, method includes measuring biological activity of a GPCR relative to that of the transgenic non-human mammal not polypeptide from the patient that is substantially identical to contacted with the compound, indicates that the candidate a polypeptide listed in Tables 27 and 33, wherein increased or compound may be useful for the treatment of a disease or decreased levels in the GPCR biological activity, relative to disorder of the spleen. normal levels, indicate that the patient may have an increased 0256 Instill another aspect, the invention features another risk for developing a disease or disorder of the spleen. method for determining whether a candidate compound may 0263. In still another aspect, the invention features yet be useful for the treatment of a disease or disorder of the another method for determining whether a patient has an spleen. This method includes (a) providing a nucleic acid increased risk for developing a disease or disorder of the molecule comprising a promoter from a gene encoding a spleen. The method includes the step of measuring the GPCR polypeptide listed in Tables 27 and 33, the promoter patient's expression levels of a polypeptide listed in Tables 27 operably linked to a reporter system; (b) contacting the and 33, wherein altered levels in the expression, relative to nucleic acid molecule with the candidate compound; and (c) normal, indicate that the patient has an increased risk for measuring reporter activity, wherein altered reporter activity, developing a disease or disorder of the spleen. Preferably, the relative to a nucleic acid molecule not contacted with the expression levels are determined by measuring levels of compound, indicates that the candidate compound may be polypeptide or mRNA. useful for the treatment of a disease or disorder of the spleen. 0264 Diseases of the spleen that can be treated or diag 0257. In another aspect, the invention features yet another nosed using the methods of the invention or for which candi method for determining whether a candidate compound may date therapeutic compounds may be identified include abnor be useful for the treatment of a disease or disorder of the mal immunoblastic proliferations of unknown origin, acute spleen. This method includes the steps of: (a) providing a infections, acute parasitemias, agnogenic myeloid metapla GPCR polypeptide substantially identical to a polypeptide sia, amyloidosis, angioimmunoblastic lymphadenopathy, listed in Tables 27 and 33; (b) contacting the polypeptide with antibody-coated cells, asplenia, autoimmune diseases, the candidate compound; and (c) measuring interaction of the autoimmune hemolytic anemias, B-cell chronic lymphocytic candidate compound to the polypeptide. Interaction of the leukemia and prolymphocytic leukemia, babesiosis, bone compound to the polypeptide indicates that the candidate marrow involvement by carcinoma, brucellosis, carcinoma, compound may be useful for the treatment of a disease or ceroid histiocytosis, chronic alcoholism, chronic granuloma disorder of the spleen. tous disease, chronic hemolytic anemias, chronic hemolytic 0258. In still another aspect, the invention features another disorders, chronic immunologic inflammatory disorders, method for determining whether a candidate compound may chronic infections, chronic lymphocytic leukemia, chronic be useful for the treatment of a disease or disorder of the myelogenous leukemia, chronic parasitemias, chronic ure spleen. This method includes (a) providing a GPCR polypep mia, cirrhosis, cold agglutinin disease, congestive splenom tide substantially identical to a polypeptide listed in Tables 27 egaly, cryoglobulinemia, disseminated tuberculosis, dyspro and 33; (b) contacting the polypeptide with the candidate teinemias, endocrine disorders, erythroblastic leukemia, compound; and (c) measuring the half-life of the polypeptide, erythropoiesis, essential thrombocythemia, extramedullary wherein an alteration in the half-life of the polypeptide, rela hematopoiesis, Felty syndrome, fibrocongestive splenom tive to that of the polypeptide not contacted with the com egaly, fungal infections, gamm heavy-chain disease, Gauch pound, indicates that the candidate compound may be useful er's disease, graft rejection, granulomatous infiltration, hairy for the treatment of a disease or disorder of the spleen. Pref cell leukemia, hamartomas, Hand-Schüller-Christian dis erably the GPCR polypeptide is in a cell or a cell free assay ease, hemangiomas, hemangiosarcomas, hematologic disor system. ders, hemoglobinopathies, hemolytic anemias, hereditary 0259. In another aspect, the invention features a method elliptocytosis, hereditary spherocytosis, histiocytic medul for determining whether a patient has an increased risk for lary reticulosis, histiocytosis X, Hodgkin's disease, hyper developing a disease or disorder of the spleen. The method sensitivity reactions, hypersplenism, hyposplenism, idio US 2009/0178153 A1 Jul. 9, 2009 29 pathic thrombocytopenic purpura, IgA deficiency, immune GPCR polypeptide not contacted with the compound, indi granulomas, immune thrombocytopenia, immune thromb cates that the candidate compound may be useful for the ocytopenic purpura, immunodeficiency disorders, infection treatment of a disease or disorder of the stomach. The GPCR associated hemophagocytic syndrome, infectious granulo polypeptide can be in a cell or in a cell-free assay System. mas, infectious mononucleosis, infective endocarditis, infil 0272. In yet another aspect, the invention features a trative splenomegaly, inflammatory pseudotumors, leishma method for determining whether a candidate compound is a niasis, Leterer-Siwe disease, leukemia, lipogranulomas, compound that may be useful for the treatment of a disease or lymphocytic leukemias, lymphoma, malabsorption syn disorder of the stomach. This method includes the steps of (a) dromes, malaria, malignant lymphoma, megakaryoblastic providing a transgenic non-human mammal (e.g., a knock leukemia, metastatic tumor, monocytic leukemias, muco out mouse) having a disruption in a nucleic acid molecule polysaccharidoses, multicentric Castleman's disease, mul encoding a GPCR polypeptide substantially identical to a tiple myeloma, myelocytic leukemias, myelofibrosis, myelo polypeptide listed in Tables 28 and 33; (b) contacting the proliferative syndromes, neoplasms, Niemann-Pick disease, transgenic non-human mammal with the candidate com non-Hodgkin’s lymphoma, parasitic disorders, parasitized pound; and (c) measuring biological activity of the GPCR red blood cells, peliosis, polycythemia rubra Vera, portal vein polypeptide in the transgenic non-human mammal, wherein congestion, portal vein Stenosis, portal vein thrombosis, por altered biological activity, relative to that of the transgenic tal venous hypertension, rheumatoid arthritis, right-sided car non-human mammal not contacted with the compound, indi diac failure, sarcoidosis, sarcoma, secondary amyloidosis, cates that the candidate compound may be useful for the secondary myeloid metaplasia, serum sickness, sickle-cell treatment of a disease or disorder of the stomach. disease, splenic cysts, splenic infarction, splenic vein hyper 0273. In yet another aspect, the invention features a tension, splenic vein Stenosis, splenic vein thrombosis, sple method for determining whether a candidate compound is a nomegaly, storage diseases, systemic lupus erythematosus, compound that may be useful for the treatment of a disease or systemic vasculitides, T-cell chronic lymphocytic leukemia, disorder of the stomach. This method includes the steps of (a) thalasemia, thrombocytopenic purpura, thyrotoxicosis, trap providing a transgenic non-human mammal (e.g., a mouse) ping of immature hematologic cells, tuberculosis, tumorlike overexpressing a nucleic acid molecule encoding a GPCR conditions, typhoid fever, vascular tumors, vasculitis, and polypeptide Substantially identical to a polypeptide listed in viral infections. Tables 28 and 33; (b) contacting the transgenic non-human 0265. In another aspect, the invention features a non-hu mammal with the candidate compound; and (c) measuring man mammal (e.g., a mouse), having a transgene that biological activity of the GPCR polypeptide in the transgenic includes a nucleic acid molecule encoding a GPCR polypep non-human mammal, wherein altered biological activity, tide substantially identical to a polypeptide listed in Table 27. relative to that of the transgenic non-human mammal not 0266. In yet another aspect, the invention features a non contacted with the compound, indicates that the candidate human mammal (e.g., a mouse), having a mutation in a compound may be useful for the treatment of a disease or nucleic acid molecule encoding a GPCR polypeptide sub disorder of the stomach. stantially identical to a polypeptide listed in Table 27. 0274 Instill another aspect, the invention features another 0267 In a related aspect, the invention features a cell from method for determining whether a candidate compound may a non-human mammal having a transgene that includes a be useful for the treatment of a disease or disorder of the nucleic acid molecule encoding a GPCR polypeptide sub stomach. This method includes (a) providing a nucleic acid stantially identical to a polypeptide listed in Table 27. molecule comprising a promoter from a gene encoding a 0268. In another aspect, the invention features a cell from GPCR polypeptide listed in Tables 28 and 33, the promoter a non-human mammal having a mutation in a nucleic acid operably linked to a reporter system; (b) contacting the molecule encoding a GPCR polypeptide substantially identi nucleic acid molecule with the candidate compound; and (c) cal to a polypeptide listed in Table 27. measuring reporter activity, wherein altered reporter activity, 0269. In another aspect, the invention features a method of relative to a nucleic acid molecule not contacted with the preventing or treating a disease of the stomach including compound, indicates that the candidate compound may be introducing into a human an expression vector that includes a useful for the treatment of a disease or disorder of the stom nucleic acid molecule encoding a GPCR polypeptide sub ach. stantially identical to a polypeptide listed in Tables 28 and 33, 0275. In another aspect, the invention features yet another operably linked to a promoter. method for determining whether a candidate compound may 0270. In still another aspect, the invention features a be useful for the treatment of a disease or disorder of the method of treating or preventing a disease of the stomach stomach. This method includes the steps of: (a) providing a including administering to an animal (e.g., a human) a com GPCR polypeptide substantially identical to a polypeptide pound that modulates the biological activity of a GPCR listed in Tables 28 and 33; (b) contacting the polypeptide with polypeptide Substantially identical to a polypeptide listed in the candidate compound; and (c) measuring interaction of the Tables 28 and 33. candidate compound to the polypeptide. Interaction of the 0271 In yet another aspect, the invention features a compound to the polypeptide indicates that the candidate method for determining whether a candidate compound is a compound may be useful for the treatment of a disease or compound that may be useful for the treatment of a disease or disorder of the stomach. disorder of the stomach. This method includes the steps of (a) 0276 Instill another aspect, the invention features another providing a GPCR polypeptide substantially identical to a method for determining whether a candidate compound may polypeptide listed in Tables 28 and 33; (b) contacting the be useful for the treatment of a disease or disorder of the GPCR polypeptide with the candidate compound; and (c) stomach. This method includes (a) providing a GPCR measuring biological activity of the GPCR polypeptide, polypeptide Substantially identical to a polypeptide listed in wherein altered biological activity, relative to that of the Tables 28 and 33; (b) contacting the polypeptide with the US 2009/0178153 A1 Jul. 9, 2009 30 candidate compound; and (c) measuring the half-life of the antral vascular ectasia, gastric adenocarcinoma, gastric outlet polypeptide, wherein an alteration in the half-life of the obstruction (pyloric Stenosis), gastric ulcers, gastritis, gas polypeptide, relative to that of the polypeptide not contacted troesophageal reflux, gastroparesis, granulomatous gastritis, with the compound, indicates that the candidate compound H. Pylori infection, hamartomatous polyps, heterotopias, het may be useful for the treatment of a disease or disorder of the erotopic pancreatic tissue, heterotopic polyps, hyperplastic stomach. Preferably the GPCR polypeptide is in a cellora cell gastropathy, hyperplastic polyps, hypersecretion of acid, free assay system. infectious gastritis, inflammatory lesions of the stomach, 0277. In another aspect, the invention features a method inflammatory polyps, intestinal metaplasia, invasive carci for determining whether a patient has an increased risk for noma, ischemia, leiomyoma, linitis plastica, luminally acting developing a disease or disorder of the stomach. The method toxic chemicals, lymphocytic gastritis, lymphomas, malig includes the step of determining whether the patient has a nant gastric stromal neoplasms, malignantlymphoma, malig mutation in a gene encoding a polypeptide listed in Tables 28 nant transformation of a benign gastric ulcer, Menentrier's and 33, wherein presence of the mutation indicates that the disease (hypertrophic gastritis, rugal hypertrophy), mesen patient may have an increased risk for developing a disease or chymal neoplasms, metastatic tumors, mucosal polyps, myo disorder of the stomach. epithelial adenomas, myoepithelial hamartomas, neoplasms, 0278. In a related aspect, the invention features another neuroendocrine hyperplasias, neuroendocrine tumors, non method for determining whether a patient has an increased erosive gastritis and stomach cancer, normeoplastic polyps, risk for developing a disease or disorder of the stomach. This parasitic gastritis, peptic ulcer disease, phlegmonous gastri method includes the step of determining whether the patient tis, plasma cell gastritis, polypoid (fungating) adenocarci has a polymorphism in a gene encoding a polypeptide listed in noma, poorly differentiated neuroendocrine carcinomas, pre Tables 28 and 33, wherein presence of the polymorphism cancerous lesions, Puetz-Jeghers syndrome, pyloric atresia, indicates that the patient may have an increased risk for rapid gastric emptying, reflux of bile, stress ulcers, stromal developing a disease or disorder of the stomach. tumors, Superficial gastritis, type A chronic gastritis (autoim 0279. In either of these two methods, the mutation or poly mune gastritis and pernicious anemia), type B chronic gastri morphism is preferably associated with an alteration (for tis (chronic antral gastritis, H. Pylori gastritis), ulcerating example, a decrease) in the biological activity of the polypep adenocarcinoma, Vasculitis, viral gastritis, Xanthomatous tide. gastritis, and Zollinger-Ellison syndrome. 0280. In another aspect, the invention features another 0283. In another aspect, the invention features a non-hu method for determining whether a patient has an increased man mammal (e.g., a mouse), having a transgene that risk for developing a disease or disorder of the stomach. The includes a nucleic acid molecule encoding a GPCR polypep method includes measuring biological activity of a GPCR tide substantially identical to a polypeptide listed in Table 28. polypeptide from the patient that is substantially identical to 0284. In yet another aspect, the invention features a non a polypeptide listed in Tables 28 and 33, wherein increased or human mammal (e.g., a mouse), having a mutation in a decreased levels in the GPCR biological activity, relative to nucleic acid molecule encoding a GPCR polypeptide sub normal levels, indicate that the patient may have an increased stantially identical to a polypeptide listed in Table 28. risk for developing a disease or disorder of the stomach. 0285. In a related aspect, the invention features a cell from 0281. In still another aspect, the invention features yet a non-human mammal having a transgene that includes a another method for determining whether a patient has an nucleic acid molecule encoding a GPCR polypeptide sub increased risk for developing a disease or disorder of the stantially identical to a polypeptide listed in Table 28. stomach. The method includes the step of measuring the 0286. In another aspect, the invention features a cell from patient's expression levels of a polypeptide listed in Tables 28 a non-human mammal having a mutation in a nucleic acid and 33, wherein altered levels in the expression, relative to molecule encoding a GPCR polypeptide substantially identi normal, indicate that the patient has an increased risk for cal to a polypeptide listed in Table 28. developing a disease or disorder of the stomach. Preferably, 0287. In another aspect, the invention features a method of the expression levels are determined by measuring levels of preventing or treating a disease of the testes including intro polypeptide or mRNA. ducing into a human an expression vector that includes a 0282 Diseases of the stomach that can be treated or diag nucleic acid molecule encoding a GPCR polypeptide sub nosed using the methods of the invention or for which candi stantially identical to a polypeptide listed in Tables 29 and 33, date therapeutic compounds may be identified include acute operably linked to a promoter. erosive gastropathy, acute gastric ulcers, adenocarcinomas, 0288. In still another aspect, the invention features a adenomas, adenomatous polyps, advanced gastric cancer, method of treating or preventing a disease of the testes includ ampullary carcinoma, atrophic gastritis, bacterial gastritis, ing administering to an animal (e.g., a human) a compound carcinoid tumors, carcinoma of the stomach, chemical gas that modulates the biological activity of a GPCR polypeptide tritis, chronic (nonerosive) gastritis, chronic idiopathic gas substantially identical to a polypeptide listed in Tables 29 and tritis, chronic nonatrophic gastritis, Chronkhite-Canada Syn 33. drome, congenital cysts, congenital diaphragmatic hernias, 0289. In yet another aspect, the invention features a congenital diverticula, congenital duplications, congenital method for determining whether a candidate compound is a pyloric Stenosis, congestive gastropathy, cyclic vomiting Syn compound that may be useful for the treatment of a disease or drome, decreased mucosal resistance to acid, diffuse or infil disorder of the testes. This method includes the steps of (a) trating adenocarcinoma, early gastric cancer, emphysema providing a GPCR polypeptide substantially identical to a tous gastritis, endocrine cell hyperplasia, environmental polypeptide listed in Tables 29 and 33; (b) contacting the gastritis, eosinophilic gastritis, eosinophilic gastroenteritis, GPCR polypeptide with the candidate compound; and (c) epithelial polyps, erosive (acute) gastritis, fundic gland pol measuring biological activity of the GPCR polypeptide, yps, fungal gastritis, gangliocytic paragangliomas, gastral wherein altered biological activity, relative to that of the US 2009/0178153 A1 Jul. 9, 2009

GPCR polypeptide not contacted with the compound, indi wherein an alteration in the half-life of the polypeptide, rela cates that the candidate compound may be useful for the tive to that of the polypeptide not contacted with the com treatment of a disease or disorder of the testes. The GPCR pound, indicates that the candidate compound may be useful polypeptide can be in a cell or in a cell-free assay System. for the treatment of a disease or disorder of the testes. Pref 0290. In yet another aspect, the invention features a erably the GPCR polypeptide is in a cell or a cell free assay method for determining whether a candidate compound is a system. compound that may be useful for the treatment of a disease or 0295. In another aspect, the invention features a method disorder of the testes. This method includes the steps of (a) for determining whether a patient has an increased risk for providing a transgenic non-human mammal (e.g., a knock developing a disease or disorder of the testes. The method out mouse) having a disruption in a nucleic acid molecule includes the step of determining whether the patient has a encoding a GPCR polypeptide substantially identical to a mutation in a gene encoding a polypeptide listed in Tables 29 polypeptide listed in Tables 29 and 33; (b) contacting the and 33, wherein presence of the mutation indicates that the transgenic non-human mammal with the candidate com patient may have an increased risk for developing a disease or pound; and (c) measuring biological activity of the GPCR disorder of the testes. In a related aspect, the invention fea polypeptide in the transgenic non-human mammal, wherein tures another method for determining whetherapatient has an altered biological activity, relative to that of the transgenic increased risk for developing a disease or disorder of the non-human mammal not contacted with the compound, indi testes. This method includes the step of determining whether cates that the candidate compound may be useful for the the patient has a polymorphism in a gene encoding a polypep treatment of a disease or disorder of the testes. tide listed in Tables 29 and 33, wherein presence of the poly 0291. In yet another aspect, the invention features a morphism indicates that the patient may have an increased method for determining whether a candidate compound is a risk for developing a disease or disorder of the testes. compound that may be useful for the treatment of a disease or 0296. In either of these two methods, the mutation or poly disorder of the testes. This method includes the steps of (a) morphism is preferably associated with an alteration (for providing a transgenic non-human mammal (e.g., a mouse) example, a decrease) in the biological activity of the polypep overexpressing a nucleic acid molecule encoding a GPCR tide. polypeptide Substantially identical to a polypeptide listed in 0297. In another aspect, the invention features another Tables 29 and 33; (b) contacting the transgenic non-human method for determining whether a patient has an increased mammal with the candidate compound; and (c) measuring risk for developing a disease or disorder of the testes. The biological activity of the GPCR polypeptide in the transgenic method includes measuring biological activity of a GPCR non-human mammal, wherein altered biological activity, polypeptide from the patient that is substantially identical to relative to that of the transgenic non-human mammal not a polypeptide listed in Tables 29 and 33, wherein increased or contacted with the compound, indicates that the candidate decreased levels in the GPCR biological activity, relative to compound may be useful for the treatment of a disease or normal levels, indicate that the patient may have an increased disorder of the testes. risk for developing a disease or disorder of the testes. 0292. In still another aspect, the invention features another 0298. In still another aspect, the invention features yet method for determining whether a candidate compound may another method for determining whether a patient has an be useful for the treatment of a disease or disorder of the increased risk for developing a disease or disorder of the testes. This method includes (a) providing a nucleic acid testes. The method includes the step of measuring the molecule comprising a promoter from a gene encoding a patient's expression levels of a polypeptide listed in Tables 29 GPCR polypeptide listed in Tables 29 and 33, the promoter and 33, wherein altered levels in the expression, relative to operably linked to a reporter system; (b) contacting the normal, indicate that the patient has an increased risk for nucleic acid molecule with the candidate compound; and (c) developing a disease or disorder of the testes. Preferably, the measuring reporter activity, wherein altered reporter activity, expression levels are determined by measuring levels of relative to a nucleic acid molecule not contacted with the polypeptide or mRNA. compound, indicates that the candidate compound may be 0299 Diseases of the testes that can be treated or diag useful for the treatment of a disease or disorder of the testes. nosed using the methods of the invention or for which candi 0293. In another aspect, the invention features yet another date therapeutic compounds may be identified include aber method for determining whether a candidate compound may rant ducts of Haller, abnormal productions of hormones, be useful for the treatment of a disease or disorder of the abnormalities of testicular descent, acute epididymoorhcitis, testes. This method includes the steps of: (a) providing a adenomatoid tumor, adenomatous hyperplasia of the rete tes GPCR polypeptide substantially identical to a polypeptide tis, adenovirus, administration of estrogens, adrenal rests, listed in Tables 29 and 33; (b) contacting the polypeptide with alcoholic cirrhosis, amyloidosis, anorchism, appendix testes, the candidate compound; and (c) measuring interaction of the bacterial infections, Brucella, cachexia, carcinoma in situ, candidate compound to the polypeptide. Interaction of the carcinoma of the rete testis, chlamydia, choriocarcinoma, compound to the polypeptide indicates that the candidate choristomas, chronic fibrosing epididymoorchitis, coxsackie compound may be useful for the treatment of a disease or virus B, cryptorchidism, cystic dysplasia of the rete testis, disorder of the testes. cytomegalovirus, dystopia, E. coli, Echinococcus granulo 0294. In still another aspect, the invention features another sus, ectopic testes, embryonal carcinoma, epididymoorchitis, method for determining whether a candidate compound may Fournier's scrotal gangrene, fungal infection, germ cell apla be useful for the treatment of a disease or disorder of the sia, germ cell neoplasms, gonadal dysgenesis, gonadal stro testes. This method includes (a) providing a GPCR polypep mal neoplasms, granulomatous orchitis, granulosa cell tide substantially identical to a polypeptide listed in Tables 29 tumors, Haemophilus influenzae, HIV, hypergonadism, and 33; (b) contacting the polypeptide with the candidate hypogonadotropic hypogonadism, hypopituitarism, compound; and (c) measuring the half-life of the polypeptide, hypospermatogenesis, hyrocele, idiopathic granulomatous US 2009/0178153 A1 Jul. 9, 2009 32 orchitis, incomplete maturation arrest, infarction, infertility, encoding a GPCR polypeptide substantially identical to a inflammatory diseases, inflammatory lesions, interstitial polypeptide listed in Tables 30 and 33; (b) contacting the (Leydig) cell tumors, Klinfelter's syndrome, latrogenic transgenic non-human mammal with the candidate com lesions, Leydig cell tumors, malaknock outplakia, malignant pound; and (c) measuring biological activity of the GPCR lymphoma, malnutrition, maturation arrest of spermatogen polypeptide in the transgenic non-human mammal, wherein esis, metastatic tumors, mixed germ cell tumors, altered biological activity, relative to that of the transgenic monorchism, mumps orchitis, mycobacteria, Neisseria gon non-human mammal not contacted with the compound, indi orrhoeae, neoplasms, obstruction to outflow of semen, orchi cates that the candidate compound may be useful for the tis, parasitic infection, polyorchidism, radiation, Salmonella, treatment of a disease or disorder of the thymus. sarcoidosis, Schistosoma haematobium, seminoma, Sertoli 0308. In yet another aspect, the invention features a cell tumors, sex cord stromal tumors, sperm granuloma, sper method for determining whether a candidate compound is a matocytic seminoma, Syphilis, teratocarcinoma, teratoma, compound that may be useful for the treatment of a disease or testicular atrophy, testicular neoplasms, testicular torsion, disorder of the thymus. This method includes the steps of (a) Treponema pallidum, tuberculous epididymoorchitis, tumors providing a transgenic non-human mammal (e.g., a mouse) of nonspecific stroma, undescended testes, uropathogens, overexpressing a nucleic acid molecule encoding a GPCR Varicocele, vascular disturbances, vasculitis, viral infection, polypeptide Substantially identical to a polypeptide listed in Wuchereria bancrofti, and yolk sac carcinoma. Tables 30 and 33; (b) contacting the transgenic non-human 0300. In another aspect, the invention features a non-hu mammal with the candidate compound; and (c) measuring man mammal (e.g., a mouse), having a transgene that biological activity of the GPCR polypeptide in the transgenic includes a nucleic acid molecule encoding a GPCR polypep non-human mammal, wherein altered biological activity, tide substantially identical to a polypeptide listed in Table 29. relative to that of the transgenic non-human mammal not 0301 In yet another aspect, the invention features a non contacted with the compound, indicates that the candidate human mammal (e.g., a mouse), having a mutation in a compound may be useful for the treatment of a disease or nucleic acid molecule encoding a GPCR polypeptide sub disorder of the thymus. stantially identical to a polypeptide listed in Table 29. 0309 Instill another aspect, the invention features another 0302) In a related aspect, the invention features a cell from method for determining whether a candidate compound may a non-human mammal having a transgene that includes a be useful for the treatment of a disease or disorder of the nucleic acid molecule encoding a GPCR polypeptide sub thymus. This method includes (a) providing a nucleic acid stantially identical to a polypeptide listed in Table 29. molecule comprising a promoter from a gene encoding a 0303. In another aspect, the invention features a cell from GPCR polypeptide listed in Tables 30 and 33, the promoter a non-human mammal having a mutation in a nucleic acid operably linked to a reporter system; (b) contacting the molecule encoding a GPCR polypeptide substantially identi nucleic acid molecule with the candidate compound; and (c) cal to a polypeptide listed in Table 29. measuring reporter activity, wherein altered reporter activity, 0304. In another aspect, the invention features a method of relative to a nucleic acid molecule not contacted with the preventing or treating a disease of the thymus including intro compound, indicates that the candidate compound may be ducing into a human an expression vector that includes a useful for the treatment of a disease or disorder of the thymus. nucleic acid molecule encoding a GPCR polypeptide sub 0310. In another aspect, the invention features yet another stantially identical to a polypeptide listed in Tables 30 and 33, method for determining whether a candidate compound may operably linked to a promoter. be useful for the treatment of a disease or disorder of the 0305. In still another aspect, the invention features a thymus. This method includes the steps of: (a) providing a method of treating or preventing a disease of the thymus GPCR polypeptide substantially identical to a polypeptide including administering to an animal (e.g., a human) a com listed in Tables 30 and 33; (b) contacting the polypeptide with pound that modulates the biological activity of a GPCR the candidate compound; and (c) measuring interaction of the polypeptide Substantially identical to a polypeptide listed in candidate compound to the polypeptide. Interaction of the Tables 30 and 33. compound to the polypeptide indicates that the candidate 0306 In yet another aspect, the invention features a compound may be useful for the treatment of a disease or method for determining whether a candidate compound is a disorder of the thymus. compound that may be useful for the treatment of a disease or 0311. In still another aspect, the invention features another disorder of the thymus. This method includes the steps of (a) method for determining whether a candidate compound may providing a GPCR polypeptide substantially identical to a be useful for the treatment of a disease or disorder of the polypeptide listed in Tables 30 and 33; (b) contacting the thymus. This method includes (a) providing a GPCR GPCR polypeptide with the candidate compound; and (c) polypeptide Substantially identical to a polypeptide listed in measuring biological activity of the GPCR polypeptide, Tables 30 and 33; (b) contacting the polypeptide with the wherein altered biological activity, relative to that of the candidate compound; and (c) measuring the half-life of the GPCR polypeptide not contacted with the compound, indi polypeptide, wherein an alteration in the half-life of the cates that the candidate compound may be useful for the polypeptide, relative to that of the polypeptide not contacted treatment of a disease or disorder of the thymus. The GPCR with the compound, indicates that the candidate compound polypeptide can be in a cell or in a cell-free assay System. may be useful for the treatment of a disease or disorder of the 0307. In yet another aspect, the invention features a thymus. Preferably the GPCR polypeptide is in a cell or a cell method for determining whether a candidate compound is a free assay system. compound that may be useful for the treatment of a disease or 0312. In another aspect, the invention features a method disorder of the thymus. This method includes the steps of (a) for determining whether a patient has an increased risk for providing a transgenic non-human mammal (e.g., a knock developing a disease or disorder of the thymus. The method out mouse) having a disruption in a nucleic acid molecule includes the step of determining whether the patient has a US 2009/0178153 A1 Jul. 9, 2009 mutation in a gene encoding a polypeptide listed in Tables 30 mic neoplasms, thymitis with diffuse B-cell infiltrations, thy and 33, wherein presence of the mutation indicates that the molipoma, thymoma, true thymic hyperplasia, varicella patient may have an increased risk for developing a disease or Zoster, viral infections, well differentiated thymic carcinoma, disorder of the thymus. and Wiscott-Aldrich syndrome. 0313. In a related aspect, the invention features another 0318. In another aspect, the invention features a non-hu method for determining whether a patient has an increased man mammal (e.g., a mouse), having a transgene that risk for developing a disease or disorder of the thymus. This includes a nucleic acid molecule encoding a GPCR polypep method includes the step of determining whether the patient tide substantially identical to a polypeptide listed in Table 30. has a polymorphism in a gene encoding a polypeptide listed in 0319. In yet another aspect, the invention features a non Tables 30 and 33, wherein presence of the polymorphism human mammal (e.g., a mouse), having a mutation in a indicates that the patient may have an increased risk for nucleic acid molecule encoding a GPCR polypeptide sub developing a disease or disorder of the thymus. stantially identical to a polypeptide listed in Table 30. 0314. In either of these two methods, the mutation or poly 0320 In a related aspect, the invention features a cell from morphism is preferably associated with an alteration (for a non-human mammal having a transgene that includes a example, a decrease) in the biological activity of the polypep nucleic acid molecule encoding a GPCR polypeptide sub tide. stantially identical to a polypeptide listed in Table 30. 0315. In another aspect, the invention features another 0321. In another aspect, the invention features a cell from method for determining whether a patient has an increased a non-human mammal having a mutation in a nucleic acid risk for developing a disease or disorder of the thymus. The molecule encoding a GPCR polypeptide substantially identi method includes measuring biological activity of a GPCR cal to a polypeptide listed in Table 30. polypeptide from the patient that is substantially identical to 0322. In another aspect, the invention features a method of a polypeptide listed in Tables 30 and 33, wherein increased or preventing or treating a disease of the thyroid including intro decreased levels in the GPCR biological activity, relative to ducing into a human an expression vector that includes a normal levels, indicate that the patient may have an increased nucleic acid molecule encoding a GPCR polypeptide sub risk for developing a disease or disorder of the thymus. stantially identical to a polypeptide listed in Tables 31 and 33, 0316. In still another aspect, the invention features yet operably linked to a promoter. another method for determining whether a patient has an 0323. In still another aspect, the invention features a increased risk for developing a disease or disorder of the method of treating or preventing a disease of the thyroid thymus. The method includes the step of measuring the including administering to an animal (e.g., a human) a com patient's expression levels of a polypeptide listed in Tables 30 pound that modulates the biological activity of a GPCR and 33, wherein altered levels in the expression, relative to polypeptide Substantially identical to a polypeptide listed in normal, indicate that the patient has an increased risk for Tables 31 and 33. developing a disease or disorder of the thymus. Preferably, 0324. In yet another aspect, the invention features a the expression levels are determined by measuring levels of method for determining whether a candidate compound is a polypeptide or mRNA. compound that may be useful for the treatment of a disease or 0317 Diseases of the thymus that can be treated or diag disorder of the thyroid. This method includes the steps of (a) nosed using the methods of the invention or for which candi providing a GPCR polypeptide substantially identical to a date therapeutic compounds may be identified include acci polypeptide listed in Tables 31 and 33; (b) contacting the dental involution, acute accidental involution, acute GPCR polypeptide with the candidate compound; and (c) lymphoblastic leukemia of T cell type, agenesis, age-related measuring biological activity of the GPCR polypeptide, involution, anaplastic carcinoma, ataxia telangiectasia, atro wherein altered biological activity, relative to that of the phy, bacterial infections, bacterial mediastinitis, basaloid car GPCR polypeptide not contacted with the compound, indi cinoma, bone marrow transplantation, Bruton's agamma cates that the candidate compound may be useful for the globulinemia, carcinosarcoma, chronic accidental involution, treatment of a disease or disorder of the thyroid. The GPCR clear cell carcinoma, cortical thymoma, cytomegalovirus, polypeptide can be in a cell or in a cell-free assay System. DiGeorge syndrome, dysgenesis, dysplasia with pattern simi 0325 In yet another aspect, the invention features a lar to severe atrophy, dysplasia with pseudoglandular appear method for determining whether a candidate compound is a ance, dysplasia with Stromal conticomedullary differentia compound that may be useful for the treatment of a disease or tion, ectopia, germ cell tumors, Grave's disease, histiocytosis disorder of the thyroid. This method includes the steps of (a) X, HIV. Hodgkin's disease, hyperplasia, infectious mono providing a transgenic non-human mammal (e.g., a knock nucleosis, involution, lymphoblastic lymphoma of T-cell out mouse) having a disruption in a nucleic acid molecule type, lymphoepithelioma-like carcinoma, lymphofollicular encoding a GPCR polypeptide substantially identical to a thymitis, maldescent, malignantlymphomas, malignant thy polypeptide listed in Tables 31 and 33; (b) contacting the moma, measles giant cell pneumonia, medullary thymoma, transgenic non-human mammal with the candidate com mixed (composite) thymoma, mucoepidermoid carcinoma, pound; and (c) measuring biological activity of transgenic myasthenia gravis, neonatal syphilis, neoplasms, Omenn's non-human mammal, wherein altered biological activity, syndrome, predominantly cortical (organoid) thymoma, pri relative to that of the GPCR transgenic non-human mammal mary mediastinal B-cell lymphoma of high-grade malig not contacted with the compound, indicates that the candidate nancy, sarcomatoid carcinoma, seminoma, severe combined compound may be useful for the treatment of a disease or immunodeficiency, short limb dwarfism, simple dysplasia, disorder of the thyroid. small cell carcinoma, small-cell B-cell lymphoma of MALT 0326 In yet another aspect, the invention features a type, squamous cell carcinoma, systemic lupus erythemato method for determining whether a candidate compound is a Sus, teratoma, thymic carcinoid, thymic carcinoma, thymic compound that may be useful for the treatment of a disease or cysts, thymic epithelial cysts, thymic epithelial tumorw, thy disorder of the thyroid. This method includes the steps of (a) US 2009/0178153 A1 Jul. 9, 2009 34 providing a transgenic non-human mammal (e.g., a mouse) 0331. In either of these two methods, the mutation or poly overexpressing a nucleic acid molecule encoding a GPCR morphism is preferably associated with an alteration (for polypeptide Substantially identical to a polypeptide listed in example, a decrease) in the biological activity of the polypep Tables 31 and 33; (b) contacting the transgenic non-human tide. mammal with the candidate compound; and (c) measuring 0332. In another aspect, the invention features another biological activity of the GPCR polypeptide in the transgenic method for determining whether a patient has an increased non-human mammal, wherein altered biological activity, risk for developing a disease or disorder of the thyroid. The relative to that of the transgenic non-human mammal not method includes measuring biological activity of a GPCR contacted with the compound, indicates that the candidate polypeptide from the patient that is substantially identical to compound may be useful for the treatment of a disease or a polypeptide listed in Tables 31 and 33, wherein increased or disorder of the thyroid. decreased levels in the GPCR biological activity, relative to 0327 Instill another aspect, the invention features another normal levels, indicate that the patient may have an increased method for determining whether a candidate compound may risk for developing a disease or disorder of the thyroid. 0333. In still another aspect, the invention features yet be useful for the treatment of a disease or disorder of the another method for determining whether a patient has an thyroid. This method includes (a) providing a nucleic acid increased risk for developing a disease or disorder of the molecule comprising a promoter from a gene encoding a thyroid. The method includes the step of measuring the GPCR polypeptide listed in Tables 31 and 33, the promoter patient's expression levels of a polypeptide listed in Tables 31 operably linked to a reporter system; (b) contacting the and 33, wherein altered levels in the expression, relative to nucleic acid molecule with the candidate compound; and (c) normal, indicate that the patient has an increased risk for measuring reporter activity, wherein altered reporter activity, developing a disease or disorder of the thyroid. Preferably, the relative to a nucleic acid molecule not contacted with the expression levels are determined by measuring levels of compound, indicates that the candidate compound may be polypeptide or mRNA. useful for the treatment of a disease or disorder of the thyroid. 0334 Diseases of the thyroid that can be treated or diag 0328. In another aspect, the invention features yet another nosed using the methods of the invention or for which candi method for determining whether a candidate compound may date therapeutic compounds may be identified include aber be useful for the treatment of a disease or disorder of the rant thyroid glands, accessory thyroid glands, adenoma with thyroid. This method includes the steps of: (a) providing a bizarre nuclei, agenesis, amphicrine variant of medullary car GPCR polypeptide substantially identical to a polypeptide cinoma, anaplastic (undifferentiated) carcinoma, aplasia, listed in Tables 31 and 33; (b) contacting the polypeptide with atrophic thyroiditis, atypical adenoma, autoimmune thyroidi the candidate compound; and (c) measuring interaction of the tis, carcinoma, C-cell hyperplasia, clear cell tumors, clear cell candidate compound to the polypeptide. Interaction of the variant of medullary carcinoma, colloid adenoma, columnar compound to the polypeptide indicates that the candidate variant of papillary carcinoma, congenital hypothyroidism compound may be useful for the treatment of a disease or (cretinism), diffuse nontoxic goiter, diffuse Sclerosing variant disorder of the thyroid. of papillary carcinoma, dyshormonogenic goiter, embryonal 0329 Instill another aspect, the invention features another adenoma, encapsulated variant of papillary carcinome, method for determining whether a candidate compound may endemic cretinism, endemic goiter, enzyme deficiency, fetal be useful for the treatment of a disease or disorder of the adenoma, follicular adenoma, follicular carcinoma, follicular thyroid. This method includes (a) providing a GPCR variant of medullary carcinoma, follicular variant of papillary polypeptide Substantially identical to a polypeptide listed in carcinoma, fungal infection, giant cell variant of medullary Tables 31 and 33; (b) contacting the polypeptide with the carcinoma, goiter induced by antithyroid agents, goitrous candidate compound; and (c) measuring the half-life of the hypothyroidism, Graves disease, Hashimoto's autoimmune polypeptide, wherein an alteration in the half-life of the thyroiditis, Hirthle cell (oncocytic) adenoma, hyalinized tra polypeptide, relative to that of the polypeptide not contacted becular adenoma, hyperthyroidism, hypothyroid cretinism, with the compound, indicates that the candidate compound hypothyroidism, iodine deficiency, juvenile thyroiditis, latro may be useful for the treatment of a disease or disorder of the genic hypothyroidism, lingual thyroid glands, malignant thyroid. Preferably the GPCR polypeptide is in a cell or a cell lymphoma, medullary carcinoma, melanocytic variant of free assay system. medullary carcinoma, mesenchymal tumors, metastatic 0330. In another aspect, the invention features a method tumors, minimally invasive follicular carcinoma, mixed med for determining whether a patient has an increased risk for ullary and follicular carcinoma, mixed medullary and papil developing a disease or disorder of the thyroid. The method lary carcinoma, mucinous carcinoma, mucoepidermoid car includes the step of determining whether the patient has a cinoma, multinodular goiter, myxedema, neoplasms, mutation in a gene encoding a polypeptide listed in Tables 31 neurologic cretinism, nonspecific lymphocytic (simple and 33, wherein presence of the mutation indicates that the chronic) thyroiditis, oncocytic variant of medullary carci patient may have an increased risk for developing a disease or noma, palpation thyroiditis, papillary carcinoma, papillary disorder of the thyroid. In a related aspect, the invention microcarcinoma, papillary variant of medullary carcinoma, features another method for determining whether a patient partial agenesis, pituitary thyrotropic adenoma, poorly differ has an increased risk for developing a disease or disorder of entiated carcinoma, primary hypothyroidism, pseudopapil the thyroid. This method includes the step of determining lary variant of medullary carcinoma, Riedel's thyroiditis, whether the patient has a polymorphism in a gene encoding a Sclerosing mucoepidermoid carcinoma with eosinophilia, polypeptide listed in Tables 31 and 33, wherein presence of silent thyroiditis, simple adenoma, Small cell variant of med the polymorphism indicates that the patient may have an ullary carcinoma, Solitary thyroid nodule, sporadic goiter, increased risk for developing a disease or disorder of the squamous cell carcinoma, squamous variant of medullary thyroid. carcinoma, Subacute throiditis (DeCuervain, granulomatous, US 2009/0178153 A1 Jul. 9, 2009

giant cell thyroiditis), tall cell variant of papillary carcinoma, compound that may be useful for the treatment of a disease or tertiary syphilis, thyroglossal duct cyst, thyroid agenesis, thy disorder of the uterus. This method includes the steps of (a) roid nodules, thyroiditis, thyrotoxicosis, toxic adenoma, toxic providing a transgenic non-human mammal (e.g., a mouse) multinodular goiter, toxic nodular goiter (Plummer's dis overexpressing a nucleic acid molecule encoding a GPCR ease), tuberculosis, tubular variant of medullary carcinoma, polypeptide Substantially identical to a polypeptide listed in and widely invasive follicular carcinoma. Tables 32 and 33; (b) contacting the transgenic non-human 0335. In another aspect, the invention features a non-hu mammal with the candidate compound; and (c) measuring man mammal (e.g., a mouse), having a transgene that biological activity of the GPCR polypeptide in the transgenic includes a nucleic acid molecule encoding a GPCR polypep non-human mammal, wherein altered biological activity, tide substantially identical to a polypeptide listed in Table 31. relative to that of the transgenic non-human mammal not 0336. In yet another aspect, the invention features a non human mammal (e.g., a mouse), having a mutation in a contacted with the compound, indicates that the candidate nucleic acid molecule encoding a GPCR polypeptide sub compound may be useful for the treatment of a disease or stantially identical to a polypeptide listed in Table 31. disorder of the uterus. 0337. In a related aspect, the invention features a cell from 0344 Instill another aspect, the invention features another a non-human mammal having a transgene that includes a method for determining whether a candidate compound may nucleic acid molecule encoding a GPCR polypeptide sub be useful for the treatment of a disease or disorder of the stantially identical to a polypeptide listed in Table 31. uterus. This method includes (a) providing a nucleic acid 0338. In another aspect, the invention features a cell from molecule comprising a promoter from a gene encoding a a non-human mammal having a mutation in a nucleic acid GPCR polypeptide listed in Tables 32 and 33, the promoter molecule encoding a GPCR polypeptide substantially identi operably linked to a reporter system; (b) contacting the cal to a polypeptide listed in Table 31. nucleic acid molecule with the candidate compound; and (c) 0339. In another aspect, the invention features a method of measuring reporter activity, wherein altered reporter activity, preventing or treating a disease of the uterus including intro relative to a nucleic acid molecule not contacted with the ducing into a human an expression vector that includes a compound, indicates that the candidate compound may be nucleic acid molecule encoding a GPCR polypeptide sub useful for the treatment of a disease or disorder of the uterus. stantially identical to a polypeptide listed in Tables 32 and 33, 0345. In another aspect, the invention features yet another operably linked to a promoter. method for determining whether a candidate compound may 0340. In still another aspect, the invention features a be useful for the treatment of a disease or disorder of the method of treating or preventing a disease of the uterus uterus. This method includes the steps of: (a) providing a including administering to an animal (e.g., a human) a com GPCR polypeptide substantially identical to a polypeptide pound that modulates the biological activity of a GPCR listed in Tables 32 and 33; (b) contacting the polypeptide with polypeptide Substantially identical to a polypeptide listed in the candidate compound; and (c) measuring interaction of the Tables 32 and 33. candidate compound to the polypeptide. Interaction of the 0341. In yet another aspect, the invention features a compound to the polypeptide indicates that the candidate method for determining whether a candidate compound is a compound may be useful for the treatment of a disease or compound that may be useful for the treatment of a disease or disorder of the uterus. disorder of the uterus. This method includes the steps of (a) 0346. In still another aspect, the invention features another providing a GPCR polypeptide substantially identical to a method for determining whether a candidate compound may polypeptide listed in Tables 32 and 33; (b) contacting the be useful for the treatment of a disease or disorder of the GPCR polypeptide with the candidate compound; and (c) uterus. This method includes (a) providing a GPCR polypep measuring biological activity of the GPCR polypeptide, tide substantially identical to a polypeptide listed in Tables 32 wherein altered biological activity, relative to that of the and 33; (b) contacting the polypeptide with the candidate GPCR polypeptide not contacted with the compound, indi compound; and (c) measuring the half-life of the polypeptide, cates that the candidate compound may be useful for the wherein an alteration in the half-life of the polypeptide, rela treatment of a disease or disorder of the uterus. The GPCR tive to that of the polypeptide not contacted with the com polypeptide can be in a cell or in a cell-free assay System. pound, indicates that the candidate compound may be useful 0342. In yet another aspect, the invention features a for the treatment of a disease or disorder of the uterus. Pref method for determining whether a candidate compound is a erably the GPCR polypeptide is in a cell or a cell free assay compound that may be useful for the treatment of a disease or system. disorder of the uterus. This method includes the steps of (a) 0347 In another aspect, the invention features a method providing a transgenic non-human mammal (e.g., a knock for determining whether a patient has an increased risk for out mouse) having a disruption in a nucleic acid molecule developing a disease or disorder of the uterus. The method encoding a GPCR polypeptide substantially identical to a includes the step of determining whether the patient has a polypeptide listed in Tables 32 and 33; (b) contacting trans mutation in a gene encoding a polypeptide listed in Tables 32 genic non-human mammal with the candidate compound; and 33, wherein presence of the mutation indicates that the and (c) measuring biological activity of the GPCR transgenic patient may have an increased risk for developing a disease or non-human mammal, wherein altered biological activity, disorder of the uterus. relative to that of the transgenic non-human mammal not 0348. In a related aspect, the invention features another contacted with the compound, indicates that the candidate method for determining whether a patient has an increased compound may be useful for the treatment of a disease or risk for developing a disease or disorder of the uterus. This disorder of the uterus. method includes the step of determining whether the patient 0343. In yet another aspect, the invention features a has a polymorphism in a gene encoding a polypeptide listed in method for determining whether a candidate compound is a Tables 32 and 33, wherein presence of the polymorphism US 2009/0178153 A1 Jul. 9, 2009 36 indicates that the patient may have an increased risk for plasia, neoplasms of the cervix, neoplasms of the developing a disease or disorder of the uterus. endometrium, neoplasms of the myometrium, normeoplastic 0349. In either of these two methods, the mutation or poly cervical proliferations, papillary synctial metaplasia, papil morphism is preferably associated with an alteration (for loma, pelvic inflammatory disease, peritoneal leiomyomato example, a decrease) in the biological activity of the polypep sis, persistent luteal phase, postmenopausal bleeding, serous tide. papillary adenocarcinoma, simple hyperplasia with atypia, 0350. In another aspect, the invention features another simple hyperplasia without atypia, spontaneous abortion, method for determining whether a patient has an increased Squamous carcinoma, Squamous cell neoplasia, squamous risk for developing a disease or disorder of the uterus. The intraepithelial lesions, squamous metaplasia, squamous method includes measuring biological activity of a GPCR metaplasia (acanthosis), Stromal sarcoma, tuberculous polypeptide from the patient that is substantially identical to endometritis, unopposed estrogen effect, uterine leiomyo a polypeptide listed in Tables -32 and 33, wherein increased mata, Verrucou carcinoma, Vestigial and heterotopic struc or decreased levels in the GPCR biological activity, relative to tures, villoglandular papillary adenocarcinoma, and viral normal levels, indicate that the patient may have an increased endometritis. risk for developing a disease or disorder of the uterus. 0353. In another aspect, the invention features a non-hu 0351. In still another aspect, the invention features yet man mammal (e.g., a mouse), having a transgene that another method for determining whether a patient has an includes a nucleic acid molecule encoding a GPCR polypep increased risk for developing a disease or disorder of the tide substantially identical to a polypeptide listed in Table 32. uterus. The method includes the step of measuring the 0354. In yet another aspect, the invention features a non patient's expression levels of a polypeptide listed in Tables 32 human mammal (e.g., a mouse), having a mutation in a and 33, wherein altered levels in the expression, relative to nucleic acid molecule encoding a GPCR polypeptide sub normal, indicate that the patient has an increased risk for stantially identical to a polypeptide listed in Table 32. developing a disease or disorder of the uterus. Preferably, the 0355. In a related aspect, the invention features a cell from expression levels are determined by measuring levels of a non-human mammal having a transgene that includes a polypeptide or mRNA. nucleic acid molecule encoding a GPCR polypeptide sub 0352 Diseases of the uterus that can be treated or diag stantially identical to a polypeptide listed in Table 32. nosed using the methods of the invention or for which candi 0356. In another aspect, the invention features a cell from date therapeutic compounds may be identified include acute a non-human mammal having a mutation in a nucleic acid cervicitis, acute endometritis, adenocanthoma, adenocarci molecule encoding a GPCR polypeptide substantially identi noma, adenocarcinoma in situ, adenoid cystic carcinoma, cal to a polypeptide listed in Table 32. adenomatoid tumor, adenomyoma, adenomyosis (en 0357. In another aspect, the invention features a method of dometriosis interna), adenosquamous carcinoma, amebiasis, preventing or treating a disease of the pancreas including arias-Stella phenomenon, atrophy of the endometrium, atypi introducing into a human an expression vector that includes a cal hyperplasia, benign polypoid lesions, benign stromal nod nucleic acid molecule encoding a GPCR polypeptide sub ule, carcinoid tumors, carcinoma in situ, cervical intraepithe stantially identical to a polypeptide listed in Table 1 operably lial neoplasia, chlamydia, chronic cerviciitis, chronic linked to a promoter. nonspecific endometritis, ciliated (tubal) metaplasia, clear 0358. In still another aspect, the invention features a cell adenocarcinoma, clear cell carcinoma, clear cell meta method of treating or preventing a disease of the pancreas plasia, complex hyperplasia with atypia, complex hyperpla including administering to an animal (e.g., a human) a com sia without atypia, condyloma aduminatum, congenital pound that modulates the biological activity of a GPCR abnormalities, corpus cancer syndrome, cystic hyperplasia, polypeptide Substantially identical to a polypeptide listed in dysfunctional uterine bleeding, dysmenorrhea, dysplasia of Table 1. the cervix (cervical intraepithelial neoplasia, squamous 0359. In yet another aspect, the invention features a intraepithelial lesion), endocervical adenocarcinoma, method for determining whether a candidate compound is a endocervical polyp, endolymphatic stromal myosis, endome compound that may be useful for the treatment of a disease or trial adenocarcinoma, endometrial carcinoma, endometrial disorder of the pancreas. This method includes the steps of (a) hyperplasia, endometrial polyps, endometrial stromal neo providing a GPCR polypeptide substantially identical to a plasms, endometriosis, endometritis, endometroid (pure) polypeptide listed in Table 1; (b) contacting the GPCR adenocarcinoma of the endometrium, endometroid adenocar polypeptide with the candidate compound; and (c) measuring cinoma with squamous differentiation, eosinophilic metapla biological activity of the GPCR polypeptide, wherein altered sia, epimenorrhea, exogenous progestational hormone effect, biological activity, relative to that of the GPCR polypeptide extrauterine endometriosis (endometriosis externia), gesta not contacted with the compound, indicates that the candidate tional trophoplastic disease, gonorrhea, hemangioma, herpes compound may be useful for the treatment of a disease or simplex virus type 2, high-grade squamous intraepithelial disorder of the pancreas. The GPCR polypeptide can be in a lesion, human papillomavirus, hyperplasia, inadequate luteal cell or in a cell-free assay system. phase, infertility, inflammatory cervical lesions, inflamma 0360. In yet another aspect, the invention features a tory lesions of the endometrium, intravenous leiomyomato method for determining whether a candidate compound is a sis, invasive carcinoma of cervix, invasive squamous cell compound that may be useful for the treatment of a disease or carcinoma, leiomyoma, leiomyosarcoma, lipoma, low-grade disorder of the pancreas. This method includes the steps of (a) squamous intraepithelial lesion, malignant mixed mesoder providing a transgenic non-human mammal (e.g., a knock mal (Millerian) tumor, menorrhagia, metaplasia, metastasiz out mouse) having a disruption in a nucleic acid molecule ing leiomyoma, metastatic carcinoma, microglandular hyper encoding a GPCR polypeptide substantially identical to a plasia, microinvasive carcinoma, microinvasive squamous polypeptide listed in Table 1; (b) contacting the transgenic cell carcinoma, mucinous adenocarcinoma, mucinous meta non-human mammal with the candidate compound; and (c) US 2009/0178153 A1 Jul. 9, 2009 37 measuring biological activity of the GPCR polypeptide in the wherein presence of the mutation indicates that the patient transgenic non-human mammal, wherein altered biological has an increased risk for developing a disease or disorder of activity, relative to that of the transgenic non-human mammal the pancreas. not contacted with the compound, indicates that the candidate 0366. In a related aspect, the invention features another compound may be useful for the treatment of a disease or method for determining whether a patient has an increased disorder of the pancreas. risk for developing a disease or disorder of the pancreas. This method includes the step of determining whether the patient 0361. In yet another aspect, the invention features a has a polymorphism in a gene encoding a polypeptide listed in method for determining whether a candidate compound is a Table 1, wherein presence of the polymorphism indicates that compound that may be useful for the treatment of a disease or the patient may have an increased risk for developing a dis disorder of the pancreas. This method includes the steps of (a) ease or disorder of the pancreas. providing a transgenic non-human mammal (e.g., a mouse) 0367. In either of these two methods, the mutation or poly overexpressing a nucleic acid molecule encoding a GPCR morphism is preferably associated with an alteration (for polypeptide Substantially identical to a polypeptide listed in example, a decrease) in the biological activity of the polypep any one of Table 1; (b) contacting the transgenic non-human tide. mammal with the candidate compound; and (c) measuring 0368. In another aspect, the invention features another biological activity of the GPCR polypeptide in the transgenic method for determining whether a patient has an increased non-human mammal, wherein altered biological activity, risk for developing a disease or disorder of the pancreas. The relative to that of the transgenic non-human mammal not method includes measuring biological activity of a GPCR contacted with the compound, indicates that the candidate polypeptide from the patient that is substantially identical to compound may be useful for the treatment of a disease or a polypeptide listed in Table 1, wherein increased or disorder of the pancreas. decreased levels in the GPCR biological activity, relative to 0362. In still another aspect, the invention features another normal levels, indicates that the patient has an increased risk method for determining whether a candidate compound may for developing a disease or disorder of the pancreas. be useful for the treatment of a disease or disorder of the 0369. In still another aspect, the invention features yet pancreas. This method includes (a) providing a nucleic acid another method for determining whether a patient has an molecule comprising a promoter from a gene encoding a increased risk for developing a disease or disorder of the GPCR polypeptide listed in Table 1, the promoter operably pancreas. The method includes the step of measuring the linked to a reporter system; (b) contacting the nucleic acid patient’s expression levels of a polypeptide listed in Table 1, wherein altered levels in the expression, relative to normal, molecule with the candidate compound; and (c) measuring indicate that the patient has an increased risk for developing a reporter activity, wherein altered reporter activity, relative to disease or disorder of the pancreas. Preferably, the expression a nucleic acid molecule not contacted with the compound, levels are determined by measuring levels of polypeptide or indicates that the candidate compound may be useful for the mRNA. treatment of a disease or disorder of the pancreas. 0370 Diseases of the pancreas that can be treated or diag 0363. In another aspect, the invention features yet another nosed using the methods of the invention or for which candi method for determining whether a candidate compound may date therapeutic compounds may be identified include be useful for the treatment of a disease or disorder of the ACTHoma, acute pancreatitis, adult onset diabetes, annulare pancreas. This method includes the steps of: (a) providing a pancreas, carcinoid syndrome, carcinoid tumors, carcinoma GPCR polypeptide substantially identical to a polypeptide of the pancreas, chronic pancreatitis, congenital cysts, Cush listed in Table 1; (b) contacting the polypeptide with the ing's syndrome, cystadenocarcinoma, cystic fibrosis (muco candidate compound; and (c) measuring interaction of the viscidosis, fibrocystic disease), diabetes mellitus, ectopic candidate compound to the polypeptide. Interaction of the pancreatic tissue, gastinoma, gastrin excess, glucagon excess, compound to the polypeptide indicates that the candidate glucagonomas, GRFomas, hereditary pancreatitis, hyperin compound may be useful for the treatment of a disease or Sulinism, impaired insulin release, infected pancreatic necro disorder of the pancreas. sis, insulin resistance, insulinomas, islet cell hyperplasia, islet 0364. In still another aspect, the invention features another cell neoplasms, juvenile onset diabetes, macroamylasemia, method for determining whether a candidate compound may maldevelopment of the pancreas, maturity-onset diabetes of be useful for the treatment of a disease or disorder of the the young, metastatic neoplasms, mucinous cystadenoma, pancreas. This method includes (a) providing a GPCR neoplastic cysts, nonfunctional pancreatic endocrine tumors, polypeptide Substantially identical to a polypeptide listed in pancreas divisum, pancreatic abcess, pancreatic cancer, pan Table 1; (b) contacting the polypeptide with the candidate creatic cholera, pancreatic cysts, pancreatic endocrine tumor compound; and (c) measuring the half-life of the polypeptide, causing carcinoid syndrome, pancreatic endocrine tumor wherein an alteration in the half-life of the polypeptide, rela causing hypercalcemia, pancreatic endocrine tumors, pancre tive to that of the polypeptide not contacted with the com atic exocrine insufficiency, pancreatic pleural effusion, pan pound, indicates that the candidate compound may be useful creatic polypeptide excess, pancreatic pseudocyst, pancreatic for the treatment of a disease or disorder of the pancreas. trauma, pancreatogenous ascites, serous cystadenoma, Preferably the GPCR polypeptide is in a cell or a cell free Shwachman’s syndrome, somatostatin excess. Somatostati assay system. noma syndrome, traumatic pancreatitis, type 1 (insulin-de 0365. In another aspect, the invention features a method pendent) diabetes, type 2 (non-insulin-dependent) diabetes, for determining whether a patient has an increased risk for vasoactive intestinal polypeptide excess, VIPomas, developing a disease or disorder of the pancreas. The method Zollinger-Ellison syndrome. includes the step of determining whether the patient has a 0371. In another aspect, the invention features a non-hu mutation in a gene encoding a polypeptide listed in Table 1, man mammal (e.g., a mouse), having a transgene that US 2009/0178153 A1 Jul. 9, 2009 includes a nucleic acid molecule encoding a GPCR polypep measuring biological activity of the GPCR polypeptide in the tide substantially identical to a polypeptide listed in Table 1. transgenic non-human mammal, wherein altered biological 0372. In yet another aspect, the invention features a non activity, relative to that of the transgenic non-human mammal human mammal (e.g., a mouse), having a mutation in a not contacted with the compound, indicates that the candidate nucleic acid molecule encoding a GPCR polypeptide sub compound may be useful for the treatment of a disease or stantially identical to a polypeptide listed in Table 1. disorder of the bone and joints. 0373) In a related aspect, the invention features a cell from 0380 Instill another aspect, the invention features another a non-human mammal having a transgene that includes a method for determining whether a candidate compound may nucleic acid molecule encoding a GPCR polypeptide sub be useful for the treatment of a disease or disorder of the bone stantially identical to a polypeptide listed in Table 1. and joints. This method includes (a) providing a nucleic acid 0374. In another aspect, the invention features a cell from molecule comprising a promoter from a gene encoding a a non-human mammal having a mutation in a nucleic acid GPCR polypeptide listed in Table 1, the promoter operably molecule encoding a GPCR polypeptide substantially identi linked to a reporter system; (b) contacting the nucleic acid cal to a polypeptide listed in Table 1. molecule with the candidate compound; and (c) measuring 0375. In another aspect, the invention features a method of reporter activity, wherein altered reporter activity, relative to preventing or treating a disease of the bone and joints includ a nucleic acid molecule not contacted with the compound, ing introducing into a human an expression vector that indicates that the candidate compound may be useful for the includes a nucleic acid molecule encoding a GPCR polypep treatment of a disease or disorder of the bone and joints. tide substantially identical to a polypeptide listed in Table 1 0381. In another aspect, the invention features yet another operably linked to a promoter. method for determining whether a candidate compound may 0376. In still another aspect, the invention features a be useful for the treatment of a disease or disorder of the bone method of treating or preventing a disease of the bone and and joints. This method includes the steps of: (a) providing a joints including administering to an animal (e.g., a human) a GPCR polypeptide substantially identical to a polypeptide compound that modulates the biological activity of a GPCR listed in Table 1; (b) contacting the polypeptide with the polypeptide Substantially identical to a polypeptide listed in candidate compound; and (c) measuring interaction of the Table 1. candidate compound to the polypeptide. Interaction of the 0377. In yet another aspect, the invention features a compound to the polypeptide indicates that the candidate method for determining whether a candidate compound is a compound may be useful for the treatment of a disease or compound that may be useful for the treatment of a disease or disorder of the bone and joints. disorder of the bone and joints. This method includes the 0382 Instill another aspect, the invention features another steps of (a) providing a GPCR polypeptide substantially iden method for determining whether a candidate compound may tical to a polypeptide listed in Table 1; (b) contacting the be useful for the treatment of a disease or disorder of the bone GPCR polypeptide with the candidate compound; and (c) and joints. This method includes (a) providing a GPCR measuring biological activity of the GPCR polypeptide, polypeptide Substantially identical to a polypeptide listed in wherein altered biological activity, relative to that of the Table 1; (b) contacting the polypeptide with the candidate GPCR polypeptide not contacted with the compound, indi compound; and (c) measuring the half-life of the polypeptide, cates that the candidate compound may be useful for the wherein an alteration in the half-life of the polypeptide, rela treatment of a disease or disorder of the bone and joints. The tive to that of the polypeptide not contacted with the com GPCR polypeptide can be in a cell or in a cell-free assay pound, indicates that the candidate compound may be useful system. for the treatment of a disease or disorder of the bone and 0378. In yet another aspect, the invention features a joints. Preferably the GPCR polypeptide is in a cell or a cell method for determining whether a candidate compound is a free assay system. compound that may be useful for the treatment of a disease or 0383. In another aspect, the invention features a method disorder of the bone and joints. This method includes the for determining whether a patient has an increased risk for steps of (a) providing a transgenic non-human mammal (e.g., developing a disease or disorder of the bone and joints. The a knock-out mouse) having a disruption in a nucleic acid method includes the step of determining whether the patient molecule encoding a GPCR polypeptide substantially identi has a mutation in a gene encoding a polypeptide listed in cal to a polypeptide listed in Table 1; (b) contacting the Table 1, wherein presence of the mutation indicates that the transgenic non-human mammal with the candidate com patient has an increased risk for developing a disease or pound; and (c) measuring biological activity of the GPCR disorder of the bone and joints. polypeptide in the transgenic non-human mammal, wherein 0384. In a related aspect, the invention features another altered biological activity, relative to that of the transgenic method for determining whether a patient has an increased non-human mammal not contacted with the compound, indi risk for developing a disease or disorder of the bone and cates that the candidate compound may be useful for the joints. This method includes the step of determining whether treatment of a disease or disorder of the bone and joints. the patient has a polymorphism in a gene encoding a polypep 0379. In yet another aspect, the invention features a tide listed in Table 1, wherein presence of the polymorphism method for determining whether a candidate compound is a indicates that the patient may have an increased risk for compound that may be useful for the treatment of a disease or developing a disease or disorder of the bone and joints. disorder of the bone and joints. This method includes the 0385. In either of these two methods, the mutation or poly steps of (a) providing a transgenic non-human mammal (e.g., morphism is preferably associated with an alteration (for a mouse) overexpressing a nucleic acid molecule encoding a example, a decrease) in the biological activity of the polypep GPCR polypeptide substantially identical to a polypeptide tide. listed in any one of Table 1; (b) contacting the transgenic 0386. In another aspect, the invention features another non-human mammal with the candidate compound; and (c) method for determining whether a patient has an increased US 2009/0178153 A1 Jul. 9, 2009 39 risk for developing a disease or disorder of the bone and ducing into a human an expression vector that includes a joints. The method includes measuring biological activity of nucleic acid molecule encoding a GPCR polypeptide sub a GPCR polypeptide from the patient that is substantially stantially identical to a polypeptide listed in Table 1 operably identical to a polypeptide listed in Table 1, wherein increased linked to a promoter. or decreased levels in the GPCR biological activity, relative to 0390. In still another aspect, the invention features a normal levels, indicates that the patient has an increased risk method of treating or preventing a disease of the breast for developing a disease or disorder of the bone and joints. including administering to an animal (e.g., a human) a com 0387. In still another aspect, the invention features yet pound that modulates the biological activity of a GPCR another method for determining whether a patient has an polypeptide Substantially identical to a polypeptide listed in increased risk for developing a disease or disorder of the bone and joints. The method includes the step of measuring the Table 1. patient's expression levels of a polypeptide listed in Table 1, 0391. In yet another aspect, the invention features a wherein altered levels in the expression, relative to normal, method for determining whether a candidate compound is a indicate that the patient has an increased risk for developing a compound that may be useful for the treatment of a disease or disease or disorder of the bone and joints. Preferably, the disorder of the breast. This method includes the steps of (a) expression levels are determined by measuring levels of providing a GPCR polypeptide substantially identical to a polypeptide or mRNA. polypeptide listed in Table 1; (b) contacting the GPCR 0388 Diseases of the bone and joints that can be treated or polypeptide with the candidate compound; and (c) measuring diagnosed using the methods of the invention or for which biological activity of the GPCR polypeptide, wherein altered candidate therapeutic compounds may be identified include biological activity, relative to that of the GPCR polypeptide achondroplasia, acute bacterial arthritis, acute pyogenic not contacted with the compound, indicates that the candidate osteomyelitis, Albright's syndrome, alkaptonuria (ochrono compound may be useful for the treatment of a disease or sis), aneurysmal bone cyst, ankylosing spondylitis, arthritic, disorder of the breast. The GPCR polypeptide can be in a cell arthropathies associated with hemoglobinopathies, arthropa or in a cell-free assay system. thy of acromegaly, arthropathy of hemochromatosis, bone 0392. In yet another aspect, the invention features a cysts, calcium hydroxyapatite deposition disease, calcium method for determining whether a candidate compound is a pyrophosphate deposition disease, chondrocalcinosis, chon compound that may be useful for the treatment of a disease or droma, chondrosarcoma, choStochondritis, chrondromblas disorder of the breast. This method includes the steps of (a) toma, congenital dislocation of the hip, congenital disorders providing a transgenic non-human mammal (e.g., a knock of joints, echondromatosis (dyschondroplasia, Ollier's dis out mouse) having a disruption in a nucleic acid molecule ease), erosive osteoarthritis, Ewing's sarcoma, Felty's Syn encoding a GPCR polypeptide substantially identical to a drome, fibromyalgia, fibrous cortical defect, fibrous dyspla polypeptide listed in Table 1; (b) contacting the transgenic sia (McCune-Albright syndrome, fungal arthritis, ganglion, non-human mammal with the candidate compound; and (c) giant cell tumor, gout, hematogenous osteomyelitis, hemo measuring biological activity of the GPCR polypeptide in the philic arthropathy, hereditary hyperphosphatasia, hyperosto transgenic non-human mammal, wherein altered biological sis, hyperostosis frontalis interna, hyperparathyroidism (os activity, relative to that of the transgenic non-human mammal teitis fibrosa cystica), hypertrophic osteoarthropathy, not contacted with the compound, indicates that the candidate infections diseases of joints, juvenile rheumatoid arthritis compound may be useful for the treatment of a disease or (Still's disease), lyme disease, lymphoid neoplasms, disorder of the breast. melorheostosis, metabolic diseases of joints, metastatic car 0393. In yet another aspect, the invention features a cinoma, metastatic neoplasms, monostatic fibrous dysplasia, method for determining whether a candidate compound is a multiple exostoses (diaphyseal aclasis, osteochondromato compound that may be useful for the treatment of a disease or sis), neoplasms, neuropathic joint (Charcot's joint), osteoar disorder of the breast. This method includes the steps of (a) thritis, osteoarthrosis, osteoblastoma, osteochondroma (ex providing a transgenic non-human mammal (e.g., a mouse) ostosis), osteogenesis imperfecta (brittle bone disease), overexpressing a nucleic acid molecule encoding a GPCR osteoid osteoma, osteoma, osteomalacia, osteomyelitis, polypeptide Substantially identical to a polypeptide listed in osteomyelosclerosis, osteopetrosis (marbel bone disease, any one of Table 1; (b) contacting the transgenic non-human Albers-Schönberg disease), osteopoikilosis, osteoporosis mammal with the candidate compound; and (c) measuring (osteopenia), osteosarcoma, osteosclerosis, Paget's disease biological activity of the GPCR polypeptide in the transgenic of bone (osteitis deformans), parasitic arthritis, parosteal non-human mammal, wherein altered biological activity, osteosarcome, pigmented villonodular synovitis, polyostotic relative to that of the transgenic non-human mammal not fibrous dysplasia, postinfectious or reactive arthritis, progres contacted with the compound, indicates that the candidate sive diaphyseal dysplasia (Camurati-Engelmann disease), compound may be useful for the treatment of a disease or pseudogout, psoriatic arthritis, pyknodysostosis, pyogenic disorder of the breast. arthritis, reflex sympathetic dystrophy syndrome, relapsing 0394 Instill another aspect, the invention features another polychondritis, rheumatoid arthritis, rickets, senile method for determining whether a candidate compound may osteoporosis, sickle cell disease, spondyloepiphyseal dyspla be useful for the treatment of a disease or disorder of the sia, synovial chondromatosis, synovial sarcoma, syphilitic breast. This method includes (a) providing a nucleic acid arthritis, talipes calcaneovalgus, talipes equinovarus, thalas molecule comprising a promoter from a gene encoding a semia, Tietze's syndrome, tuberculosis of bone, tuberculous GPCR polypeptide listed in Table 1, the promoter operably arthritis, unicameral bone cyst (Solitary bone cyst), viral linked to a reporter system; (b) contacting the nucleic acid arthritis. molecule with the candidate compound; and (c) measuring 0389. In another aspect, the invention features a method of reporter activity, wherein altered reporter activity, relative to preventing or treating a disease of the breast including intro a nucleic acid molecule not contacted with the compound, US 2009/0178153 A1 Jul. 9, 2009 40 indicates that the candidate compound may be useful for the 04.02 Diseases of the breast that can be treated or diag treatment of a disease or disorder of the breast. nosed using the methods of the invention or for which candi 0395. In another aspect, the invention features yet another date therapeutic compounds may be identified include acute method for determining whether a candidate compound may mastitis, breast abcess, carcinoma, chronic mastitis, congeni be useful for the treatment of a disease or disorder of the tal breast anomalies, cystic mastopathy, ductal carcinoma, breast. This method includes the steps of: (a) providing a ductal carcinoma in situ, ductal papilloma, fat necrosis, GPCR polypeptide substantially identical to a polypeptide fibroadenoma, fibrocystic changes, fibrocystic disease, galac listed in Table 1; (b) contacting the polypeptide with the torrhea, granular cell tumor, gynecomastia, infiltrating ductal candidate compound; and (c) measuring interaction of the carcinoma, inflammatory breast carcinoma, inflammatory candidate compound to the polypeptide. Interaction of the breast lesions, invasive lobular carcinoma, juvenile hypertro compound to the polypeptide indicates that the candidate phy of the breast, lactating adenoma, lobular carcinoma in compound may be useful for the treatment of a disease or situ, neoplasms, Paget’s disease of the nipple, phyllodes disorder of the breast. tumor (cystosarcome phyllodes), polymastia, polymazia, 0396. In still another aspect, the invention features another polythelia, silicone granuloma, Supernumerary breast, and method for determining whether a candidate compound may Supernumerary nipples. be useful for the treatment of a disease or disorder of the 0403. In another aspect, the invention features a method of breast. This method includes (a) providing a GPCR polypep preventing or treating a disease of the immune system includ tide substantially identical to a polypeptide listed in Table 1: ing introducing into a human an expression vector that (b) contacting the polypeptide with the candidate compound; includes a nucleic acid molecule encoding a GPCR polypep and (c) measuring the half-life of the polypeptide, wherein an tide substantially identical to a polypeptide listed in Table 1 alteration in the half-life of the polypeptide, relative to that of operably linked to a promoter. the polypeptide not contacted with the compound, indicates 04.04. In still another aspect, the invention features a that the candidate compound may be useful for the treatment method of treating or preventing a disease of the immune of a disease or disorder of the breast. Preferably the GPCR system including administering to an animal (e.g., a human) polypeptide is in a cell or a cell free assay system. a compound that modulates the biological activity of a GPCR 0397. In another aspect, the invention features a method polypeptide Substantially identical to a polypeptide listed in for determining whether a patient has an increased risk for Table 1. developing a disease or disorder of the breast. The method 0405. In yet another aspect, the invention features a includes the step of determining whether the patient has a method for determining whether a candidate compound is a mutation in a gene encoding a polypeptide listed in Table 1, compound that may be useful for the treatment of a disease or wherein presence of the mutation indicates that the patient disorder of the immune system. This method includes the has an increased risk for developing a disease or disorder of steps of (a) providing a GPCR polypeptide substantially iden the breast. tical to a polypeptide listed in Table 1; (b) contacting the 0398. In a related aspect, the invention features another GPCR polypeptide with the candidate compound; and (c) method for determining whether a patient has an increased measuring biological activity of the GPCR polypeptide, risk for developing a disease or disorder of the breast. This wherein altered biological activity, relative to that of the method includes the step of determining whether the patient GPCR polypeptide not contacted with the compound, indi has a polymorphism in a gene encoding a polypeptide listed in cates that the candidate compound may be useful for the Table 1, wherein presence of the polymorphism indicates that treatment of a disease or disorder of the immune system. The the patient may have an increased risk for developing a dis GPCR polypeptide can be in a cell or in a cell-free assay ease or disorder of the breast. system. 0399. In either of these two methods, the mutation or poly 0406. In yet another aspect, the invention features a morphism is preferably associated with an alteration (for method for determining whether a candidate compound is a example, a decrease) in the biological activity of the polypep compound that may be useful for the treatment of a disease or tide. disorder of the immune system. This method includes the 0400. In another aspect, the invention features another steps of (a) providing a transgenic non-human mammal (e.g., method for determining whether a patient has an increased a knock-out mouse) having a disruption in a nucleic acid risk for developing a disease or disorder of the breast. The molecule encoding a GPCR polypeptide substantially identi method includes measuring biological activity of a GPCR cal to a polypeptide listed in Table 1; (b) contacting the polypeptide from the patient that is substantially identical to transgenic non-human mammal with the candidate com a polypeptide listed in Table 1, wherein increased or pound; and (c) measuring biological activity of the GPCR decreased levels in the GPCR biological activity, relative to polypeptide in the transgenic non-human mammal, wherein normal levels, indicates that the patient has an increased risk altered biological activity, relative to that of the transgenic for developing a disease or disorder of the breast. non-human mammal not contacted with the compound, indi 04.01. In still another aspect, the invention features yet cates that the candidate compound may be useful for the another method for determining whether a patient has an treatment of a disease or disorder of the immune system. increased risk for developing a disease or disorder of the 0407. In yet another aspect, the invention features a breast. The method includes the step of measuring the method for determining whether a candidate compound is a patient's expression levels of a polypeptide listed in Table 1, compound that may be useful for the treatment of a disease or wherein altered levels in the expression, relative to normal, disorder of the immune system. This method includes the indicate that the patient has an increased risk for developing a steps of (a) providing a transgenic non-human mammal (e.g., disease or disorder of the breast. Preferably, the expression a mouse) overexpressing a nucleic acid molecule encoding a levels are determined by measuring levels of polypeptide or GPCR polypeptide substantially identical to a polypeptide mRNA. listed in any one of Table 1; (b) contacting the transgenic US 2009/0178153 A1 Jul. 9, 2009

non-human mammal with the candidate compound; and (c) 0414. In another aspect, the invention features another measuring biological activity of the GPCR polypeptide in the method for determining whether a patient has an increased transgenic non-human mammal, wherein altered biological risk for developing a disease or disorder of the immune sys activity, relative to that of the transgenic non-human mammal tem. The method includes measuring biological activity of a not contacted with the compound, indicates that the candidate GPCR polypeptide from the patient that is substantially iden compound may be useful for the treatment of a disease or tical to a polypeptide listed in Table 1, wherein increased or disorder of the immune system. decreased levels in the GPCR biological activity, relative to 0408. In still another aspect, the invention features another normal levels, indicates that the patient has an increased risk method for determining whether a candidate compound may for developing a disease or disorder of the immune system. be useful for the treatment of a disease or disorder of the 0415. In still another aspect, the invention features yet immune system. This method includes (a) providing a nucleic another method for determining whether a patient has an acid molecule comprising a promoter from a gene encoding a increased risk for developing a disease or disorder of the GPCR polypeptide listed in Table 1, the promoter operably immune system. The method includes the step of measuring linked to a reporter system; (b) contacting the nucleic acid the patient's expression levels of a polypeptide listed in Table molecule with the candidate compound; and (c) measuring 1, wherein altered levels in the expression, relative to normal, reporter activity, wherein altered reporter activity, relative to indicate that the patient has an increased risk for developing a a nucleic acid molecule not contacted with the compound, disease or disorder of the immune system. Preferably, the indicates that the candidate compound may be useful for the expression levels are determined by measuring levels of treatment of a disease or disorder of the immune system. polypeptide or mRNA. 04.09. In another aspect, the invention features yet another 0416 Diseases of the immune system that can be treated method for determining whether a candidate compound may or diagnosed using the methods of the invention or for which be useful for the treatment of a disease or disorder of the candidate therapeutic compounds may be identified include immune system. This method includes the steps of: (a) pro abnormal neutrophil function, acquired immunodeficiency, viding a GPCR polypeptide substantially identical to a acute rejection, Addison's disease, advanced cancer, aging, polypeptide listed in Table 1; (b) contacting the polypeptide allergic rhinitis, angioedema, arthrus-type hypersensitivity with the candidate compound; and (c) measuring interaction reaction, ataxia-telangiectasia, autoimmune disorders, of the candidate compound to the polypeptide. Interaction of autoimmune gastritis, autosomal recessive agammaglobu the compound to the polypeptide indicates that the candidate linemia, blood transfusion reactions, Bloom's syndrome, compound may be useful for the treatment of a disease or Bruton's congenital agammaglobulinemia, bullous pemphig disorder of the immune system. oid, Chédiak-Higashi syndrome, chronic active hepatitis, 0410. In still another aspect, the invention features another chronic granulomatous disease of childhood, chronic rejec method for determining whether a candidate compound may tion, chronic renal failure, common variable immunodefi be useful for the treatment of a disease or disorder of the ciency, complement deficiency, congenital (primary) immu immune system. This method includes (a) providing a GPCR nodeficiency, contact dermatitis, deficiencies of immune polypeptide Substantially identical to a polypeptide listed in response, deficiency of the vascular response, dermatomyo sitis, diabetes mellitus, disorders of microbial killing, disor Table 1; (b) contacting the polypeptide with the candidate ders of phagocytosis, Goodpasture's syndrome, graft rejec compound; and (c) measuring the half-life of the polypeptide, tion, graft-Versus-host disease, granulocyt deficiency, wherein an alteration in the half-life of the polypeptide, rela granulocytic leukemia, Graves disease, Hashimoto's thy tive to that of the polypeptide not contacted with the com roiditis, hemolytic anemia, hemolytic disease of the newborn, pound, indicates that the candidate compound may be useful HIV infection (AIDS), Hodgkin's disease, hyperacute rejec for the treatment of a disease or disorder of the immune tion, hyper-IgE syndrome, hypersensitivity pneumonitis, system. Preferably the GPCR polypeptide is in a cellor a cell hypoparathyroidism, IgA deficiency, IgG subclass deficien free assay system. cies, immunodeficiency with thymoma, immunoglobulin 0411. In another aspect, the invention features a method deficiency syndromes, immunologic hypersensitivity, immu for determining whether a patient has an increased risk for nosuppressive drug therapy, infertility, insulin-resistant dia developing a disease or disorder of the immune system. The betes mellitus, interferony receptor deficiency, interleukin 12 method includes the step of determining whether the patient receptor deficiency, iron deficiency, juvenile insulin-depen has a mutation in a gene encoding a polypeptide listed in dent diabetes mellitus, Kaposi's sarcoma, lazy leuknock out Table 1, wherein presence of the mutation indicates that the cyte syndrom, localized type I hypersensitivity, lymphocytic patient has an increased risk for developing a disease or leukemia, lymphoma, maignant B cell lymphoma, major his disorder of the immune system. tocompatibility complex class 2 deficiency, mixed connective 0412. In a related aspect, the invention features another tissue disease, multiple myeloma, myasthenia gravis, method for determining whether a patient has an increased myeloperoxidase deficiency, neutropenia, nude syndrome, risk for developing a disease or disorder of the immune sys pemphigus Vulgaris, pernicious anemia, postinfectious tem. This method includes the step of determining whether immunodeficiency, primary biliary cirrhosis, primary immu the patient has a polymorphism in a gene encoding a polypep nodeficiency, primary T cell immunodeficiency, progressive tide listed in Table 1, wherein presence of the polymorphism systemic Sclerosis, protein-calorie malnutrition, purine indicates that the patient may have an increased risk for nucleoside phosphorylation deficiency, rheumatic fever, developing a disease or disorder of the immune system. rheumatoid arthritis, secondary immunodeficiency, selective 0413. In either of these two methods, the mutation or poly (isolated) IgA deficiency, serum sickness type hypersensitiv morphism is preferably associated with an alteration (for ity reaction, severe combined immunodeficiency, Sjögren's example, a decrease) in the biological activity of the polypep syndrome, sympathetic ophthalmitis, Systemic lupus erythe tide. matosus, systemic mastocytosis, systemic type 1 hypersensi US 2009/0178153 A1 Jul. 9, 2009 42 tivity, T cell receptro deficiency, T lymphopenia (Nezelof's not contacted with the compound, indicates that the candidate syndrome), thrombocytopenia, thymic hypoplasia (DiGeorge compound may be useful for the treatment of a metabolic or syndrome), thymic neoplasms, thymoma (Goode's Syn nutritive disease or disorder. drome), transient hypogammaglobulinemia of infancy, type 1 0422. In still another aspect, the invention features another (immediate) hypersensitivity (atopy, anaphylaxis), type 2 method for determining whether a candidate compound may hypersensitivity, type 3 hypersensitivity (immune complex be useful for the treatment of a metabolic or nutritive disease injury), type 4 (delayed) hypersensitivity, urticaria, variable or disorder. This method includes (a) providing a nucleic acid immunodeficiency, vitiligo, Wisknock outtt-Aldrich syn molecule comprising a promoter from a gene encoding a drom, X-linked agammaglobulinemia, X-linked immunodefi GPCR polypeptide listed in Table 1, the promoter operably ciency with hyper IgM, X-linked lymphoproliferative syn linked to a reporter system; (b) contacting the nucleic acid drome, Zap70 tyrosine kinase deficiency. molecule with the candidate compound; and (c) measuring 0417. In another aspect, the invention features a method of reporter activity, wherein altered reporter activity, relative to preventing or treating a metabolic or nutritive disease or a nucleic acid molecule not contacted with the compound, disorder, including introducing into a human an expression indicates that the candidate compound may be useful for the vector that includes a nucleic acid molecule encoding a treatment of a metabolic or nutritive disease or disorder. GPCR polypeptide substantially identical to a polypeptide 0423. In another aspect, the invention features yet another listed in Table 1 operably linked to a promoter. method for determining whether a candidate compound may 0418. In still another aspect, the invention features a be useful for the treatment of a metabolic or nutritive disease method of treating or preventing a metabolic or nutritive or disorder. This method includes the steps of: (a) providing a disease or disorder, including administering to an animal GPCR polypeptide substantially identical to a polypeptide (e.g., a human) a compound that modulates the biological listed in Table 1; (b) contacting the polypeptide with the activity of a GPCR polypeptide substantially identical to a candidate compound; and (c) measuring interaction of the polypeptide listed in Table 1. candidate compound to the polypeptide. Interaction of the 0419. In yet another aspect, the invention features a compound to the polypeptide indicates that the candidate method for determining whether a candidate compound is a compound may be useful for the treatment of a metabolic or compound that may be useful for the treatment of a metabolic nutritive disease or disorder. or nutritive disease or disorder. This method includes the 0424. In still another aspect, the invention features another steps of (a) providing a GPCR polypeptide substantially iden method for determining whether a candidate compound may tical to a polypeptide listed in Table 1; (b) contacting the be useful for the treatment of a metabolic or nutritive disease GPCR polypeptide with the candidate compound; and (c) or disorder. This method includes (a) providing a GPCR measuring biological activity of the GPCR polypeptide, polypeptide Substantially identical to a polypeptide listed in wherein altered biological activity, relative to that of the Table 1; (b) contacting the polypeptide with the candidate GPCR polypeptide not contacted with the compound, indi compound; and (c) measuring the half-life of the polypeptide, cates that the candidate compound may be useful for the wherein an alteration in the half-life of the polypeptide, rela treatment of a metabolic or nutritive disease or disorder. The tive to that of the polypeptide not contacted with the com GPCR polypeptide can be in a cell or in a cell-free assay pound, indicates that the candidate compound may be useful system. for the treatment of a metabolic or nutritive disease or disor 0420. In yet another aspect, the invention features a der. Preferably the GPCR polypeptide is in a cell or a cell free method for determining whether a candidate compound is a assay system. compound that may be useful for the treatment of a metabolic 0425. In another aspect, the invention features a method or nutritive disease or disorder. This method includes the for determining whether a patient has an increased risk for steps of (a) providing a transgenic non-human mammal (e.g., developing a metabolic or nutritive disease or disorder. The a knock-out mouse) having a disruption in a nucleic acid method includes the step of determining whether the patient molecule encoding a GPCR polypeptide substantially identi has a mutation in a gene encoding a polypeptide listed in cal to a polypeptide listed in Table 1; (b) contacting the Table 1, wherein presence of the mutation indicates that the transgenic non-human mammal with the candidate com patient has an increased risk for developing a metabolic or pound; and (c) measuring biological activity of the GPCR nutritive disease or disorder. polypeptide in the transgenic non-human mammal, wherein 0426 In a related aspect, the invention features another altered biological activity, relative to that of the transgenic method for determining whether a patient has an increased non-human mammal not contacted with the compound, indi risk for developing a metabolic or nutritive disease or disor cates that the candidate compound may be useful for the der. This method includes the step of determining whether the treatment of a metabolic or nutritive disease or disorder. patient has a polymorphism in a gene encoding a polypeptide 0421. In yet another aspect, the invention features a listed in Table 1, wherein presence of the polymorphism method for determining whether a candidate compound is a indicates that the patient may have an increased risk for compound that may be useful for the treatment of a metabolic developing a metabolic or nutritive disease or disorder. or nutritive disease or disorder. This method includes the 0427. In either of these two methods, the mutation or poly steps of (a) providing a transgenic non-human mammal (e.g., morphism is preferably associated with an alteration (for a mouse) overexpressing a nucleic acid molecule encoding a example, a decrease) in the biological activity of the polypep GPCR polypeptide substantially identical to a polypeptide tide. listed in any one of Table 1; (b) contacting the transgenic 0428. In another aspect, the invention features another non-human mammal with the candidate compound; and (c) method for determining whether a patient has an increased measuring biological activity of the GPCR polypeptide in the risk for developing a metabolic or nutritive disease or disor transgenic non-human mammal, wherein altered biological der. The method includes measuring biological activity of a activity, relative to that of the transgenic non-human mammal GPCR polypeptide from the patient that is substantially iden US 2009/0178153 A1 Jul. 9, 2009

tical to a polypeptide listed in Table 1, wherein increased or ria, hereditary coproporphyria, hereditary fructose intoler decreased levels in the GPCR biological activity, relative to ance, hereditary Xanthinuria, Hers disease, histidinemia, his normal levels, indicates that the patient has an increased risk tidinuria, HIV-1 protease inhibitor-induced lipodystrophy, for developing a metabolic or nutritive disease or disorder. homocitrullinuria, homocystinuria, homocystinuria, 0429. In still another aspect, the invention features yet homocystinuria and methylmalonic acidemia, homocystinur another method for determining whether a patient has an ias, Hunter syndrome, Hurler disease, Hurler-Scheie disease, increased risk for developing a metabolic or nutritive disease hyophosphatemic rickets, hyperammonemia, hyperammone or disorder. The method includes the step of measuring the mia, hypercholesterolemia, hypercystinuria, hyperglycin patient's expression levels of a polypeptide listed in Table 1, emia, hyperhydroxyprolinemia, hyperkalemic periodic wherein altered levels in the expression, relative to normal, paralysis, hyperleucineisoleucinemia, hyperlipoproteine indicate that the patient has an increased risk for developing a mias, hyperlysinemia, hypermagnesemia, hypermetabolism, metabolic or nutritive disease or disorder. Preferably, the hypermethioninemia, hyperornithinemia, hyperoxaluria, expression levels are determined by measuring levels of hyperphenylalaninemia with primapterinuria, hyperphenyla polypeptide or mRNA. laninemias, hyperphosphatemia, hyperprolinemia, hypertrig 0430 Preferred metabolic or nutritive diseases and disor lyceridemia, hyperuricemia, hypervalinemia, hypervitami ders that can be treated or diagnosed using the methods of the nosis A, hypervitaminosis D, hypocholesterolemia, invention or for which candidate therapeutic compounds may hypometabolism, hypophosphatemia, hypouricemia, hypovi be identified include 5,10-methylenetetrahydrofolate reduc taminosis A, hypoxanthine phosphoribosyltransferase defi tase deficiency, achondrogenesis type 1B, acid C-1,4-glucosi ciency, iminoglycinuria, iminopeptiduria, intermittent dase deficiency, acquired generalized lipodystrophy branched-chain ketoaciduria, intestinal malabsorption, (Lawrence syndrome), acquired partial lipodystrophy (Bar iodine deficiency, iron deficiency, isovaleric acidemia, Jervell raquer-Simons syndrome), acute intermittent porphyria, and Lange-Nielsen syndrome, juvenile pernicious anemia, acute panniculitis, adenine phosphoribosyltransferase defi keshan disease, Knock outrsaknockoutffs syndrome, kwash ciency, adenosine deaminase deficiency, adenyloSuccinate iorknock outr, leuknock outdystrophies, Liddle's syndrome, lyase deficiency, adiposis dolorosa (Dercum disease), ALA lipodystrophies, lipomatosis, liver glycogenoses, liver phos dehydratase-deficient porphyria, albinism, alkaptonuria, phorylase kinase deficiency, long QT syndrome, lysinuria, amulopectinosis, Andersen disease, argininemia, arginino lysosomal storage diseases, magnesium deficiency, malab Succinic aciduria, astelosteogenesis type 2, Bartter's Syn Sorptive diseases, malignant hyperphenylalaninemia, manga drome, benign familial neonatal epilepsy, benign fructosuria, nese deficiency, marasmus, Maroteaux-Lamy disease, benign recurrent and progressive familial intrahepatic McArdle disease, Menkes' disease, metachromatic leuknock cholestasis, biotin deficiency, branching enzyme deficiency, outdystrophy, methionine malabsorption, methylmalonic calcium deficiency, carnitine transport defect, choline defi acidemia, molybdenum deficiency, monosodiumurate gout, ciency, choline toxicity, chromium deficiency, chronic fat Morquio syndrome, mucolipidoses, mucopolysaccharidoses, malabsorption, citrullinemia, classic branched-chain ketoaci multiple carboxylase deficiency syndrome, multiple symmet duria, classic cystinuria, congenital chloridorrhea, congenital ric lipomatosis (Madelung disease, muscle glycogenoses, erythropoietic porphyria, congenital generalized lipodystro muscle phosphofructokinase deficiency, muscle phosphory phy, congenital myotonia, copper deficiency, copper toxicity, lase deficiency, myoadenylate deaminase deficiency, nephro cyStathionine B-synthase deficiency, cyStathioninuria, cystic genic diabetes insipidus, nesidioblastosis of pancreas, niacin fibrosis, cystinosis, cystinuria, Darier disease, defect in trans deficiency, niacintoxicity, Niemann-Pick disease, obesity, port of long-chain fatty acids, deficiency of cobalamin coen orotic aciduria, osteomalacia, paramyotonia congenita, pel Zyme deficiency, Dent's syndrome, diatrophic dysplasia, lagra, Pendred syndrome, phenylketonuria, phenylketonuria dibasic aminoaciduria, dicarboxylic aminoaciduria, dihydro type 1, phenylketonuria type 2, phenylketonuria type 3. phos pyrimidine dehydrogenase deficiency, distal renal tubular phate deficiency, phosphoribosylpyrophosphate synthetase acidosis, dry beriberi, Dubin-Johnson syndrome, dysbetali overactivity, polygenic hypercholesterolemia, Pompe dis poproteinemia, end-organ insensitivity to vitamin D. eryth ease, porphyria cutanea tarda, porphyrias, primary bile acid ropoietic protoporphyria, Fabry disease, failure of intestinal malabsorption, primary hyperoxaluria, primary hypoalphali absorption, familial apoprotein C2 deficiency, familial com poproteinemia, propionic acidemia, protein-energy malnutri bined hyperlipidemia, familial defective Apo B100, familial tion, proximal renal tubular acidosis, purine nucleoside phos goiter, familial hypercholesterolemia, familial hypertriglyc phorylase deficiency, pyridoxine deficiency, pyrimidine eridemia, familial hypophosphatemic rickets, familial lipo 5'-nucleotidase deficiency, renal glycosuria, riboflavin defi protein lipase deficiency, familial partial lipodystrophy, Fan ciency, rickets, Rogers' Syndrome, saccharopinuria, Sandhoff coni-Bickel syndrome, fluoride deficiency, folate disease, Sanfilippo syndromes, sarcosinemia, Scheie disease, malabsorption, folic adic deficiency, formiminoglutamic aci Scurvy (vitamin C deficiency), selenium deficiency, seleno duria, fructose 1.6 diphosphatase deficiency, galactokinase sis, sialic acid storage disease, S-Sulfo-L-cysteine, Sulfite, deficiency, galactose 1-phosphate uridyl transferase defi thiosulfaturia, Tarui disease, Tay-Sachs disease, thiamine ciency galactosemia, Gaucher disease, Gitelman's syndrome, deficiency, tryptophan malabsorption, tryptophanuria, type 1 globoid cell leuknock outdystrophy, glucose-6-phosphatease pseudohypoaldosteronism, type 3 glycogen storage disease deficiency, glucose-6-translocase deficiency, glucose-galac (debrancher deficiency, limit dextrinosis), tyrosinemia, tose malabsorption, glucose-transporter protein syndrome, tyrosinemia type 1, tyrosinemia type 2, tyrosinemia type 3. glutaric adiduria, glycogen storage disease type 2, glycogen uridine diphosphate galactose 4-epimerase deficiency, uro storage disease type Ib, glycogen storage disease type ID. canic aciduria, variegate porphyria, Vitamin B12 deficiency, glycogen synthase deficiency, gout, Hartnup disease, hawk vitamin C toxicity, vitamin D deficiency, vitamin D-resistant insinuria, hemochromatosis, hepatic glycogenosis with renal rickets, vitamind-sensitive rickets, vitamin E deficiency, Vita fanconi syndrome, hepatic lipase deficiency, hepatic porphy min E toxicity, Vitamin K deficiency, vitamin K toxicity, Von US 2009/0178153 A1 Jul. 9, 2009 44

Gierke disease, Wernicke's encephalopathy, wet beriberi, decreases the biological activity of the GPCR polypeptide. A Wilson's disease, Xanthurenic aciduria, X-linked sideroblas decrease in the biological activity of the GPCR polypeptide tic anemia, Zinc deficiency, Zinc toxicity, C.-ketoadipic aci identifies the candidate compound as a compound that may be duria, C.-methylacetoacetic aciduria, 3-hydroxy-3-methyl useful for the treatment of a disease or disorder. In one glutaric aciduria, B-methylcrotonylglycinuria. embodiment, the transgenic mouse from which the cell was 0431. In another aspect, the invention features a transgenic derived has a mutation (e.g., a deletion, frameshift, insertion mouse expressing a transgene encoding a human GPCR or a point mutation) in a gene listed in Table 1. In a related polypeptide listed in Table 1. The transgene may be operably embodiment, the mouse has a mutation in the polypeptide that linked, e.g., to an inducible, cell-type, or tissue-specific pro is orthologous to the GPCR polypeptide encoded by the trans moter. In one embodiment, the transgenic mouse has a muta gene. tion in a gene that is orthologous to the transgene. For 0438. The invention also features a kit that includes a example, the transgene encoding the human GPCR polypep plurality of polynucleotides, wherein each polynucleotide tide may entirely replace the coding sequence of the ortholo hybridizes under high stringency conditions to a GPCR poly gous mouse gene or the transgene might complement a knock nucleotide of Table 1. At least 50 different polynucleotides, out of the orthologous mouse gene. each capable of hybridizing under high stringency conditions 0432. In a related embodiment, the transgenic mouse has a to a different huma GPCR polynucleotide listed on Table 1, mutation (e.g., a deletion, frameshift, insertion or a point are present in the kit. mutation) in a gene listed in Table 1. 0439. The invention features another kit that includes a 0433. In another aspect, the invention features an isolated plurality of polynucleotides. In this kit, polynucleotides that cell or population of cells derived from a transgenic mouse hybridize under high Stringency conditions, each to a differ either expressing a transgene encoding a huma GPCR ent GPCR polynucleotide listed on one of Tables 3-33, are polypeptide listed in Table 1 or has a mutation (e.g., a dele present in the kit such that the kit includes polynucleotides tion, frameshift, insertion or a point mutation) in a gene listed that collectively hybridize to every GPCR polynucleotide in Table 1. listed on one of Tables 3-33. 0434. The invention also features a method for identifying 0440 The invention features another kit, this kit including a compound that may be useful for the treatment of a disease a plurality of mice, each mouse having a mutation in a GPCR or disorder described herein. The method includes the steps of polynucleotide of Table 1, wherein at least 50 mice, each administering a candidate compound to a transgenic mouse having a mutation in a different GPCR polynucleotide listed expressing a transgene encoding a GPCR polypeptide listed on Table 1, are present in the kit. This kit may optionally in Table 1; and determining whether the candidate compound include a plurality of polynucleotides, wherein each poly decreases the biological activity of the GPCR polypeptide, nucleotide hybridizes under high Stringency conditions to a wherein a decrease in the biological activity of the GPCR GPCR polynucleotide of Table 1, wherein at least 50 different polypeptide identifies the candidate compound as a com polynucleotides, each capable of hybridizing under high pound that may be useful for the treatment of a disease or stringency conditions to a different mouse GPCR polynucle disorder. In one embodiment, the transgenic mouse has a otide listed on Table 1, are present in the kit. mutation (e.g., a deletion, frameshift, insertion or a point 0441. The invention features another kit that includes a mutation) in a gene listed in Table 1. In a related embodiment, plurality of mice having a mutation in a GPCR polynucle the mouse has a mutation in the gene that is orthologous to the otide. In this kit, mice having a mutation in each GPCR transgene. polynucleotide listed on one of Tables 3-33 are present in the 0435. In a related aspect, the invention features another kit. method for identifying a compound that may be useful for the 0442. In any of the foregoing kits, at least one of the GPCR treatment of a disease or disorder described herein. This polynucleotides is desirably a GPCR polynucleotide of Table method includes the steps of administering a candidate com 2. pound to a transgenic mouse expressing a transgene encoding a GPCR polypeptide in a gene listed in Table 1, and having a DEFINITIONS disease or disorder caused by the expression of the transgene; 0443. By “polypeptide' is meant any chain of more than and determining whether the candidate compound treats the two amino acids, regardless of post-translational modifica disease or disorder. tion Such as glycosylation or phosphorylation. 0436. In a related aspect, the invention features another 0444. By “substantially identical' is meant a polypeptide method for identifying a compound that may be useful for the or nucleic acid exhibiting at least 50%, preferably 85%, more treatment of a disease or disorder described herein. This preferably 90%, and most preferably 95% identity to a refer method includes the steps of administering a candidate com ence amino acid or nucleic acid sequence. For polypeptides, pound to a transgenic mouse transgenic mouse containing a the length of comparison sequences will generally be at least mutation (e.g., a deletion, frameshift, insertion or a point 16 amino acids, preferably at least 20 amino acids, more mutation) in a gene listed in Table 1, and having a disease or preferably at least 25 amino acids, and most preferably 35 disorder caused by gene disruption; and determining whether amino acids or the full-length polypeptide. For nucleic acids, candidate compound treats the disease or disorder. the length of comparison sequences will generally be at least 0437. In still another aspect, the invention features a 50 nucleotides, preferably at least 60 nucleotides, more pref method for identifying a compound that may be useful for the erably at least 75 nucleotides, and most preferably 110 nucle treatment of a disease or disorder described herein. This otides or the full-length polynucleotide. method includes the steps of contacting a candidate com 0445 Sequence identity is typically measured using a pound with a cell from a transgenic mouse expressing a sequence analysis program (e.g., BLAST 2: Tatusova et al., transgene encoding a GPCR polypeptide in a gene listed in FEMS Microbiol Lett. 174:247-250, 1999) with the default Table 1; and determining whether the candidate compound parameters specified therein. US 2009/0178153 A1 Jul. 9, 2009

0446. By “high stringency conditions” is meant hybridiza 0455 “Dominant negative” means an effect of a mutant tion in 2xSSC at 40°C. with a DNA probe length of at least 40 form of a gene product that dominantly interferes with the nucleotides. For other definitions of high Stringency condi function of the normal gene product. tions, see F. Ausubel et al., Current Protocols in Molecular 0456 “Reporter system’ means any gene, compound or Biology, pp. 6.3.1-6.3.6. John Wiley & Sons, New York, N.Y., polypeptide whose product can be assayed, measured or 1994, hereby incorporated by reference. monitored. Examples include, but are not limited to neomy 0447 “Substantially identical polynucleotides also cin (Kang et al., Mol. Cells: 7:502-508, 1997), luciferase include those that hybridize under high Stringency conditions. (Welsh et al., Curr. Opin. Biotechnol. 8:617-622, 1997), lacz, “Substantially identical polypeptides include those encoded (Spergel et al., Prog. Neurobiol. 63:673-686, 2001), aequorin by polynucleotides that hybridize under high Stringency con (Deo et al., J. Anal. Chem. 369:258-266, 2001) and green ditions. fluorescent protein (Tsien, Annu. Rev. Biochem. 67:509-544, 0448. By “substantially pure polypeptide' is meant a 1998). polypeptide that has been separated from the components that 0457. “Conditional mutant” is any gene, cell or organism naturally accompany it. Typically, the polypeptide is Substan for which the expression of the mutant phenotype can be tially pure when it is at least 60%, by weight, free from the controlled through alteration in the temperature, diet or other proteins and naturally-occurring organic molecules with external conditions. which it is naturally associated. Preferably, the polypeptide is 0458. “Overexpression” means level of expression higher a GPCR polypeptide that is at least 75%, more preferably at than the physiological level of expression. least 90%, and most preferably at least 99%, by weight, pure. 0459 “Isolated” or “purified” means altered from its natu A substantially pure GPCR polypeptide may be obtained, for ral state, i.e., if it occurs in nature, it has been changed or example, by extraction from a natural source (e.g., a pancre removed from its original environment, or both. For example, atic cell), by expression of a recombinant nucleic acid encod a polynucleotide or a polypeptide naturally present in a living ing a GPCR polypeptide, or by chemically synthesizing the organism is not "isolated, but the same polynucleotide or polypeptide. Purity can be measured by any appropriate polypeptide separated from the coexisting materials of its method, e.g., by column chromatography, polyacrylamide natural state is "isolated as the term is employed herein. gel electrophoresis, or HPLC analysis. Moreover, a polynucleotide or polypeptide that is introduced 0449. A polypeptide is substantially free of naturally asso into an organism by transformation, genetic manipulation, or ciated components when it is separated from those contami by any other recombinant method is "isolated even if it is still nants that accompany it in its natural state. Thus, a polypep present in the organism. tide which is chemically synthesized or produced in a cellular 0460) “Polynucleotide’ generally refers to any polyribo system different from the cell from which it naturally origi nucleotide (RNA) or polydeoxyribonucleotide (DNA), which nates will be substantially free from its naturally associated may be unmodified or modified RNA or DNA. Polynucle components. Accordingly, Substantially pure polypeptides otides include, without limitation, single- and double include those that naturally occur in eukaryotic organisms but stranded DNA, DNA that is a mixture of single- and double are synthesized in E. coli, yeast or other microbial system. Stranded regions, single- and double-stranded RNA, and 0450. By “purified antibody' is meant antibody that is at RNA that is mixture of single- and double-stranded regions, least 60%, by weight, free from proteins and naturally occur hybrid molecules comprising DNA and RNA that may be ring organic molecules with which it is naturally associated. single-stranded or, more typically, double-stranded or a mix Preferably, the preparation is at least 75%, more preferably ture of single- and double-stranded regions. Polynucleotide 90%, and most preferably at least 99%, by weight, antibody. can also refer to triple helix nucleic acids. A purified antibody may be obtained, for example, by affinity 0461 “Variant” refers to a polynucleotide or polypeptide chromatography using recombinantly-produced protein or that differs from a reference polynucleotide or polypeptide, conserved motif peptides and standard techniques. but retains the essential properties thereof. A typical variant of 0451. By “specifically binds” is meant any small mol a polynucleotide differs in nucleotide sequence from the ref ecule, peptide, antibody, or polypeptide that recognizes and erence polynucleotide. Changes in the nucleotide sequence of binds, for example, a huma GPCR polypeptide but does not the variant may or may not alter the amino acid sequence of a Substantially recognize and bind other molecules in a sample, polypeptide encoded by the reference polynucleotide. Nucle e.g., a biological sample, that naturally includes the protein. otide changes may result in amino acid Substitutions, addi tions, deletions, fusions and truncations in the polypeptide 0452. By “polymorphism' is meant that a nucleotide or encoded by the reference sequence, as discussed below. A nucleotide region is characterized as occurring in several typical variant of a polypeptide differs in amino acid different sequence forms. A "mutation' is a form of a poly sequence from the reference polypeptide. Generally, alter morphism in which the expression level, stability, function, or ations are limited so that the sequences of the reference biological activity of the encoded protein is substantially polypeptide and the variant are closely similar overall and, in altered. many regions, identical. A variant and reference polypeptide 0453. By “GPCR related polypeptide' is meant a polypep may differ in amino acid sequence by one or more substitu tide having Substantial identity to any of the polypeptides tions, insertions, or deletions in any combination. A substi listed in Table 1, including polymorphic forms (e.g., tuted or inserted amino acid residue may or may not be one sequences having one or more SNPs) and splice variants. encoded by the genetic code. Typical conservative Substitu 0454. By “GPCR biological activity” is meant measurable tions include Gly, Ala; Val, Ile, Leu: Asp, Glu: Asn., Gln: Ser, effect or change in an organism or a cell resulting from the Thr; Lys, Arg; and Phe and Tyr. A variant of a polynucleotide modulation of a GPCR at the molecular, cellular, physiologi or polypeptide may be naturally occurring such as an allele, or cal or behavioral levels or alteration in the extent of activation it may be a variant that is not known to occur naturally. ordeactivation that can be elicited by an agonist orantagonist. Non-naturally occurring variants of polynucleotides and US 2009/0178153 A1 Jul. 9, 2009 46 polypeptides may be made by mutagenesis techniques or by 0470. By “candidate compound' or “test compound is direct synthesis. Also included as variants are polypeptides meant a chemical, be it naturally-occurring or artificially having one or more post-translational modifications, for derived, that is assayed for its ability to modulate gene activ instance glycosylation, phosphorylation, methylation, ADP ity or protein stability or binding, expression levels, or activ ribosylation and the like. Embodiments include methylation ity, by employing any standard assay method. Test of the N-terminal amino acid, phosphorylations of serines and compounds may include, for example, peptides, polypep threonines and modification of C-terminal glycines. tides, synthesized organic molecules, naturally occurring 0462 “Allele” refers to one of two or more alternative organic molecules, polynucleotide molecules, and compo forms of a gene occurring at a given locus in the genome. nents thereof. 0463 A “transgenic organism as used herein, is any 0471. By “promoter is meant a minimal sequence suffi organism, including but not limited to animals and plants, in cient to direct transcription. Also included in the invention are which one or more of the cells of the organism contains those promoter elements which are sufficient to render pro heterologous nucleic acid introduced by way of human inter moter-dependent gene expression controllable for cell type vention, Such as by transgenic techniques well known in the specific, tissue-specific, temporal-specific, or inducible by art. The nucleic acid is introduced into the cell, directly or external signals or agents; Such elements may be located in indirectly by introduction into a precursor of the cell, by way the 5' or 3' or intron sequence regions of the native gene. of deliberate genetic manipulation, such as by microinjection, 0472. By “operably linked' is meant that a gene and one or transfection or by infection with a recombinant virus. The more regulatory sequences are connected in Such a way as to transgenic organisms contemplated in accordance with the permit gene expression. present invention include mice, bacteria, cyanobacteria, 0473 Other features and advantages of the invention will fungi, plants and animals. The isolated DNA of the present be apparent from the following description of the preferred invention can be introduced into the host by methods known embodiments thereof and from the claims. in the art, for example infection, transfection, transformation or transconjugation. BRIEF DESCRIPTION OF THE DRAWINGS 0464 A “transgenic mice, as used herein, is a mouse, in 0474 FIG. 1 is a list of GPCR polynucleotides of the which one or more of the cells of the organism contains invention in human and mouse. Polynucleotides are divided nucleic acid introduced by way of human intervention, Such into four classes, A, B, C, and F/S, according to conventional as by transgenic techniques well known in the art. The nucleic classification of the GPCR superfamily. The “No Class” acid is introduced into the cell, directly or indirectly by intro group includes five polynucleotides that cannot be assigned duction into a precursor of the cell, by way of deliberate to any of the above four classes. Within each class, polynucle genetic manipulation, by methods known in the art, for otides are further grouped into Small families based on ligand example microinjection, infection, transfection, or transfor specificity or, in the case of orphan receptors, significant mation. sequence homology (24.0%) within each family. Orphan 0465 “Transgene' is any exogenously added nucleic acid. receptors that cannot be grouped by this criterion are alpha betically listed at the end of each class. Whenever available, 0466 “Antisense' or “Reverse complement’ means a names are adopted from the official gene names of the NCBI nucleic acid sequence complementary to the messenger LocusLink database. Orphan GPCRs are indicated with an RNA asterisk. Abbreviations: H, human; M, mouse; FMLP, fMet 0467 “Single nucleotide polymorphism” or “SNP” refers Leu-Phe: GNRH; gonadotropin-releasing hormone: PAF, to the occurrence of nucleotide variability at a single nucle platelet-activating factor: INSL3, insulin-like 3: SPC, sphin otide position in the genome, within a population. An SNP gosylphosphorylcholine; LPC, lysophosphatidylcholine; may occur within a gene or within intergenic regions of the TRH, thyrotropin-releasing hormone: LGR, leucine-rich genome. SNPs can be assayed using Allele Specific Amplifi repeat-containing G protein-coupled receptor, SREB, Super cation (ASA). For this process, at least three primers are conserved receptor expressed in brain; GIP, gastric inhibitory required. A common primer is used in reverse complement to polypeptide; GHRH, growild typeh hormone-releasing hor the polymorphism being assayed. This common primer can mone: PACAP, pituitary adenylate cyclase activating be between 50 and 1500 bps from the polymorphic base. The polypeptide: DAF, decay accelerating factor; GPRC5, G pro other two (or more) primers are identical to each other except tein-coupled receptor family C group 5. that the final 3' base wobbles to match one of the two (or more) 0475 FIG. 2 is a series of phylogenetic trees of human alleles that make up the polymorphism. Two (or more) PCR GPCRs. Lines corresponding to individual polynucleotides reactions are then conducted on sample DNA, each using the are colored black for those with known ligands, red for orphan common primer and one of the Allele Specific Primers. genes, and blue for genes with 7 trans-membrane domains but 0468 “Splice variant” as used herein refers to cDNA mol no homology to known GPCRs. The Class A tree was split ecules produced from RNA molecules initially transcribed into two parts due to size considerations (arrow line indicates from the same genomic DNA sequence but which have under the connection). Families are defined as described in FIG. 1. gone alternative RNA splicing. Alternative RNA splicing Clusters of GPCRs with significant predictive value as to occurs when a primary RNA transcript undergoes splicing, ligands are highlighted in purple on these bootstrap consen generally for the removal of introns, which results in the sus trees (bootstrap values not shown). The ruler at the bottom production of more than one distinct mRNA molecules each of each tree indicates the horizontal distance equal to 10% of which may encode different amino acid sequences. The sequence divergence. term splice variant also refers to the polypeptides encoded by 0476 FIG. 3 is a photograph showing the expression pro the above mRNA molecules. files of nine GPCRs as identified by RT-PCR. 0469 “Fusion protein’ refers to a polypeptide encoded by 0477 FIG. 4 is schematic summary of tissue expression in two, often unrelated, fused genes or fragments thereof. 100 GPCR polynucleotides. Polynucleotides were analyzed US 2009/0178153 A1 Jul. 9, 2009 47 individually by RT-PCR, as shown in FIG.3, and the intensity tified in human and 304 in mouse. Sequence alignments indi of the observed bands determined by scanning. Each gene is cated that 260 of these molecules were common to both represented by a single row of colored boxes, with four dif species (FIG. 1). ferent expression levels: no expression—blue; low expres 0485 We then asked whether the remaining GPCR genes sion purple; moderate expression—dark red; strong expres (80 human and 44 in mouse), which did not show a counter sion pure red. Polynucleotides and tissues, as well as part in the other species, might have undiscovered orthologs. groups of expression patterns, are indicated. Using the non-shared GPCRs as queries, the public human and mouse genome sequence databases were searched for 0478 FIGS.5a-5h are representative in situ hybridization orthologous genes using TBLASTN, a variation of the Basic photomicrographs of GPCR expression in the mouse brain. Local Alignment Search Tool (BLAST). These studies iden FIG. 5a: GPR63 in the Ammons horn (CA) regions of the tified mouse orthologs for 61 of the human GPCRs, but no hippocampus. FIG. 5b: PGR7 in the habenula. FIG. 5c: orthologs could be found for the remaining 19 (FIG. 1). No GRCA in the cortex and thalamus. FIG. 5d. GPR63 in the human orthologs were detected for 43 of the mouse genes. Purkinje cells of the cerebellum. FIG. 5e: GPR37 in the Thirty-three of these mouse genes belonged to the trace frontal cortex. FIG. 5f: GPR26 in the inferior olive. FIG.5g: amine and MAS-related gene families. In combination with GPR50 in the cells lining the third ventricle. FIG.5h: PGR15 the literature/database searches, these studies for orthologs in the preoptic region of the hypothalamus. Vertical lines on increased the number of GPCRs to 342 in human and 366 in Sagittal mouse brain drawing represent approximate coronal mouse, with 323 GPCRs shared by the two species (FIG. 1). plane of photomicrographs. Scale bars=500 um. 0486 We subsequently undertook an exhaustive search 0479 FIGS. 6a-6b. Home Cage Activity data for GPR85. for new human GPCR genes. Two different approaches were FIG. 6A. illustrates the average 24 hour activity of GPR85 used. In the first, we employed a homology-based strategy to wild type and knock out female mice. FIG. 6B illustrates the search the human genome sequence database for genes average 24 hour activity of GPR85 wild type and knockout encoding GPCRs (http://genome.ucsc.edu/goldenPath/ male mice. 14nov2002/chromosomes/). Two hundred fifty-four known 0480 FIGS. 7a-7b. Temperature differences between GPCRs, representative of all classes, were each used as an GPR85 knockout and wild type mice. FIG. 7A. SIH results independent query in TBLASTN searches of all human chro showing an increased body temperature change for knockout mosomes. These searches yielded ~500,000 matches, which compared to wild type mice. FIG. 7B. Baseline core body were first reduced to ~50,000 unique matches and then to temperature difference between wild type and knock out 10,000 matches with homology to known GPCRs (see Meth 1CC. ods). Among these, hits representing 315 of the 342 known 0481 FIG.8. Percentage freezing in the conditioned fear GPCR genes were detected, consistent with 90%-95% cov test. GPR85 knock out mice displayed significantly more erage of the human genome database. Approximately 1000 freezing responses during the context test. hits were homologous to chemosensory GPCR receptors. 0482 FIGS. 9a-9b. Acute effects of ethanol-induced Continued analysis of the remaining hits revealed 25 novel hypothermia. FIG.9A. Initial sensitivity to the hypothermic GPCR genes. effects of ethanol as measured by the difference before and 30 0487. In a second discovery method, a search was con minutes after an i.p. injection of 2.5 g/kg ethanol on two ducted for proteins with sequence motifs characteristic of the consecutive treatment days. GPR85 knockout mice display a four different classes of GPCRs. The Hidden Markov Model decreased initial sensitivity to the effects of ethanol. FIG.9B. (HMM) profile-based approach was used to search the human Tolerance to the hypothermic effects of ethanol as shown by proteome. This method yielded 1,100 potential matches. the difference in the change of core body temperature for day Among these hits 331 of the 342 known GPCRs were repre 1 and day 2. sented, confirming the validity of the search strategy. Follow ing elimination of known genes, three novel genes were iden tified. The combination of both genomic search strategies DETAILED DESCRIPTION OF THE INVENTION revealed 28 GPCR genes that have not been previously described. These genes are referred to as PGR1 to PGR28 0483 G protein coupled receptors (GPCRs) include (FIG. 1). Searches of the mouse genome sequence database, receptors for neurotransmitters, light, odors, hormones, and together with RT-PCR analyses, identified orthologs for 25 of molecules used for communication in the immune system. the 28 novel genes in the mouse. GPCRs are by far the largest family of receptors known. It is 0488 Altogether, these searches identified a total of 383 believed that there are as many as 1,000 different GPCRs for GPCRs in human and 391 in mouse; 358 of the GPCRs were odor recognition alone. common to the two species. Identification of GPCR Polypeptides and Polynucleotides Methods 0484. To identify the full complement of GPCRs inhuman 0489. The 254 GPCRs used as queries were aligned using and mouse, we embarked on a multi-step process; the first the Clustal W program. The amino acid sequence of the step was to identify previously known GPCR genes and then seven-transmembrane region of each GPCR was extracted the Subsequent identification of novel genes. To identify and used to search through the public human genome (HG) known genes we searched the public literature and sequence database (downloaded in August, 2001) using TBLASTN at databases of the National Center for Biotechnology Informa an E-value of 10. The resulting hits (~500,000) were com tion for human and mouse GPCRs and then performed bined and Sorted according to contig and position numbers. sequence comparisons. This procedure defined a unique gene Only the hit with the best E-value was selected among the set of GPCRs for both human and mouse and identified the group of hits within 1kb from each other on the same contig. human and mouse orthologs. In total, 34.0 GPCRs were iden Each of the 50,000 unique hits generated were used to search US 2009/0178153 A1 Jul. 9, 2009 48 against nr protein database using BLASTP. From this search, GPCRs to specific families using the criteria that members of 10,000 hits appeared to be most homologous to GPCRs. a family either recognize the same/similar ligand or show at Almost 2000 of these hits were determined to be parts of least 40% sequence homology. In this manner, 93 different various known GPCRs and were excluded from further con families of GPCRs were identified, including 16 families of sideration. The best 500 of the remaining hits were subjected orphan receptors that have not been previously described to full-length gene structure prediction. This process involved (FIG. 1). These studies assigned 12 of 145 human and 47 of comparison of 200 kb genomic DNA sequence Surrounding 178 mouse orphan GPCRs to seven different families of each hit with the full-length sequence of its most homologous receptors that interact with known ligands. The orphan recep known GPCR using BLAST2. Twenty-five candidate novel tors in these families can be predicted to recognize ligands GPCRs were obtained. Their nucleotide sequences were then similar to those detected by other members of the same fam used to search the EST database for the identification of ily. human and/or mouse ESTs. 0495 To further investigate sequence-ligand relationships 0490 For the HMM profile-based approach, GPCR Class among human GPCRs, we conducted a phylogenetic analy A, B and C HMM models were downloaded from the Pfam sis. GPCRs were aligned to the class specific HMM profile database and were used as queries in the HMMSEARCH model using the HMMALIGN program of the 1HMMER program (HMMER package) to search against the Interna package. These alignments were used for the construction of tional Protein Index (IPI) proteome database. All hits with phylogenetic trees, using the ClustalW program. The phylo E-values of less than 0.01 were evaluated for the existence of genetic trees were then overlaid with information on the 7 TM domains using the HMMTOP program. Full-length ligand specificities of individual receptors, where available. coding sequences were predicted through a combination of 0496 The combined phylogenetic/ligand analyses of methods including EST sequence assembly, ORF Finder, human GPCRs are shown in FIG. 2. The phylogenetic tree of GenomeScan, GeneWise and GeneScan programs. the class A receptors, the largest set, was composed of a 0491 GPCRs from the same class were aligned to the number of major branches that were progressively subdivided class specific HMM model using the HMMALIGN program into Smaller branches containing increasingly related of the HMMER package. Positions not aligned to matching GPCRs. The three smaller classes of receptors (classes B, C, sites in the HMM model were removed. These multiple align and F/S) exhibited a similar organization, but fewer branches. ments were used to build neighbor-joining phylogenetic trees GPCRs that recognize the same ligand, Such as receptors for by the ClustalW program. Gaps and multiple substitutions the neurotransmitter acetylcholine, or receptors that belong to were not corrected. Bootstrap consensus trees were plotted the same family, were clustered together in small branches. using TreeView. They were rooted using GPCRs that did not 0497. The phylogenetic trees, in addition, revealed a strik fit into any of four known classes. Bootstrap values for nodes ing, higher order organization relevant to GPCR functions. near the root of the Class A tree were very low (<10%), Multiple receptor families with related functions that recog reflecting the distant homology of the different families in this nize ligands of a particular chemical class were grouped in the class. same large branch. For example, the 40 neurotransmitter/ neuromodulator receptors of the dopamine, serotonin, trace Phylogenetic Analysis amine, adenosine, acetylcholine, histamine and adrenorecep 0492 Phylogenetic and receptor-ligand relationships tor C. and B families were all clustered phylogenetically. among the GPCRs were subsequently analyzed. Each human Moreover, the 106 GPCRs known to recognize peptide and mouse GPCR was first assigned to one of the four distinct ligands were clustered in four large branches, three in the classes of GPCRs (A, B, C, F/S) by comparing with HMM class A tree and one in the class B tree. This organization is of models. All but five of the receptors (TPRA40, TM7SF1, predictive value for numerous orphan GPCRs. For example, TM7SF1L1, TM7SF1L2 and TM7SF3) could be assigned to GPCRs such as PGR2, PGR3, PGR11, GPR19, GPR37, one of the four classes by this method. These assignments GPR39, GPR45, GPR63 and GPR103 could be predicted to indicate that of 370 human GPCRs. 287 belong to Class A, 50 have peptide ligands since they were grouped with other to Class B, 17 to Class C, and 11 to Class F/S. Of 393 mouse receptors activated by peptides. Other orphan receptors. Such GPCRs, 311, 50, 17, and 10 belong to Classes A, B, C, and as GPR21 and GPR52 could conceivably be activated by F/S, respectively. amine neuromodulators, as they clustered phylogenetically 0493. The GPCRs were next catalogued according to with amine-type molecules in the large neurotransmitter ligand specificities reported in the literature. This effort iden branch of the class A tree. tified 229 human and 215 mouse GPCRs with known ligands. The remaining 145 human and 178 mouse GPCRs have no Full-Length Sequence for Novel Human GPCR Genes known ligands and are therefore orphan receptors. Among the Methods orphan receptors, 100 human and 133 mouse receptors belong to Class A, 34 human and 34 mouse receptors to Class 0498 To identify full-length clones for the novel human B, 6 human and 6 mouse receptors to Class C, none to Class GPCR genes that were discovered by the gene-mining effort, F/S, and 5 human and 5 mouse receptors could not be the following methods were used: assigned to a specific class (FIG. 1). First-Strand cDNA Synthesis 0494 The GPCRs were subsequently divided into a series 0499 First strand cDNA Synthesis was performed as of families of related receptors that either recognize the same/ essentially described in the following kit, CLONTECH Labo similar ligand(s) or are highly likely to do so. Sequence com ratories, Inc., Protocol HPT3269-1 16 Version HPR14596. parisons and phylogenetic analyses (see below) showed that (0500 Two 10-ul reactions described below convert 50 GPCRs with highly related ligand specificities that are tradi ng-1 lug of total or poly A+ RNA into RACE-Ready first tionally classed as belonging to the same “family' are at least strand cDNA. For optimal results, use 1 lug of poly A+ RNA 40% homologous in protein sequence. We therefore assigned or 1 lug of total RNA in the reactions below. US 2009/0178153 A1 Jul. 9, 2009 49

1. Combined the following in separate 0.5-ml microcentri dephosphorylated, decapped RNA was incubated at 65° C. fuge tubes: for 5 minutes. Then the following were added: For preparation of 5'-RACE-Ready or cDNA 3’-RACE Ready cDNA 10x Ligase Buffer 1 ul 0501) 1-3 ul RNA sample 1-3 ul RNA sample 0502. 1 ul 5'-CDS primer 1 ul 3'-CDS primer A 10 mM ATP 1 ul 0503) 1 ul SMART II A oligo RNase0ut. (40 U/ul) 1 ul 2. Add sterile HO to a final volume of 5ul for each reaction. 0517 T4 RNA ligase (5 U?ul) 1 ul 3. Mix contents and spin the tubes briefly in a microcentri fuge. Total Volume 10 ul 4. Incubate the tubes at 70° C. for 2 min. 5. Cool the tubes on ice for 2 min. 0518. After incubation, 90 ul of DEPC treated water was 6. Spin the tubes briefly to collect the contents at the bottom. added and the reaction was extracted with phenol/chloro 7. Add the following to each reaction tube (already containing form, and precipitated with the addition of 2 ul of 10 mg/ml mussel glycogen, 10ul 3M sodium acetate, pH 5.2 and 220 ul of 95% ethanol. 0504 2 ul 5x First-Strand buffer 0519 4. Reverse-transcribe the ligated mRNA using 0505 1 ul DTT (20 mM) Cloned AMV RT or SuperScript II RT and the GeneRacer. 0506 1 ul dNTP Mix (10 mM) OligodT Primer to create RACE-ready first-strand cDNA 0507 1 ul PowerScript Reverse Transcriptase with known priming sites at the 5' and 3' ends. 0508 10 ul Total volume 0520. To 10 ul ligated mRNA, 1 ul of the desired primer 8. Mix the contents of the tubes by gently pipetting. was added and 1 ul of dNTP Mix (25 mM each) to the ligated 9. Spin the tubes briefly to collect the contents at the bottom. RNA. Then the mixture was incubated at 65° C. for 5 minutes 10. Incubate the tubes at 42°C. for 1.5 hr in an air incubator. to remove any RNA secondary structure, chilled on ice for 2 11. Dilute the first-strand reaction product with Tricine minutes and added the following reagents to the ligated RNA EDTA Buffer: and primer mixture: 0509 Added 20 ul if started with <200 ng of total RNA. 0510 Added 100 ul if started with >200 ng of total RNA. 5xRT Buffer 4 ul 0511. Added 250 ul if started with poly A+ RNA. Cloned AMV RT (15 U?ul) 1 ul 12. Heat tubes at 72° C. for 7 min. 13. Samples can be stored at -20°C. for up to three months. 0521. Sterile water 2 ul Now have 3'- and 5'-RACE-Ready cDNA samples. RNase0ut (40 U/ul) 1 ul 3' and 5 RACE Total Volume 20 ul 0512 1. Treat total RNA or mRNA with calf intestinal 0522 The reaction was incubated at 45° C. for 1 hour and phosphatase (CIP) to remove the 5' phosphates. This elimi then at 85°C. for 15 minutes to inactivate the cloned AMV nates truncated mRNA and non-mRNA from subsequent RT. ligation with the GeneRacer RNA Oligo. Dephosphorylation 0523 5. To obtain 5' ends, amplify the first-strand cDNA reaction was set up in a 1.5 ml sterile microcentrifuge tube using a reverse gene specific primer (Reverse GSP) and the using the reagents in the kit. 1-5ug total RNA was used in a GeneRacer 5' Primer. Only mRNA that has the GeneRacer total volume of 10ul with 10x RNase0ut and CIP (10 U). The RNA Oligo ligated to the 5' end AND is completely reverse reaction was incubated at 50° C. for 1 hour. After incubation, transcribed will be amplified using PCR. If needed, perform the RNA was precipitated with ethanol. additional PCR with nested primers. 0513 2. Treat dephosphorylated RNA with tobacco acid 0524 6. To obtain 3' ends, amplify the first-strand cDNA pyrophosphatase (TAP) to remove the 5' cap structure from using a forward gene-specific primer (Forward GSP) and the intact, full-length mRNA. This treatment leaves a 5" phos GeneRacer 3' Primer. Only mRNA that has a polyA tail and is phate required for ligation to the GeneRacer RNA Oligo. reverse-transcribed will be amplified using PCR. If needed, 0514. The reaction was set up on ice the using the reagents perform additional PCR with nested primers. in the kit. PCR Conditions Used for 3' or 5' RACE or Internal Fragment Dephosphorylated RNA 7 ul Amplification 10XTAP Buffer 1 ul 0525 PCR was performed using the following cycle parameters, 94 C for 2 minutes for melting, then (94C for 30 RNase0ut (40 U/1) 1 ul sec; 67 C for 1 minute; 72 C for 1.5 minutes) for 6 cycles, then TAP (0.5 U/ul) 1 ul (94C for 30 seconds, 60 C for 1 minute, 72C for 1.5 minutes) for 38 cycles, then 72 C for 7 minutes and then hold at 4 C. Total Volume 10 ul 0526 7. Purify RACE PCR products using the S.N.A.P. 0515. The reaction was incubated at 37° C. for 1 hour. columns included in the kit. After incubation, the RNA was precipitated with ethanol. Rapid Amplification of cDNA Ends (RACE) 0516 3. Ligate the GeneRacer RNA Oligo to the 5' end of 0527. This procedure describes the 5'-RACE and the mRNA using T4 RNA ligase. The GeneRacer RNA Oligo 3'-RACE PCR reactions that generate the 5' and 3' cDNA will provide a known priming site for GeneRacer. 7 ul of fragments. US 2009/0178153 A1 Jul. 9, 2009 50

0528 1. For each 50-ul reaction, mix the following Human PGR4 reagents: 0539 Full length cDNA was isolated from human Pitu 0529) 34.5 ul PCR-Grade Water itary by a combination of 5' and 3' Rapid Amplification of 0530) 5 Jul 10x Advantage 2 PCR Buffer cDNA Ends (RACE) and internal RT-PCR experiments using 0531. 1 ul DNTP Mix (10 mM) the methods described above. RACE pituitary was prepared 0532. 1 ul 50x Advantage 2 Polymerase Mix using the Invitrogen GeneRacer Kit (Cat #L1500-01). The following RACE primers were used: 0533 41.5 ul Total volume 0534 Mix well by vortexing (without introducing bubbles) and briefly spin the tube in a microcentrifuge. 5' RACE (Invitrogen) 0535 2. For 5'-RACE: PCR reactions as shown in Table III CGACTGGAGCACGAGGACACTGA (SEO ID NO: 1545) of Clontech's RACE kit. 3' RACE (Invitrogen) : 0536. For 3'-RACE: PCR reactions as shown in Table IV GCTGTCAACGATACGCTACGTAACG (SEQ ID NO: 1546) of Clontech's RACE kit. 5' nested RACE primer: 0537. PCR Cycle conditions: as described in the Clon- GGACACTGACATGGACTGAAGGAGTA (SEQ ID NO: 1547) tech's RACE kit. 0538 Complete reactions were then run on gel to visualize- 0 C3 gcc. tedfAACGGCarg RACE primer: (SEQ ID NO: 1548) PCR products. If the gel showed nothing then the reaction would be amplified for additional cycles (total of 40). The following cDNA primers were used:

HPG5dnO1, GCCGCGCTGCAGGTGCACGATG, (SEQ ID NO: 1549) HPG5-36 oup, TGCCACCTGCTCTTCTACGTGATG, (SEO ID NO: 1550) HPG5 - 6 O1dn GCAAATCAGTGTGCAAATCGAAA (SEO ID NO: 1551) HPG5-629 up CATTCCTGGAGAGATCTCGTGGGA (SEO ID NO: 1552) HPG5-1183din GGTGCCACTGATGGAGGGTACTG, (SEQ ID NO; 1553) HPG5-755up GGTAAGCCTGGCCTACTCGGAGAG, (SEO ID NO: 1554) HPGsMaxDN TGCACCTGGCCAACAAATCCTTTT, (SEO ID NO: 1555) HPGSMaxUP GGTAAGCCTGGCCTACTCGGAGAG, (SEO ID NO: 1556) HPGgMax5up18 GGGCCAGAGGCGAGATGT, (SEO ID NO: 1557) HPG5gMax5.dn GCAGGTCCGCGCAGAA, (SEO ID NO: 1558) used for 5 RACE HPG5gMax3up CCACCAGATCCGCGTGTC; (SEO ID NO: 1559) used for 3 "RACE HPG5gMax3 end GTTGGTCAGGTTGGTCTCGAAC, (SEQ ID NO: 1560) PGR4 cDNA sequence (SEQ ID NO: 88) ATGGACTCATTACAAGTTGTTTTAGGATCTAC CTCCAGACCCATGGAGTTTCTTTAGTAA

AGCCTGAACGACACAGGCCAAAATAATCTCCAAAGGCCAGCTCTGACCCTTTTAAATCAA

TTTTAGCTAAATCCGTTCACAAAAGGCTTCGCACATCCAGTGTCCCTGAAAAATAAAGGA

GGTTGGGCAGGCCCTGCGGGGGCTCGAGGAATTCGCTAAGTGAGTTTTCTGGCTTCTGGA

TACACTTTCAAAGGGCCAGAGGGCACGAGGCTTCCGCCTTGGCCGCCACCTCCCCGGCCA

GCTGCGGTGTTCGCGGCCAGTGTTGCCGGGCACTTCCTGGTTCCCGCGCGCCCCGGGTGC

AGCTCCCTGCACCCAGTGCTGGCGCTCCTCAGAAGGGAGGGGGCCAGAGGCGAGATGTCG

CAACCGCCTCCCTCCCTCTTTCCCCGCCTTGGCACTCAGTCGCCTCCCAGATGAGCACTC

TCTCAGACCGCTGCGGGCCGCCAGGCGCCGGGAATGTCCCCTGAATGCGCGCGGOCAGCG

GGCGACGCGCCCTTGCGCAGCCTGGAGCAAGCCAACCGCACCCGCTTTCCCTTCTTCTCC

GACGTCAAGGGCGACCACCGGCTGGTGCTGGCCGCGGTGGAGACAACCGTGCTGGTGCTC

ATCTTTGCAGTGTCGCTGCTGGGCAACGTGTGCGCCCTGGTGCTGGTGGCGCGCCGACGA

US 2009/0178153 A1 Jul. 9, 2009 55

- Continued

TGTCTCCCGCAGACTGGGCAATTCTCAGACTGGTAGATGAGAAGAGATGGAAGAGAAGAA

AGGAGAGCATGAAGCTTGTTTTTACTTATGCATTTATTTCCACAGAGTCGTAATGACAGC

AAAAGCTCCTACCAGTTTGAAGATGCCATTGGAGCTTGTGTCATCATCCTGTGACCAGTT

AGGACACAAAGTAGAGAAGTAGTCTGTGATTTCGCCCTGGTACCATCCACAGTCACTGGG

AACCCTTCATTTATGGGACTTACCAAGCCCCAGTAGCACATAGCTGAGCCTGCACTCTTC

TTCCGAGAGCTGAGGTCATTCATCACTTCCCTCTGCTGTTCCCAGGAGCTAACAATAATG

ACTATTTCAGGATTTTTTTCAAGGTGCCCTTTGTCCTAGAGAGGGTTGTGGTCTTGAATT

GGCTCTGGCACTCCTAGCTTCAGAATGACACTGTGGGAATAGAAGAGTATTGGATCCCAT

CCAAACTGTGGCCAGAGCTTCTTCAGGAAATCTCCAAACCCGCATAGCTGTGACCT CAAA

CCTGGGGTCTAAAAGGCAGTTTTCTATTTATCATTATGTATAGATTTTCTCTATCTCCTC

CAAAACAAAGACCCTGCCTGGTGCGCAGGGGGAAAGGAGGAATTCTCGAGCCC PGR3 polypeptide sequence (SEQ ID NO: 53 ) MEHTHAHLAANSSLSWWSPGSACGLGFWPWWYYSLLLCLGLPANILTVIILSQLWARROK

SSYNYLLALAAADILWLFFIVFWDFLLEDFILNMOMPOVPDKIIEWLEFSSIHTSIWITV

PLTIDRYITWCHPLKYHTVSYPARTRKVIWSWYITCFLTSIPYYWWPNIWTEDYSTSWH

HVLIWIHCFTWYLWPCSIFFILNSIIWYKLRRKSNFRLRGYSTGKTTAILFTITSIFATL

WAPRIIMILYHLYGAPIONRWLWHIMSDIANMLALLNTAINFFLYCFISKRFRTMAAATL

KAFFKCOKOPVOFYTNHNFSITSSPWISPANSHCIKMLVYOYDKNGKPIKVSP

Human PGR6 0542. Full length cDNA was isolated from human whole - Continued brain by a combination of s and 3' Rapid Amplification of 3' RACE (Invitrogen) : cDNA Ends (RACE) and internal RT-PCR experiments aS GCTGTCAACGATACGCTACGTAACG (SEQ ID NO: 1546) described above. RACE pituitary was prepared using the Invitrogen GeneRacer Kit (Cat #L1500-01). 5' nested RACE primer: The following RACE primers were used: GGACACTGACATGGACTGAAGGAGTA (SEQ ID NO: 1547) 3' nested RACE primer: 5' RACE (Invitrogen) CGCTACGTAACGGCATGACAGTG (SEQ ID NO: 1548) CGACTGGAGCACGAGGACACTGA (SEO ID NO: 1545) The following cDNA primers were used:

ET11-01up ATGGGGGATGAGCTGGCACCTTG (SEQ ID NO: 1583)

ET11 - Oldn TGGCACGGGGAAGCATCATGAGT (SEQ ID NO: 1584) ET11- O2up TAGTTCCAGACAGCTGCTCCTTCCTTT (SEO ID NO: 1585)

ET11 - O2din GAAGTCTTGGCCTCTGCATAGATCCTC (SEQ ID NO: 1586)

ET11-03up ATGGTGGCAGTGGGATGATCTGTTA (SEO ID NO: 1587)

ET11 - O3din AGGTAGCGCAGTGGATGGATGACT; (SEO ID NO: 1588) used in 5 RACE

ET11-04 up GCTGTACTGGCTTTTCCTTCCCTCA (SEO ID NO: 1589)

ET11 - O 4din ACACCACCCCTGTGCTCACGTA (SEO ID NO: 1590)

ET11-05up CTGCTCTCAGACCTGGCCTACAT (SEQ ID NO: 1591)

ET11 - Oson CTAGGAAATGGTAAAGATGGCCTGG (SEQ ID NO: 1592)

US 2009/0178153 A1 Jul. 9, 2009 57

Human PGR10 0543 Full length cDNA was isolated from human Pitu - Continued itary by a combination of 5' and 3' Rapid Amplification of Smart IIA cDNA Ends (RACE) and internal RT-PCR experiments as (SEO ID NO : 1599) described above. RACE pituitary was prepared using the AAGCAGTGGTATCAACGCAGAGTACGCGGG Clontech SMART RACE Kit (Cat #K1811-1). The following CLONTECH RACE primers were used: NUP (SEQ ID NO: 16 OO) AAGCAGTGGTATCAACGCAGAGT 3'-RACE - CDS (SEO ID NO : 1597) UPM-LONG AAGCAGTGGTATCAACGCAGAGTACTTTTTTTTTTTTTTTTTTTTTTTTT (SEQ ID NO: 1601) CTAATACGACT CACTATAGGGCAAGCAGTGGTATCAACGCAGAGT TTTTTVN UPM-SHORT 5'-RACE - CDS (SEO ID NO : 1598) (SEQ ID NO: 16O2) TTTTTTTTTTTTTTTTTTTTTTTTVN CTAATACGACT CACTATAGGGC (WHERE N = A, C G T AND W = A, C, G) The following cDNA primers were used:

TGGATGATCTCATGAGCGTCCTG (SEQ ID NO: 603)

1. TCTGAAACCCCACGACGTTCTG (SEQ ID NO: 604)

AGAACCGGGGGACTCTCTATGG (SEQ ID NO: 605)

2 GGTGGGCAAAAAGAGGGAGTATG (SEQ ID NO: 606)

CACAAGTCAGATCTCCATCCCTACG (SEQ ID NO:

8 TGCTGTATCCAGAAGCCTACCATGT (SEQ ID NO: 608)

GGACTGTGTCTCTCCATGCACCTAC (SEQ ID NO: 609)

GATCCATTCTTGCTCCTGTTAGACCA (SEQ ID NO: 610)

TGACTCTTATGCATGGGATTGATGA (SEQ ID NO: 611)

6 CTCCTACCAAGTTCCCCTCTAGATGTT (SEQ ID NO: 612)

AGATGGGATTCTGTGCACAAGCTC (SEQ ID NO: 613)

s ACATGAAGATGGT CACCGACAGG (SEQ ID NO: 614)

GTAGAAATCAGCACCACGCCCTCT (SEQ ID NO: 615)

CAGATCTCCATCCCTACGTTACTCCA (SEQ ID NO: 616) PGR1O cDNA sequence determined by PCR and RACE (SEQ ID NO : 6) TTTTTTTTTTTATGCTTGAAATGGAACCTAATTTTTAAATATAGCTTGAGTCAGATCTAAAG

GAGACATGGCTGACCATTTTCTGCAGGACTGACAAGGAGAACATCTAGAGGGGAACTTGGTA

GGAGGAATGAAA CTGATTTGCAGCAGCCGGTCTTTCTTTTGAGAAAATTATCAGACTCATT

GATAAGGGAAAT AAATATTGACCAAGGACA ATGTOcTTTATTTCTCAGTAACTTATCAACAAA

TGACTCTAGCCTGTGGAAAGAGAATCATAATTCTACGGACC TTTAAATCCGCCAGGAACCC

TGAATATCTATC TTTTTGCTTGACATGTCTCATGACTTTTGCAGCCTTGGTGGGCAGCATT

TATTCACTAATTT CCCTGCTGAAAATGCAGAACAGAACTGT GTGTCCATGCTTGTGGCTTC

CTGGTCTGTGGA GATCTCATGAGCGTCCTGTCGGTGACCA CTTCATGTTTTTGCAGTGGC

CAAACGAGGTCCCCGGTTAGTTCCAATTTCTGTGCACCACC CTGCCTTAATGTATTTATGC

CAGGGCCTCTCTAGCAACTTGAAGGCGACTCTCCTAGTCTC TACAACTTTTATACGATGCA

CAGAGGTGTGGGGAGCCAGACAGCCTCCAGAAGATCGGGCCAGGTGCTCGGCGTGGTGCTGA

CCGTGTGGGCAGCCAGTCTGCTGCTCTCGGCGCTCCCGCTGTGCGGCTGGGGCGCCTTCGTG

US 2009/0178153 A1 Jul. 9, 2009 59

- Continued SSSYWLFLSIWYALAFGLLVGLSVPLTHRLLCSEEPPRLHSNYOEISRGASIPGTPPTAGRV

WSLSPEDAPGPSLRRSGGCSPSSDTVFGPGAPAAAGAEACRRENRGTLYGTRSFTVSVAOKR

FALILALTKWWLWLPMMMHMVVONWVGFOSLPLETFSFLLTLLATTWTPWFVLSKRWTHLPC

GCIINCRONAYAVASDGKKIKRKGFEFNLSFOKSYGIYKIAHEDYYDDDENSIFYHNLMNSE

CETTKDPORDNRNIFNAIKVEISTTPSLDSSTORGTNKCTNTDITEAKODSNNKKDAFSDKT

GGDINYEETTFSEGPERRLISHEESOKPDLSDWEWCRSKSERTPRORSGYALAIPLCAFOGTV

SLHAPTGKTLSLSTYEVSAEGOKITPASKKIEVYRSKSVGHEPNSEDSSSTFWDTSVKIHLE

WLEICDNEEALDTVSIISNISOSSTOVRSPSLRYSRKENRFWSCDLGETASYSLFLPTSNPD

GDINISIPDTVEAHRONSKROHOERDGYOEELOLLINKAYRKREEESKGS

Human PGR25 0544) Full length cDNA was isolated from human Pitu - Continued itary by a combination of 5' and 3' Rapid Amplification of cDNA Ends (RACE) and internal RT-PCR experiments as Sma rt IIA described above. RACE pituitary was prepared using the (SEO ID NO : 1599) Clontech SMART RACE Kit (Cat #K1811-1). AAGCAGTGGTATCAACGCAGAGTACGCGGG The following CLONTECH RACE primers were used: NUP (SEQ ID NO: 16 OO) AAG CAGTGGTATCAACGCAGAGT 3'-RACE - CDS (SEO ID NO : 1597) UPM - LONG AAGCAGTGGTATCAACGCAGAGTACTTTTTTTTTTTTTTTTTTTTTTTTT (SEQ ID NO; 1601) CTAATACGACT CACTATAGGGCAAGCAGTGGTATCAACGCAGAGT TTTTTVN

5'-RACE - CDS UPM - SHORT (SEO ID NO : 1598) (SEQ ID NO: 16O2) TTTTTTTTTTTTTTTTTTTTTTTTVN CTAATACGACT CACTATAGGGC (WHERE N = A, C, G, T AND W = A, C, G) The following cDNA primers were used:

CGGTAATGGGAGGAATTCACGG (SEQ NO: 617)

CGGAGCAGACAGCCTTGAATCT (SEQ NO: 618)

GTGGATGTGGTAGCGCTGGTT (SEQ NO: 619)

AAATCCTGCCCAAGACCGTGAA (SEQ NO: 62O)

GTGGCTCGAGGCGGAAACTAA (SEQ NO: 621)

ACGGCTGTGCGCTCACGAGA (SEQ NO: 622)

AGCACGCCAAAGACCCACGAG (SEQ NO: 623)

GCTGGAAAGGAGATCGCCATGT (SEQ NO: 624)

TGGCCCATGACGGTGTCAATAG (SEQ NO: 625)

GCGTGCTTGCTGTCAACGGTT (SEQ NO: 626)

GCTCACACGGCTGACAGGTCG (SEQ NO: 627)

TGTCTTCAACGCTGCCAAGCC (SEQ NO: 628)

GGTACAGCAGACCCACGACGG (SEQ NO: 629)

J.-H-PG2O8 - U11 ATCCAAGGAGGGCCTGAAAGTCTA (SEQ NO: 630)

CAAGGCTGTCTGCTCCGAGAG (SEQ NO: 631)

GCTGGAAAGGAGATCGCCATGT (SEQ NO: 632)

US 2009/0178153 A1 Jul. 9, 2009 63

- Continued

ACCTTCTAATTTCCTATCCACATCCAGATTTACCAAGAATTCAGTTGTATCTACAACTTC

AGCAATTAAATCTCAGTCGGCTGTTACGAAGACAACATCTTTATTTTCAACTATTGAGTC

AACATCTATGTCTACAACACCTTGTCTCAAACAAAAATCCACAAATACTGGGGCACTCCC

TATCTCCACAGCTGGCCAGGAGTTCATTGAATCTACAGCTGCCGGAACTGTACCTTGGTT

TACAGTGGAAAAGACTTCACCTGCATCTACTCATGTTGGGACTGCATCATCATTCCCACC

TGAGCCTGTGCTCATCTCCACAGCTGCTCCAGTAGATTCTGTATTTCCTAGAAACCAGAC

AGCATTTCCATTGGCAACAACTGATATGAAAATAGCATTTACAGTCCATTCATTGACTCT

CCCAACTAGGCTTATTGAGACCACACCTGCCCCAAGGACAGCTGAAACAGAATTGACATC

TACAAATTTTCAGGATGTCTCTTTACCCAGAGTGGAAGATGCCATGTCTACTTCCATGTC

GAAAGAGACCTCCTCTAAGACCTTTTCTTTCTTAACATCCTTTTCATTTACTGGGACTGA

GAGTGTACAGACAGTTATTGATGCTGAAGCTACACGTACAGCCTTAACTCCTGAAATCAC

ACTTGCATCTACAGTGGCTGAAACTATGCTTTCCTCCACAATCACAGGACGAGTTTACAC

CCAGAATACACCTACAGCTGATGGACACTTGCTTACTTTGATGTCCACTAGATCAGCTTC

CACATCCAAGGCACCTGAGTCAGGTCCCACATCCACAACTGATGAAGCTGCCCATCTGTT

CTCCAGCAATGAGACCATTTGGACTTCTAGGCCAGACCAGGCCCTGCTGGCATCTATGAA

CACAACCACCATACT CACATTTGTGCCTAATGAAAATTTTACATCAGCATTTCATGAGAA

TACTACTTATACAGAATATTTATCCGCAACTACCAATATCACCCCACTGAAAGCATCTCC

AGAGGGCAAAGGTACCACTGCCAATGATGCTACTACAGCCAGATATACAACAGCTGTATC

CAAATTGACATCACCATGGTTTGCTAATTTCTCCATAGTTTCTGGAACCACATCCATAAC

CAATATGCCTGAATTTAAACTTACCACTTTACTACTAAAAACAATAC CTATGTCTACAAA

ACCTGCAAATGAACTTCCTTTGACACCAAGGGAGACTGTTGTTCCATCAGTAGATATAAT

ATCTACTCTTGCTTGCATTCAACCAAATTTTTCTACTGAGGAAAGTGCTTCTGAGACCAC

ACAAACAGAAATAAATGGTGCAATTGTATTTGGAGGTACAACGACCCCTGTACCAAAGTC

AGCAACAACACAAAGATTAAATGCCACTGTGACAAGAAAAGAAGCAACTTCCCATTATCT

TATGAGAAAATCAACTATAGCAGCAGTGGCTGAGGTTTCTCCATTTTCAACAATGCTGGA

AGTGACAGACGAATCAGCACAAAGGGTGACAGCTTCTGTCACTGTTTCCTCTTTTCCTGA

TATAGAAAAGCTAAGTACCCCATTGGATAATAAAACTGCAACAACTGAGGTGAGAGAAAG

TTGGCTTTTGACAAAATTGGTGAAAACCACACCTAGGAGTTCATACAATGAAATGACAGA

AATGTTTAATTTTAACCACACCTATGTAGCACATTGGACTTCAGAGACATCTGAGGGAAT

TTCAGCTGGATCTCCCACTTCTGGGAGCACACATATATTCGGTGAACCCCTGGGTGCTTC

TACCACAAGGATATCAGAAACCAGTTTCTCCACTACCCCTACAGACAGGACAGCTACGTC

CTTGTCTGATGGTATCTTACCTCCACAGCCTACAGCTGCTCATTCCTCAGCAACCCCTGT

GCCTGTTACTCATATGTTCTCATTGCCAGTTAATGGCAGTTCTGTGGTGGCTGAGGAGAC

TGAGGTTACCATGTCTGAGCCTTCTACACTGGCCAGGGCTTTTTCTACATCTGTGCTCTC

AGATGTCTCAAATCTATCCTCAACTACAATGACCACAGCATTGGTACCACCTTTGGATCA

GACTGCTTCCACAACCATTGTTATTGTGCCTACCCATGGAGACTTGATTCGTACCACTTC

AGAGGCCACGGTAATCTCTGTCAGGAAGACATCCATGGCAGTTCCTTCTCTGACAGAAAC

ACCATTTCATTCACTGAGACTCTCCACTCCTGTGACAGCTAAGGGTGAGACCACCCTTTT US 2009/0178153 A1 Jul. 9, 2009 64

- Continued CTCTACCTCAGTTGATACAGTAACCCCATCTACACACACTCTTGTCTGCTCAAAACCTCC

CCCTGACAACATTCCTCCTGCGTCCTCCACTCATGTGATCTCAACTACGTCTACACCAGA

AGCAACTCAACCAATATCTCAAGTAGAGGAGACTTCTACCTATGCTCTCAGCTTCCCATA

TACTTTCAGTGGTGGTGGAGTTGTTGCCAGCTTGGCTACTGGCACCACAGAGACCTCTGT

TGTTGATGAGACCACACCCTCACACATCTCTGCCAATAAGTTGACTACTTCAGTAAACAG

TCACATTTCTTCATCTGCCACATATCGTGTACACACACCAGTGTCCATCCAGTTGGTGAC

TAGCAC CTCTGTCTTATCTTCCGACAAAGACCAGATGACCATATCCCTGGGAAAAACCCC

TAGAACTATGGAGGTGACAGAAATGTCCCCATCAAAGAATTCTTTTATTTCATACTCCCG

GGGTACTCCATCTTTGGAAATGACAGATACAGGATTTCCTGAGACCACAAAAATTTCCAG

TCACCAAACACATTCGCCTTCAGAGATTCCACTTGGGACTCCCTCTGATGGAAATTTGGC

TTCATCTCCCACTTCTGGAAGCACACAGATTACACCAACCTTGACCTCAAGTAACACAGT

AGGTGTTCACATTCCAGAAATGTCTACCAGTCTTGGGAAAACAGCTCTCCCCTCACAAGC

TCTGACAATCACCACTTTTTTGTGTCCTGAAAAGGAAAGCACGAGTGCCCTTCCAGCATA

TACTCCCAGGACTGTGGAAATGATAGTAAACTCCACCTATGTGACT CACTCTGTCTCATA

TGGCCAGGATACTTCATTTGTAGATACCACAACTTCCAGCTCAACAAGGATATCAAATCC

TATGGACATCAATACAACTTTTTCACACTTGCATTCACTTAGGACACAACCTGAGGTGAC

TTCAGTTGCCTCTTTCATTTCTGAAAGCACACAGACTTTCCCTGAGTCCTTGTCTCTTTC

CACAGCTGGACTATATAATGACGGTTTTACAGTTCTCTCCGACAGGATCACTACAGCCTT

TTCTGTTCCAAATGTACC TACAATGCTTCCTAGAGAATCCTCTATGGCAACGTCCACTCC

TATTTACCAGATGTCCTCATTGCCAGTTAATGTAACTGCCTTCACCTCCAAAAAAGTTTC

TGACACTCCCCCAATAGTGATAACTAAATCTTCTAAAACAATGCATCCAGGTTGTTTGAA

AAGTCCCTGTACAGCCACTTCTGGGCCTATGTCTGAGATGTCCTCAATACCAGTTAATAA

CTCTGCTTTCACACCTGCAACAGTCTCTTCTGACACTTCCACAAGAGTTGGGTTATTCTC

TACTTTATTGTCTTCAGTTACCCCCAGGACTACTATGACCATGCAAACATCTACATTGGA

TGTCACACCTGTGATATATGCTGGGGCTACTTCAAAAAACAAAATGGTTTCCTCTGCTTT

CACTACAGAAATGATAGAGGCACCTTCCAGGATCACACCTACGACCTTTCTCTCTCCAAC

AGAGCCAACTTTGCCCTTTGTAAAAACCGTTCCCACCACCATTATGGCTGGGATAGTGAC

TCCATTTGTAGGCACCACTGCCTTCTCTCCACTCAGTTCTAAGAGCACTGGAGCTATTTC

CTCCATTCCAAAGACCACATTTTCACCATTTCTATCAGCAACT CAACAGTCATCACAAGC

AGATGAGGCTACAACTTTGGGCATATTATCTGGGATTACTAACAGGTCCCTATCTACTGT

GAACAGTGGTACAGGGGTAGCTCTCACAGATACTTATTCCAGAATCACTGTTCCTGAAAA

TATGCTTTCACC TACTCATGCAGATAGTCTCCATACTTCCTTCAATATTCAGGTTTCCCC

ATCTCTGACTAGCTTTAAGAGTGCTTCTGGACCCACAAAAAATGTTAAAACAACCACCAA

TTGCTTTTCTTCTAATACTAGAAAGATGACTTCCTTGTTAGAAAAGACTTCCTTAACAAA

CTATGCCACATCTTTGAATACCCCTGTTTCATACCCTCCATGGACCCCATCCAGTGCAAC

TCTACCCTCTTTGACATCATTTGTTTATTCACCTCATAGTACTGAAGCTGAGATCTCTAC

TCCAAAGACCTCTCCTCCTCCCACATCCCAAATGGTTGAATTTCCAGTTCTGGGAACAAG

AATGACATCTAGTAATACCCAAC CTCTGCTTATGACTTCCTGGAACATACCCACAGCTGA

AGGTTCTCAGTTTCCAATTTCCACCACTATTAATGTACC TACATCCAATGAGATGGAAAC US 2009/0178153 A1 Jul. 9, 2009 65

- Continued

AGAGACTCTACACCTTGTTCCTGGGCCTTTGTCAACATTCACAGCCTCTCAGACTGGTCT

AGTATCTAAAGATGTCATGGCAATGTCATCAATTCCTATGTCAGGAATTCTTCCTAACCA

TGGGCTTTCTGAGAACCCTTCATTATCAACATCTTTAAGAGCTATCACTTCCACATTGGC

TGACGTTAAGCACACATTTGAGAAAATGACCACATCTGTAACTCCTGGGACCACACTCCC

ATCAATTCTTTCTGGTGCCACTTCAGGATCTGTAATTTCAAAGTCACCCATTCTGACATG

GCTCTTATCTAGTCTCCCTTCTGGCTCCCCTCCGGCAACTGTATCTAATGCCCCTCATGT

TATGACTTCCTCTACAGTAGAGGTGTCAAAATCAACATTTCTGACATCTGACATGATATC

AGCGCACCCATTCACTAACTTGACAACACTACCCTCTGCTACTATGAGCACCATACT CAC

CCGAACCATTCCTACACCTACACTGGGTGGTATCACTACTGGCTTCCCAACTTCTCTCCC

TATGTCTATAAATGTCACAGATGACATTGTGTACATTTCCACACACCCTGAGGCATCCTC

CAGAACCACAATAACTGCCAACCCCAGGACTGTGTCTCATCCTTCATCCTTCAGCAGAAA

GACTATGTCACCTTCTACAACTGACCACACTCTATCTGTTGGTGCCATGCCTCTGCCTAG

CTCTACAATAACATCTTCATGGAACAGAATTCCAACTGCATCATCACCCTCTACTTTAAT

TATTCCTAAGCCCACACTGGACTCCCTTCTAAATATAATGACTACTACATCCACTGTTCC

TGGAGCCTCATTTCCACTCATATCCACTGGGGTGACATATCCTTTTACAGCAACTGTGTC

TTCACCAATATCGTCCTTTTTTGAAACAACTTGGCTGGACTCCACACCTTCCTTTCTATC

TACGGAAGCATCGACTTCGCCTACTGCCACCAAGTCCACAGTTTCCTTCTACAATGTTGA

AATGAGCTTCTCTGTCTTTGTTGAAGAGCCAAGGATCCCTATTACCAGTGTTATAAATGA

ATTTACGGAAAATTCGTTGAATTCTATATTTCAGAACAGTGAATTTTCTCTTGCTACTCT

GGAAACCCAAATTAAAAGCAGGGACATTTCAGAGGAAGAGATGGTCATGGATCGAGCTAT

TTTGGAACAGAGAGAAGGACAAGAAATGGCTACAATTTCCTATGTACCATACAGTTGTGT

TTGTCAGGTCATCATAAAAGCCAGCTCTTCCTTAGCATCCTCTGAATTGATGAGAAAAAT

CAAAAGTAAAATACATGGCAACTTCACACATGGAAACTTCACACAAGATCAATTGACGTT

ATTAGTAAACTGTGAACACGTTGCAGTGAAAAAACTAGAGCCTGGAAATTGCAAAGCTGA

TGAAACAGCCTCTAAATACAAAGGGACCTATAAGTGGCTATTAACCAACCCTACGGAGAC

AGCCCAAACCAGATGCATAAAAAATGAGGATGGAAATGCCACAAGATTCTCAATCAGCAT

CAACACGGGCAAATCTCAGTGGGAAAAGCCAAAGTTTAAACAATGCAAATTGCTTCAAGA

ACTTCCTGACAAGATTGTGGATCTTGCTAATATTACCATAAGTGATGATTTTCCTAGGCA ATGTCCCTGTGGGAGGGATTTTGGCTTCCATATATTTGCC tATcacrgacqGagagaa

TTCCTCTTAGCAACTTACAAACGATCTTGTTTAATTTCTTTGGCCAAACTTCACTCTTTA

AGACCAAAAATGTCACTAAAGCATTAACCACCTATGTTGTGAGTGCCAGCATTTCAGATG

ATATGTTCATTCAAAACTTAGCTGACCCAGTGGTTATCACTCTGCAGCATATTGGAGGAA

ACCAGAATTATGGTCAAGTTCACTGTGCCTTTTGGGATTTTGAGAATAATGGGCTGGGTG

GATGGAATTCGTCAGGCTGTAAAGTAAAGGAAACAAATGTAAATTACACAATCTGTCAGT

GTGACCACCT CACCCATTTTGGAGTCTTAATGGAAACTTCGAAAAGATTATCCTGCCAAA

ATTCTGATCAACCTGTGCACAGCACTACTGATGCTAAACCTGGTATTTTTGATCAATTCT

TGGTTGTCATCATTTCAGAAAGTGGGAGTTTGTATCACAGCTGCAGTGGCACTTCATTAC

TTCCTGCTTGTTTCTTTTACTTGGATGGGCCTGGAGGCAGTCCACATGTATTTGGCTCTA