US 2011 0185439A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0185439 A1 Gaitanaris et al. (43) Pub. Date: Jul. 28, 2011
(54) GPROTEIN COUPLED RECEPTORS AND Publication Classification USES THEREOF (51) Int. Cl. (75) Inventors: George A. Gaitanaris, Seattle, WA GOIN 33/48 (2006.01) (US); John E. Bergmann, Mercer AOIK 67/027 (2006.01) Island, WA (US); Alexander CI2N 15/87 (2006.01) Gragerov, Seattle, WA (US); John CI2N 5/10 (2006.01) Hohmann, Seattle, WA (US); C07K I4/47 (2006.01) Fusheng Li, Seattle, WA (US); C7H 2L/04 (2006.01) Linda Madisen, Seattle, WA (US); A63L/7088 (2006.01) Kellie L. McIlwain, Washington, A6IP 25/00 (2006.01) DC (US); Maria N. Pavlova, A6IP3/00 (2006.01) Seattle, WA (US); Demetri CI2O I/68 (2006.01) Vassilatis, Seattle, WA (US); A6IP 9/00 (2006.01) Hongkui Zeng, Shoreline, WA A6IP 700 (2006.01) (US) GOIN 33/53 (2006.01) (52) U.S. Cl...... 800/3; 800/18: 800/8: 800/21: (73) Assignee: OMEROS CORPORATION, 435/325; 530/350,536/23.5; 514/44 R; 435/6.11; Seattle, WA (US) 435/6.13:435/7.1 (21) Appl. No.: 12/970,094 (57) ABSTRACT (22) Filed: Dec. 16, 2010 The present invention provides GPCR polypeptides and poly nucleotides, recombinant materials, and transgenic mice, as Related U.S. Application Data well as methods for their production. The polypeptides and polynucleotides are useful, for example, in methods of diag (63) Continuation of application No. 12/243,731, filed on nosis and treatment of diseases and disorders. The invention Oct. 1, 2008, now abandoned, which is a continuation also provides methods for identifying compounds (e.g., ago of application No. 10/527,265, filed on Jan. 26, 2006, nists or antagonists) using the GPCR polypeptides and poly now abandoned, filed as application No. PCT/US03/ nucleotides of the invention, and for treating conditions asso 28226 on Sep. 9, 2003. ciated with GPCR dysfunction with the GPCR polypeptides, (60) Provisional application No. 60/409,303, filed on Sep. polynucleotides, or identified compounds. The invention also 9, 2002, provisional application No. 60/461.329, filed provides diagnostic assays for detecting diseases or disorders on Apr. 9, 2003. associated with inappropriate GPCR activity or levels. Patent Application Publication Jul. 28, 2011 Sheet 1 of 31 US 2011/O185439 A1
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GPROTEIN COUPLED RECEPTORS AND and modulating compounds for use in the treatment and diag USES THEREOF nosis of a wide variety of disorders and diseases. SUMMARY OF THE INVENTION CROSS-REFERENCES TO RELATED APPLICATIONS 0007. The present invention provides GPCR polypeptides and polynucleotides, recombinant materials, and transgenic 0001. This application is a continuation of U.S. patent mice, as well as methods for their production. The polypep application Ser. No. 12/243,731, filed Oct. 1, 2008, now tides and polynucleotides are useful, for example, in methods pending, which is a continuation of U.S. patent application of diagnosis and treatment of diseases and disorders. The Ser. No. 10/527,265, filed Jan. 26, 2006, now abandoned, invention also provides methods for identifying compounds which is a U.S. national stage application of PCT Patent (e.g., agonists or antagonists) using the GPCR polypeptides and polynucleotides of the invention, and for treating condi Application No. PCT/US03/28226, filed Sep. 9, 2003, which tions associated with GPCR dysfunction with the GPCR claims the benefit under 35 U.S.C. S 119(e) of U.S. Provi polypeptides, polynucleotides, or identified compounds. The sional Patent Application No. 60/409,303, filed Sep. 9, 2002, invention also provides diagnostic assays for detecting dis and U.S. Provisional Patent Application No. 60/461,329, filed eases or disorders associated with inappropriate GPCR activ Apr. 9, 2003, where all of the above applications are incor ity or levels. porated herein by reference in their entireties. 0008. In one aspect, the invention features a variety of substantially pure GPCR polypeptides. Such polypeptides STATEMENT REGARDING SEQUENCE include: (a) polypeptides including a polypeptide sequence LISTING having at least 90%, 95%, 97%, 98%, or 99% identity to a polypeptide listed in Table 2; (b) polypeptides that include a 0002 The Sequence Listing associated with this applica polypeptide listed in Table 2; (c) polypeptides having at least tion is provided in text format in lieu of a paper copy, and is 90%.95%,97%.98%, or 99% sequence identity to a polypep hereby incorporated by reference into the specification. The tide listed in Table 2; and (d) polypeptides listed in Table 2. name of the text file containing the Sequence Listing is 0009 Polypeptides of the present invention also include variants of the aforementioned polypeptides, including all NG 1 0058 US3 SEQUENCELISTING..txt. The text file allelic forms and splice variants. Such polypeptides vary from is 4.87 MB, was created on Dec. 13, 2010, and is being the reference polypeptide by insertions, deletions, and sub submitted electronically via EFS-Web, concurrent with the stitutions that may be conservative or non-conservative, or filing of the specification. any combination thereof. Particularly desirable variants are those in which several, for instance from 50 to 30, from 30 to BACKGROUND OF THE INVENTION 20, from 20 to 10, from 10 to 5, from 5 to 3, from 3 to 2, or from 2 to 1 amino acids are inserted. Substituted, or deleted, in 0003. The invention relates to the fields of medicine and any combination. drug discovery. 0010 Polypeptides of the present invention also include 0004 Mammalian G protein coupled receptors (GPCRs) polypeptides that include an amino acid sequence having at 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, 0011. 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. 0005 Of all currently marketed drugs, greater than 30% 0012 Polypeptides of the present invention can be pre are modulators of specific GPCRs. Only 10% of GPCRs pared in any Suitable manner, for instance by isolation from (excluding cSGPCRs) are targeted by these drugs, emphasiz naturally occurring sources, from genetically engineered host ing the potential of the remaining 90% of the gene family for cells comprising expression systems, or by chemical synthe the treatment of human disease. sis, using for instance automated peptide synthesizers, or a 0006. Despite the importance of GPCRs in physiology and combination of Such methods. For example, polypeptides of disease, the size of the GPCR superfamily is still uncertain. the invention may be produced by expressing in a cell (e.g., a Analyses of genome sequences have generated markedly var yeast, bacterial, mammalian, or insect cell) a vector contain ied estimates (Venter, J. C. et al., Science 291, 1304-51 ing a polynucleotide that encodes a GPCR of the invention (2001); Lander, E. S. et al., Nature 409, 860-921 (2001): under condition in which the polypeptide (e.g., one listed in Takeda, S. et al., FEBS Lett 520,97-101 (2002)). In addition, Table 2) is expressed. Means for preparing such polypeptides while most GPCRs are known to be selectively expressed in are well understood in the art. subsets of cells, the expression patterns of most GPCRs are 0013. In another aspect, the invention features substan incomplete or unknown. Thus, there is a need for GPCR tially pure GPCR polynucleotides. Such polynucleotides polypeptides, polynucleotides, antibodies, genetic models, include: (a) polynucleotides that include a polynucleotide US 2011/O 185439 A1 Jul. 28, 2011 sequence having at least 90%. 95%, 97%, 98%, or 99% a polypeptide listed in any one of Tables 3-14 and 33; (b) sequence identity to a polynucleotide listed in Table 2; (b) contacting the transgenic non-human mammal with the can polynucleotides that include a polynucleotide sequence hav didate compound; and (c) measuring biological activity of the ing at least 90%, 95%, 97%, 98%, or 99% sequence identity GPCR polypeptide in the transgenic non-human mammal, to the reverse complement of polynucleotide listed in Table 2: wherein altered biological activity, relative to that of the (c) polynucleotides that include a polynucleotide listed in transgenic non-human mammal not contacted with the com Table 2; (d) polynucleotides that are the reverse complement pound, indicates that the candidate compound may be useful of polynucleotide listed in Table 2: (e) polynucleotides hav for the treatment of a neurological disease or disorder. ing at least 90%, 95%, 97%, 98%, or 99% sequence identity 0020. In yet another aspect, the invention features a to a polynucleotide listed in Table 2: (f) polynucleotides hav method for determining whether a candidate compound is a ing at least 90%, 95%, 97%, 98%, or 99% sequence identity compound that may be useful for the treatment of a neuro to the reverse complement of polynucleotide listed in Table 2: logical disease or disorder. This method includes the steps of (g) polynucleotides listed in Table 2: (h) reverse complement (a) providing a transgenic non-human mammal (e.g., a of polynucleotides listed in Table 2: (i) polynucleotides that mouse) overexpressing a nucleic acid molecule encoding a include a polynucleotide sequence encoding a polypeptide GPCR polypeptide substantially identical to a polypeptide sequence having at least 90%. 95%, 97%, 98%, or 99% iden listed in any one of Tables 3-14 and 33; (b) contacting the tity to a polypeptide listed in Table 2: (i) polynucleotides transgenic non-human mammal with the candidate com including a nucleotide sequence encoding a polypeptide pound; and (c) measuring biological activity of the GPCR listed in Table2; and (k) polynucleotides encoding a polypep polypeptide in the transgenic non-human mammal, wherein tide listed in Table 2. Preferred GPCR polynucleotides of the altered biological activity, relative to that of the GPCR present invention have at least 15, 30, 50 or 100 contiguous polypeptide in the transgenic non-human mammal not con nucleotides from any of the polynucleotides listed in Table 2. tacted with the compound, indicates that the candidate com 0014. In one embodiment, the polynucleotide is operably pound may be useful for the treatment of a neurological linked to a promoter for expression of the polypeptide disease or disorder. encoded by the polynucleotide. In certain embodiments, the 0021. In still another aspect, the invention features another promoter is a constitutive promoter, is inducible by one or method for determining whether a candidate compound may more external agents, or is cell-type specific. be useful for the treatment of a neurological disease or disor 0015. 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 0016. 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. 0022. In another aspect, the invention features yet another 0017. 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 0023 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 0018. 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) 0024. 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 0019. 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 0025. 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 US 2011/O 185439 A1 Jul. 28, 2011
includes the step of determining whether the patient has a cerebellar degeneration, alcoholic dementia, alcoholic hallu mutation in a gene encoding a polypeptide listed in one of cinosis, alcoholic polyneuropathy, alcohol-induced anxiety Tables 3-14 and 33, wherein presence of the mutation indi disorders, alcohol-induced dementia, alcohol-induced mood cates that the patient has an increased risk for developing a disorders, alcohol-induced psychosis, alcoholism, Alex neurological disease or disorder. ander's syndrome, alexia, alexia with agrphia, alexia without 0026. In a related aspect, the invention features another agraphia, alien hand syndrome, Alper's disease, altered sexu method for determining whether a patient has an increased ality syndromes, alternating hemiplagia, Alzheimer's dis risk for developing a neurological disease or disorder. This ease, Alzheimer-like senile dementia, Alzheimer-like juve method includes the step of determining whether the patient nile dementia, amenorrea, aminoacidurias, amnesia, amnesia has a polymorphism in a gene encoding a polypeptide listed in for offences, amok-type reactions, amorphognosia, amphet any one of Tables 3-14 and 33, wherein presence of the amine addiction, amphetamine or amphetamine-like related polymorphism indicates that the patient has an increased risk disorders, amphetamine withdrawal, amyloid neuropathy, for developing a neurological disease or disorder. amyotrophic lateral Sclerosis, anencephaly, aneurysms, 0027. In either of these two methods, the mutation or poly angioblastic meningiomas, Angleman's syndrome, anhidro morphism is preferably associated with an alteration (for sis, anisocoria, anomia, anomic aphasia, anorexia nervosa, example, a decrease) in the expression level or biological anoSmia, anosognosia, anterior cingulate syndrome, antero activity of the polypeptide. grade amnesia, antibiotic-induced neuromuscular blockade, 0028. In another aspect, the invention features another antisocial personality disorder, Anton's syndrome, anxiety method for determining whether a patient has an increased and obsessive-compulsive disorder syndromes, anxiety dis risk for developing a neurological disease or disorder. The orders, apathy syndromes, aphasia, aphemia, aplasia, apnea, method includes measuring biological activity of a GPCR apraxia, arachnoid cyst, archicerebellar syndrome, Arnold polypeptide from the patient that is substantially identical to Chiari malformation, arousal disorders, arrhinencephaly, a polypeptide listed in any one of Tables 3-14 and 33, wherein arsenic poisoning, arteriosclerotic Parkinsonism, arterio increased or decreased levels in the GPCR biological activity, venous aneurysm, arteriovenous malformations, aseptic relative to normal levels, indicates that the patient has an 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, 0029. 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 0030 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 1 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, Bouffée 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, cancer pain, cannabis dependence, idiopathic sensory neuronopathy, acute intermittent porphy cannabis flashbacks, cannabis psychosis, cannabis related ria, acute mania, acute mixed episode, acute pandysautono disorders, carcinoma-associated retinopathy, cardiac arrest, mia, acute polymorphic disorder with symptoms of Schizo cavernous 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, US 2011/O 185439 A1 Jul. 28, 2011
choreoathetosis, chromophobe adenoma, chromosomal dis bral palsy, dyslexia, dysmetria, dysomnia, dysosmia, orders, chronic biplar major depression, chronic bipolar dis dyspareunia, dysphagia, dysphasia, dysphonia, dysplasia, order, chronic demyelinating polyneuritis, chronic depres dyspnea, dysprosody, dyssomnia, dyssynergia, dysthesia, Sion, chronic fatigue syndrome, chronic gm2 gangliosidosis, dysthymia, dystonia, dystrophinopathies, early adolescent chronic idiopathic sensory neuropathy, chronic inflammatory gender identity disorder, early infantile epileptic encepha demyelinating polyneuropathy, chronic inflammatory demy lopthy (Ohtahara syndrome, early myoclonic epileptic elinating polyradiculoneuropathy, chronic pain, chronic par encephalopathy, Eaton-Lambert syndrome, echinococcus oxysmal hemicrania, chronic Sclerosing panencephalitis, (hydatid cysts), echolalia, echovirus, eclampsia, Edward's chronic traumatic encphalopathy, chronobiological disor syndrome, elimination disorders, embolismintracerebral ders, circadian rhythm disorder, circadian rhythm disorders, hemorrhage, Emery-Dreifuss muscular dystrophy, encepha Claude's syndrome, clonic seizures, cluster headache, litis lethargica, encephaloceles, encephalotrigeminal angi cocaine addiction, cocaine withdrawal, cocaine-related dis omatosis, enophthalmos, enterovirus, enuresis, eosinophilic orders, Cockayne's syndrome, colloid cysts of the third ven meningitis, ependymoma, epidural spinal cord compression, tricle, colorado tick fever, coma, communicating hydroceph epilepsy, episodic ataxia, epstein-barr, equine encephalomy alus, communication disorders, complex partial seizures, elitis, erectile dysfunction, essential thrombocythemia, compression neuropathy, compulsive buying disorder, con essential tremor, esthesioneuroblastoma, excessive daytime ceptual apraxia, conduct disorders, conduction aphasia, con Somnolence, excessive secretion of antidiuretic hormone, duction apraxia, congenital analgesia, congenital cytomega excessive sleepiness, exhibitionism, expressive language dis lovirus disease, congenital hydrocephalus, congenital order, extramedullary tumors, extrasylvian aphasias, hypothyroidism, congenital muscular dystrophy, congenital extratemporal neocortical epilepsy, fabry's disease, facios myasthenia, congenital myotonic dystrophy, congenital capulohumeral muscular dystrophy, factitious disorder, fac rubella syndrome, congophilic angiopathy, constipation, titious disorders, false memories, familial dysautonomia, coprophilia, cornedlia de lange syndrome, cortical demen familial periodic paralysis, familial spastic paraparesis, tias, cortical heteropias, corticobasal degeneration, cortico familial spastic paraplegias, fear disorders, feeding and eat basal ganglionic degeneration, coxsackievirus, cranial men ing disorders of infancy or early childhood, female sexual ingoceles, craniopharyngioma, craniorachischisis, arousal disorder, fetal alcohol Syndrome, fetishism, flaccid craniosynostosis, cranium bifidum, cretinism, Creutzfeldt dysarthria, floppy infant syndrome, focal inflammatory Jaknock outb disease, Cri-du-Chat syndrome, cruciate demyelinating lesions with mass effect, focal neonatal hypo hemiplegia, cryptococcal granulomas, cryptococcosis, cul tonia, folie à deux, foramen magnum tumors, Foville's syn turally related syndromes, culturally Stereotyped reactions to drome, fragile-X syndrome, Freidrich's ataxia, Frolich syn extreme environmental conditions (arctic hysteria), Cushing drome, frontal alexia, frontal convexity syndrome, syndrome, cyclothymia, cysticercosis, cytomegalovirus, frontotemporal dementia, frontotemporal dementias, frot Dandy-Walker malformation, deafness, defects in the teurism, fungal infection, galactocerebroside lipidosis, galac metabolism of amino acids, dehydration, Deerine-Roussy torrhea, ganglioneuroma, Gaucher disease, gaZe palsy, gen syndrome, Deerine-Sottas disease, delayed and advanced der identity disorder, generalized anxiety disorder, genital sleep phase syndromes, delayed ejaculation, delayed puberty, shrinking syndrome (Knock outro, Suo-Yang), germ cell delayed-sleep-phase syndrome, delerium due to alcohol, tumors, Gerstmann's syndrome, Gerstmann-Stratissler Syn delerium due to intoxication, delerium due to withdrawal, drome, Gerstmann-Straussler-Schenker disease, Gertmann's delirium, dementia, and amnestic and other cognitive disor syndrome, gestational Substance abuse syndromes, giant ders, delusional disorder, delusional disorder: erotomania axonal neuropathy, gigantism, Gilles de la Tourette Syn Subtype, delusional disorder: grandiose Subtype, delusional drome, glioblastoma multiforme, gliomas, gliomatosis cere disorderjealousy subtype, delusional misidentification syn bri, global aphasia, glossopharyngeal neuralgia, glycogen dromes, dementia due to HIV disease, dementia pugilistica, storage diseases, gm1-gangliosidosis, gm2-gangliosidoses, dementias, dementias associated with extrapyramidal Syn granular cell tumor, granulocytic brain edema, granulomas, drome, dentatorubral-pallidoluysian atrophy, dependent per granulomatous angiitis of the brain, Grave's disease, growild Sonality disorder, depersonalization disorder, depression, typeh hormone deficit, growild typeh-hormone secreting depressive personality disorder, dermoids, developmental adenomas, guam-Parkinson complex dementia, Guillain speech and language disorder, devic syndrome, devivo dis Barré syndrome, Hallervorden-Spatz disease, hallucinogen ease, diabetes, diabetes insipidus, diabetic neuropathy, dialy persisting perception disorder, hallucinogen related disor sis demential, dialysis dysequilibrium syndrome, diencepha ders, hartinup disease, headache, helminthic infections (tri lic dementias, diencephalic dysfunction, diencephalic chinellosis), hemangioblastomas, hemangiopericytomas, syndrome of infancy, diencephalic vascular dementia, diffuse hemiachromatopsia, hemianesthesia, hemianopsia, hemibal Sclerosis, digestive disorders, diphtheria, diplopia, disarthria, lism, hemibalismus, hemihypacusis, hemihypesthesia, disassociation apraxia, disorders of carbohydrate metabo hemiparesis, hemispatial neglect, hemophilus influenza men lism, disorders of excessive Somnolence, disorders of metal ingitis, hemorrhagic cerebrovascular disease, hepatic coma, metabolism, disorders of purine metabolism, disorders of hepatic encephalopathy, hepatolenticular degeneration (Wil sexual arousal, disorders of sexual aversion, disorders of son disease), hereditary amyloid neuropathy, hereditary atax sexual desire, disorders of the sleep-wake schedule, dissocia ias, hereditary cerebellar ataxia, hereditary neuropathies, tive disorders, dorsolateral tegmental pontine syndrome, hereditary nonprogressive chorea, hereditary predisposition Down syndrome, Down syndrome with dementia, drug to pressure palsies, hereditary sensory autonomic neuropathy, dependance, drug overdose, drug-induced myasthenia, hereditary sensory neuropathy, hereditary spastic paraplegia, Duchenne muscular dystrophy, dwarfism, dysarthria, dysdia hereditary tyrosinemia, hermichorea, hermifacial spasm, her dochokinesia, dysembryoplastic neuroepithelial tumor, dys niation syndromes, herpes encephalitis, herpes infections, executive syndrome, dysgraphia, dyskinesia, dyskinetic cere herpes Zoster, herpres simplex, heterotopia, hexacarbon neu US 2011/O 185439 A1 Jul. 28, 2011 ropathy, histrionic personality disorder, HIV. Holmes-Adie major depression with melancholia, major depression with syndrome, homonymous quadrantaposia, Horner's Syn psychotic features, major depression without melancholia, drome, human B-mannosidosis, Hunter's syndrome, Hun major depressive (unipolar) disorder, male orgasmic disorder, tington's chorea, Huntington's disease, Hurler's syndrome, malformations of septum pellucidum, malignant peripheral Hwa-Byung, hydraencephaly, hydrocephalus, hyperthyroid nerve sheath tumors, malingers, mania, mania with psychotic ism, hyperacusis, hyperalgesia, hyperammonemia, hyper features, mania without psychotic features, maple syrup urine eosinophilic syndrome, hyperglycemia, hyperkalemic peri disease, Marchiafava-Bignami syndrome, Marcus Gunn syn odic paralysis, hyperkinesia, hyperkinesis, hyperkinetic drome, Marie-Foix syndrome, Marinesco-Sjögren syndrome, dysarthria, hyperosmia, hyperosmolar hyperglygemic nonke Maroteaux-Lamy syndrome, masochism, masturbatory pain, tonic diabetic coma, hyperparathyroidism, hyperphagia, measles, medial frontal syndrome, medial medullary Syn hyperpituitarism, hyperprolactinemia, hypersexuality, hyper drome, medial tegmental syndrome, medication-induced Somnia, hypersomnia secondary to drug intake, hyperSom movement disorders, medullary dysfunction, medulloblasto nia-Sleep-apnea syndrome, hypersomnolence, hypertension, mas, medulloepithelioma, megalencephaly, melanocytic hypertensive encephalopathy, hyperthermia, hyperthyroid neoplasms, memory disorders, memory disturbances, ism (Graves disease), hypertonia, hypnagogic (predormital) meniere syndrome, meningeal carcinomatosis, meningeal hallucinations, hypnogenic paroxysmal dystonia, hypoadren sarcoma, meningial gliomatosis, meningiomas, meningism, alism, hypoalgesia, hypochondriasis, hypoglycemia, hypoin meningitis, meningococcal meningitis, mental neuropathy Sulinism, hypokalemic periodic paralysis, hypokinesia, (the numb chin syndrome), mental retardation, mercury poi hypokinetic dysarthria, hypomania, hypoparathyroidism, soning, metabolic neuropathies, metachromatic leuknock hypophagia, hypopituitarism, hypoplasia, hyposmia, hypos outdystrophy, metastatic neuropathy, metastatic tumors, thenuria, hypotension, hypothermia, hypothyroid neuropa metazoal infections, microcephaly, microencephaly, thy, hypothyroidism, hypotonia, Hyrler syndrome, hysteria, micropolygyria, midbrain dysfunction, midline syndrome, 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 gammopathy, 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 ophthalmoplegia, 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, Kearns-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, Lévy-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-alzherimer fron lysosomal and other storage diseases, macroglobinemia, tal-lobe degeneration, nonamyloid polyneuropathies associ US 2011/O 185439 A1 Jul. 28, 2011 ated with plasma cell dyscrasia, non-lethal Suicidal behavior, menstrual stress disorder, premenstrual syndrome, primary nonlocalizing aphasic syndromes, normal pressure hydro amebic meningoencephalitis, primary CNS lymphoma, pri cephalus, Nothnagel's syndrome, nystagmus, obesity, obses mary idiopathic thrombosis, primary lateral Sclerosis, primi sive-compulsive (anankastic) personality disorder, obses tive neuroectodermal tumors, prion disease, problems related sive-compulsive disorder, obstetric factitious disorder, to abuse or neglect, progressive bulbar palsy, progressive obstructive hyrocephalus, obstructive sleep apnea, obstruc frontal lobe dementias, progressive multifocal lueknock out tive sleep apnoea syndrome, obstructive sleep hypopnoea encephalopathy, progressive muscular atrophy, progressive syndrome, occipital dementia, occlusive cerebrovascular dis muscular dystrophies, progressive myoclonic epilepsies, pro ease, oculocerebrorenal syndrome of lowe, oculomotor nerve gressive myoclonus epilepsies, progressive non-fluent apha palsy, oculopharyngeal muscular dystrophy, oligodendro sia, progressive partial epilepsies, progressive rubella gliomas, olivopontocerebellar atrophy, ondine's curse, one encephalitis, progressive Sclerosing poliodystrophy (Alpers and a half syndrome, onychophagia, opiate dependance, opi disease), progressive Subcortical gliosis, progressive Supra ate overdose, opiate withdrawal, opioid related disorders, nuclear palsy, progressive Supranuclear paralysis, progrssive oppositional defiant disorder, opSoclonus, orbitofrontal Syn external ophthalmoplegia, prolactinemia, prolactin-sectret drome, orgasmic anhedonia, orgasmic disorders, osteoscle ing adenomas, prosopagnosia, protozoan infection, pseudob rotic myeloma, other disorders of infancy, childhood, orado ulbar palsy, pseudocyesis, pseudodementia, psychic blind lescence, other medication-induced movement disorders, ness, psychogenic excoriation, psychogenic fugue, pachygyria, paedophilia, pain, pain syndromes, painful legs psychogenic pain syndromes, psychological mutism, psy moving toes syndrome, paleocerebellar syndrome, palilalia, chosis after brain injury, psychotic syndromes, ptosis, public panhypopituitarism, panic disorder, panic disorders, papillo masturbation, puerperal panic, pulmonary edema, pure word mas of the choroid plexus, paraganglioma, paragonimiasis, deafness, pyromania, quadrantanopsia, rabies, radiation neu paralysis, paralysis agitans (shaking palsy), paramyotonia ropathy, Ramsay Hunt syndrome, rape traume syndrome, 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 US 2011/O 185439 A1 Jul. 28, 2011
cific disorders of arithmetical skills, specific phobia, specific disturbances, withdrawal without complications, Wolman speech articulation disorder, specific spelling disorder, disease, Xeroderma pigmentosum, Xyy syndrome, Zellweger speech impairment, spina bifida, spinal epidural abcess, spi syndrome. nal muscular atrophies, spinocerebellar ataxias, spirochete 0031 Neurological diseases and disorders that are treated infections, spongiform encephalopathies, spongy degenera or diagnosed by methods of the invention or for which can tion of the nervous system, St. Louis encephalitis, Stammer, didate therapeutic compounds are identified preferably staphylococcal meningitis, startle syndromes, status marm involve at least one of the following neurological tissues: oratus, Steele-richardson-olszewski syndrome, Stereotypic hypothalamus, amygdala, pituitary, nervous system, brain movement disorder, Stereotypies, stiff-man syndrome, stiff stem, cerebellum, cortex, frontal cortex, hippocampus, stria person syndrome, stimulant psychosis, Strachan syndrome tum, and thalamus or other regions of the central or peripheral (nutritional neuropathy), Streptococcal meningitis, striatoni nervous system. gral degeneration, stroke, strongyloidiasis, Sturge-Weber dis 0032. In another aspect, the invention features a non-hu man mammal (e.g., a mouse), having a transgene that ease (Krabbe-Weber-Dimitri disease), stutter, subacute com includes a nucleic acid molecule encoding a GPCR polypep bined degeneration of the spinal cord, Subacute motor tide Substantially identical to a polypeptide listed in any one neuronopathy, Subacute necrotic myelopathy, Subacute scle of Tables 3-14 and 33. rosing panencephalitis, Subacute sensory neuronopathy, Sub 0033. In yet another aspect, the invention features a non arachniod hemorrhage, Subcortical aphasia, Subfalcine her human mammal (e.g., a mouse), having a mutation in a niation syndrome, Substance abuse, Substance related nucleic acid molecule encoding a GPCR polypeptide sub disorders, Sudanophilic leuknock outdystrophis, Sudden stantially identical to a polypeptide listed in any one of Tables infant death syndrome, Suicide, Sulfatide lipidosis, Susto, 3-14 and 33. espanto, meido, Sydenham chorea, symetric neuropathy 0034. In a related aspect, the invention features a cell from associated with carcinoma, sympathotonic orthostatic a non-human mammal having a transgene that includes a 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 apprearance pleasing 3-14 and 33. to others (taijin-kyofu reactions), syndromes related to accul 0035. 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, 0036. 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, 0037. In still another aspect, the invention features a Tourette syndrome, toxic neuropathies, toxoplasmosis, method of treating or preventing a disease of the adrenal gland including administering to an animal (e.g., a human) a transcortical motor aphasia, transcortical sensory aphasia, compound that modulates the biological activity of a GPCR transient epileptic amnesia, transient global amnesia, transi polypeptide Substantially identical to a polypeptide listed in tional sclerosis, transvestic fetishism, traumatic brain injury, Tables 15 and 33. traumatic neuroma, traumiatic mutism, tremors, trichinosis, 0038. In yet another aspect, the invention features a trichotillomania, trigeminal neuralgia, trochlear nerve palsy, method for determining whether a candidate compound is a tropical ataxic neuropathy, tropical spastic paraparesis, try compound that may be useful for the treatment of a disease or panosomiasis, tuberculomas, tuberculous meningitis, tuber disorder of the adrenal gland. This method includes the steps ous Sclerosis, tumors, Turner's syndrome, typhus fever, of (a) providing a GPCR polypeptide substantially identical ulegyria, uncinate fits, Unverricht-Lundborg's disease, upper to a polypeptide listed in Tables 15 and 33; (b) contacting the airway resistance syndrome, upward transtentorial herniation GPCR polypeptide with the candidate compound; and (c) syndrome, uremic encephalopathy, uremic neuropathy, uro measuring biological activity of the GPCR polypeptide, philia, Vaccinia, Varicella-Zoster, Vascular dementia, Vascular wherein altered biological activity, relative to that of the malformations, vasculitic neuropathies, vasogenic edema, GPCR polypeptide not contacted with the compound, indi Velocardiofacial syndrome, venous malformations, ventila cates that the candidate compound may be useful for the tory arrest, vertigo, Vincristine toxicity, Viral infections, visu treatment of a disease or disorder of the adrenal gland. The ospatial impairment, Vogt-Knock outyanagi-Harada Syn GPCR polypeptide can be in a cell or in a cell-free assay drome, Von Hippel-Lindau disease, Von Racklinghousen system. disease, Voyeurism, Waldenström's macroglobulinemia, 0039. In yet another aspect, the invention features a Walker-Warburg syndrome, Wallenburg's syndrome, Wall method for determining whether a candidate compound is a eyed syndrome, Weber's syndrome, Wenicke's encephalopa compound that may be useful for the treatment of a disease or thy, Werdnig-Hoffmann disease, Wernicke's encephalopathy, disorder of the adrenal gland. This method includes the steps Wernicke-Knock outrsaknock outff syndrome, Wernicke's of (a) providing a transgenic non-human mammal (e.g., a aphasia, West's syndrome, whipple disease, Williams syn knock-out mouse) having a disruption in a nucleic acid mol drome, Wilson disease, windigo, witiknockout, witigo, with ecule encoding a GPCR polypeptide substantially identical to drawal with grand mal seizures, withdrawal with perceptual a polypeptide listed in Tables 15 and 33; (b) contacting the US 2011/O 185439 A1 Jul. 28, 2011
transgenic non-human mammal with the candidate com Tables 15 and 33, wherein presence of the mutation indicates pound; and (c) measuring biological activity of the GPCR that the patient has an increased risk for developing a disease polypeptide in the transgenic non-human mammal, wherein or disorder of the adrenal gland. altered biological activity, relative to that of the transgenic 0045. In a related aspect, the invention features another non-human mammal not contacted with the compound, indi method for determining whether a patient has an increased cates that the candidate compound may be useful for the risk for developing a disease or disorder of the adrenal gland. treatment of a disease or disorder of the adrenal gland. This method includes the step of determining whether the 0040. In yet another aspect, the invention features a patient has a polymorphism in a gene encoding a polypeptide method for determining whether a candidate compound is a listed in Tables 15 and 33, wherein presence of the polymor compound that may be useful for the treatment of a disease or phism indicates that the patient may have an increased risk for disorder of the adrenal gland. This method includes the steps developing a disease or disorder of the adrenal gland. of (a) providing a transgenic non-human mammal (e.g., a 0046. In either of these two methods, the mutation or poly mouse) overexpressing a nucleic acid molecule encoding a morphism is preferably associated with an alteration (for GPCR polypeptide substantially identical to a polypeptide example, a decrease) in the biological activity of the polypep listed in Tables 15 and 33; (b) contacting the transgenic non tide. human mammal with the candidate compound; and (c) mea 0047. 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 disease or disorder of the adrenal gland. activity, relative to that of the transgenic non-human mammal 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 Tables 15 and 33, wherein disorder of the adrenal gland. increased or decreased levels in the GPCR biological activity, 0041. 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 0048. 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. 0042. In another aspect, the invention features yet another 0049 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 0043. 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, 0044. 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 US 2011/O 185439 A1 Jul. 28, 2011
corticoid remediable hyperaldosteronism, herpetic adrenali 0057. In yet another aspect, the invention features a tis, hyperaldosteronism, idiopathic Addison's disease, idio method for determining whether a candidate compound is a pathic hyperaldosteronism with bilateral hyperplasia of Zona compound that may be useful for the treatment of a disease or glomerulosa, latrogenic hypercortisolism, lysosomal storage disorder of the colon. This method includes the steps of (a) diseases, macronodular hyperplasia, macronodular hyperpla providing a transgenic non-human mammal (e.g., a knock sia with marked adrenal enlargement, malignant lymphoma, out mouse) having a disruption in a nucleic acid molecule malignant melanoma, metastatic carcinoma, metastatic encoding a GPCR polypeptide substantially identical to a tumors, micronocular hyperplasia, multiple endocrine neo polypeptide listed in Tables 16 and 33; (b) contacting the plasia syndromes, multiple endocrine neoplasia type 1 transgenic non-human mammal with the candidate com (Wermer syndrome), multiple endocrine neoplasia type 2a pound; and (c) measuring biological activity of the GPCR (Sipple syndrome), multiple endocrine neoplasia type 2b, polypeptide in the transgenic non-human mammal, wherein neuroblastoma, Niemann-Pick disease, ovarian thecal meta plasia, paraganglioma, partial 21-hydroxylase deficiency, altered biological activity, relative to that of the transgenic pheochromocytoma, primary aldosteronism (Conn's Syn non-human mammal not contacted with the compound, indi drome), primary chronic adrenal insufficiency (Addison's cates that the candidate compound may be useful for the disease), primary hyperaldosteronism, primary mesenchy treatment of a disease or disorder of the colon. mal tumors, primary pigmented nodular adrenocortical dis 0058. In yet another aspect, the invention features a ease, salt-wasting congenital adrenal hyperplasia, secondary method for determining whether a candidate compound is a Addison's disease, secondary hyperaldosteronsim, selective compound that may be useful for the treatment of a disease or hypoaldosteronism, simple virilizing congenital adrenal disorder of the colon. This method includes the steps of (a) hyperplasia, Waterhouse-Friderichsen syndrome, and Wol providing a transgenic non-human mammal (e.g., a mouse) man's disease. overexpressing a nucleic acid molecule encoding a GPCR 0050. In another aspect, the invention features a non-hu polypeptide Substantially identical to a polypeptide listed in man mammal (e.g., a mouse), having a transgene that Tables 16 and 33; (b) contacting the GPCR polypeptide with includes a nucleic acid molecule encoding a GPCR polypep the candidate compound; and (c) measuring biological activ tide substantially identical to a polypeptide listed in Table 15. ity of the GPCR polypeptide in the transgenic non-human 0051. In yet another aspect, the invention features a non mammal, wherein altered biological activity, relative to that human mammal (e.g., a mouse), having a mutation in a of the transgenic non-human mammal not contacted with the nucleic acid molecule encoding a GPCR polypeptide sub compound, indicates that the candidate compound may be stantially identical to a polypeptide listed in Table 15. useful for the treatment of a disease or disorder of the colon. 0052. In a related aspect, the invention features a cell from 0059. In still 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 15. colon. This method includes (a) providing a nucleic acid 0053. 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 16 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 15. nucleic acid molecule with the candidate compound; and (c) 0054. In another aspect, the invention features a method of measuring reporter activity, wherein altered reporter activity, preventing or treating a disease of the colon 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 colon. stantially identical to a polypeptide listed in Tables 16 and 33, 0060. In another aspect, the invention features yet another operably linked to a promoter. method for determining whether a candidate compound may 0055. 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 colon includ colon. This method includes the steps of: (a) providing a ing administering to an animal (e.g., a human) a compound GPCR polypeptide substantially identical to a polypeptide that modulates the biological activity of a GPCR polypeptide listed in Tables 16 and 33; (b) contacting the polypeptide with substantially identical to a polypeptide listed in Tables 16 and the candidate compound; and (c) measuring interaction of the 33. candidate compound to the polypeptide. Interaction of the 0056. 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 colon. disorder of the colon. This method includes the steps of (a) 0061 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 16 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) colon. This method includes (a) providing a GPCR polypep measuring biological activity of the GPCR polypeptide, tide substantially identical to a polypeptide listed in Tables 16 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 colon. 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 US 2011/O 185439 A1 Jul. 28, 2011
for the treatment of a disease or disorder of the colon. Pref and vascular anomalies, hemorrhoids, hereditary hemor erably the GPCR polypeptide is in a cell or a cell free assay rhagic telangiectasia, herpes colitis, hyperplastic polyps, system. idiopathic inflammatory bowel disease, incontinence, inflam 0062. In another aspect, the invention features a method matory bowel syndrome, inflammatory polyps, inherited for determining whether a patient has an increased risk for adenomatous polyposis syndromes, intestinal hamartomas, developing a disease or disorder of the colon. The method intestinal pseudo-obstruction, irritable bowel syndrome, includes the step of determining whether the patient has a ischemic colitis,juvenile polyposis,juvenile polyps, Klippel mutation in a gene encoding a polypeptide listed in Tables 16 Trenaunay-Weber syndrome, leiomyomas, lipomas, lympho and 33, wherein presence of the mutation indicates that the cytic (microscopic) colitis, lymphoid hyperplasia and lym patient has an increased risk for developing a disease or phoma, malaknock outplakia, malignant lymphoma, disorder of the colon. malignant neoplasms, malrotation, metastatic neoplasms, 0063. In a related aspect, the invention features another mixed hyperplastic and adenomatous polyps, mucosal pro method for determining whether a patient has an increased lapse syndrome, neonatal necrotizing enterocolitis, neuroen risk for developing a disease or disorder of the colon. This docrine cell tumors, neurogenic tumors, neutropenic entero method includes the step of determining whether the patient colitis, non-neoplastic polyps, Peutz-Jeghers syndrome, has a polymorphism in a gene encoding a polypeptide listed in pneumatosis cystoides intestinalis, polyposis coli, Tables 16 and 33, wherein presence of the polymorphism pseudomembranous colitis, pseudoxanthoma elasticum, pure indicates that the patient may have an increased risk for squamous carcinomas, radiation colitis, Schistosomiasis, Shi developing a disease or disorder of the colon. gella colitis (bacilliary dysentery), spindle cell carcinomas, 0064. In either of these two methods, the mutation or poly spirochetosis, Stercolar ulcers, stromal tumors, systemic scle morphism is preferably associated with an alteration (for rosis and CREST syndrome, trichuriasis, tubular adenoma example, a decrease) in the biological activity of the polypep (adenomatous polyp, polypoid adenoma), Turcot's Syn tide. drome, Turner's syndrome, ulcerative colitis, villous 0065. In another aspect, the invention features another adenoma, and Volvulus. method for determining whether a patient has an increased 0068. In another aspect, the invention features a non-hu risk for developing a disease or disorder of the colon. The man mammal (e.g., a mouse), having a transgene that method includes measuring biological activity of a GPCR includes a nucleic acid molecule encoding a GPCR polypep polypeptide from the patient that is substantially identical to tide substantially identical to a polypeptide listed in Table 16. a polypeptide listed in Tables 16 and 33, wherein increased or 0069. In yet another aspect, the invention features a non decreased levels in the GPCR biological activity, relative to human mammal (e.g., a mouse), having a mutation in 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 colon. stantially identical to a polypeptide listed in Table 16. 0066. In still another aspect, the invention features yet 0070. 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 16. patient's expression levels of a polypeptide listed in Tables 16 and 33, wherein altered levels in the expression, relative to 0071. In another aspect, the invention features a cell from normal, indicate that the patient has an increased risk for a non-human mammal having a mutation in a nucleic acid developing a disease or disorder of the colon. Preferably, the molecule encoding a GPCR polypeptide substantially identi expression levels are determined by measuring levels of cal to a polypeptide listed in Table 16. polypeptide or mRNA. 0072. In another aspect, the invention features a method of 0067. Diseases of the colon that can be treated or diag preventing or treating cardiovascular disease, including intro nosed using the methods of the invention or for which candi ducing into a human an expression vector that includes a date therapeutic compounds may be identified include acute nucleic acid molecule encoding a GPCR polypeptide sub self-limited infectious colitis, adenocarcinoma, adenoma, stantially identical to a polypeptide listed in Tables 17 and 33, adenoma-carcinoma sequence, adenomatous polyposis coli, operably linked to a promoter. adenosquamous carcinomas, allergic (eosinophilic) proctitis 0073. In still another aspect, the invention features a and colitis, amebiasis, amyloidosis, angiodysplasia, anorec method of treating or preventing cardiovascular disease, tal malformations, blue rubber bleb nevus syndrome, brown including administering to an animal (e.g., a human) a com bowel syndrome, Campylobacter fetus infection, carcinoid pound that modulates the biological activity of a GPCR tumors, carcinoma of the anal canal, carcinoma of the colon polypeptide Substantially identical to a polypeptide listed in and rectum, chlamidial proctitis, Crohn's disease, clear cell Tables 17 and 33. carcinomas, Clostridium difficile pseudomembranous entero 0074. In yet another aspect, the invention features a colitis, collagenous colitis, colonic adenoma, colonic diver method for determining whether a candidate compound is a ticulosis, colonic inertia, colonic ischemia, congenital atresia, compound that may be useful for the treatment of a cardio congenital megacolon (Hirschsprung's disease), congenital vascular disease or disorder. This method includes the steps of Stenosis, constipation, Cowden's syndrome, cystic fibrosis, (a) providing a GPCR polypeptide substantially identical to a cytomegalovirus colitis, diarrhea, dieulafor lesion, diversion polypeptide listed in Tables 17 and 33; (b) contacting the colitis, diverticulitis, diverticulosis, drug-induced diseases, GPCR polypeptide with the candidate compound; and (c) dysplasia and malignancy in inflammatory bowel disease, measuring biological activity of the GPCR polypeptide, Ehlers-Danlos syndromes, enterobiasis, familial adenoma wherein altered biological activity, relative to that of the tous polyposis, familial polyposis syndromes, Gardner's Syn GPCR polypeptide not contacted with the compound, indi drome, gastrointestinal Stromal neoplasms, hemangiomas cates that the candidate compound may be useful for the US 2011/O 185439 A1 Jul. 28, 2011
treatment of a cardiovascular disease or disorder. 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 0075. In yet another aspect, the invention features a may be useful for the treatment of a cardiovascular disease or method for determining whether a candidate compound is a disorder. Preferably the GPCR polypeptide is in a cellor a cell compound that may be useful for the treatment of a cardio free assay system. vascular disease or disorder. This method includes the steps of 0080. In another aspect, the invention features a method (a) providing a transgenic non-human mammal (e.g., a for determining whether a patient has an increased risk for knock-out mouse) having a disruption in a nucleic acid mol developing a cardiovascular disease or disorder. The method ecule encoding a GPCR polypeptide substantially identical to includes the step of determining whether the patient has a a polypeptide listed in Tables 17 and 33; (b) contacting the mutation in a gene encoding a polypeptide listed in Tables 17 transgenic non-human mammal with the candidate com and 33, wherein presence of the mutation indicates that the pound; and (c) measuring biological activity of the GPCR patient may have an increased risk for developing a cardio polypeptide in the transgenic non-human mammal, wherein vascular disease or disorder. altered biological activity, relative to that of the transgenic I0081. In a related aspect, the invention features another non-human mammal not contacted with the compound, indi method for determining whether a patient has an increased cates that the candidate compound may be useful for the risk for developing a cardiovascular disease or disorder. This treatment of a cardiovascular disease or disorder. method includes the step of determining whether the patient 0076. 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 17 and 33, wherein presence of the polymorphism compound that may be useful for the treatment of a cardio indicates that the patient may have an increased risk for vascular disease or disorder. This method includes the steps of developing a cardiovascular disease or disorder. (a) providing a transgenic non-human mammal (e.g., a I0082 In either of these two methods, the mutation or poly mouse) overexpressing a nucleic acid molecule encoding a morphism is preferably associated with an alteration (for GPCR polypeptide substantially identical to a polypeptide example, a decrease) in the biological activity of the polypep listed in Tables 17 and 33; (b) contacting the transgenic non tide. human mammal with the candidate compound; and (c) mea I0083. 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 0077. 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 I0084. 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. I0085. One preferred cardiovascular disease that can be 0078. 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 0079. 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 cental valve, calcification of the valvering, be useful for the treatment of a cardiovascular disease or carcinoid heart disease, cardiac amyloidosis, cardiac arrest, disorder. This method includes (a) providing a GPCR cardiac arrhythmia, cardiac failure, cardiac myxoma, cardiac polypeptide Substantially identical to a polypeptide listed in rejection, cardiac tamponade, cardiogenic shock, cardiomy Tables 17 and 33; (b) contacting the polypeptide with the opathy of pregnancy, chronic adhesive pericarditis, chronic candidate compound; and (c) measuring the half-life of the constrictive pericarditis, chronic left ventricular failure, polypeptide, wherein an alteration in the half-life of the coarctation of the aorta, complete heart block, complete US 2011/O 185439 A1 Jul. 28, 2011
transposition of the great vessels, congenital bicuspid aortic 0090. In another aspect, the invention features a method of valves, congenital narrowing of the left ventricular outflow preventing or treating a disease of the intestine including tract, congenital pulmonary valve Stenosis, congenitally cor introducing into a human an expression vector that includes a rected transposition of the great arteries, congestive heart nucleic acid molecule encoding a GPCR polypeptide sub failure, constrictive pericarditis, cor pulmonale, coronary stantially identical to a polypeptide listed in Tables 18 and 33, artery origin from pulmonary artery, coronary atherosclero operably linked to a promoter. sis, dilated (congestive) cardiomyopathy, diphtheria, double 0091. In still another aspect, the invention features a inlet left ventricle, double outlet right ventricle, Ebstein's method of treating or preventing a disease of the intestine malformation, endocardial fibroelastosis, endocarditis, including administering to an animal (e.g., a human) a com endomyocardial fibrosis, eosinophilic endomyocardial dis pound that modulates the biological activity of a GPCR ease (Loffler endocarditis), fibroma, glycogen storage dis polypeptide Substantially identical to a polypeptide listed in eases, hemochromatosis, hypertensive heart disease, hyper Tables 18 and 33. thyroid heart disease, hypertrophic cardiomyopathy, 0092. In yet another aspect, the invention features a hypothyroid heart disease, idiopathic dilated cardiomyopa method for determining whether a candidate compound is a compound that may be useful for the treatment of a disease or thy, idiopathic myocarditis, infectious myocarditis, infective disorder of the intestine. This method includes the steps of (a) endocarditis, ischemic heart disease, left ventricular failure, providing a GPCR polypeptide substantially identical to a Libman-Sachs endocarditis, lupus erythematosus, lyme dis polypeptide listed in Tables 18 and 33; (b) contacting the ease, marantic endocarditis, metastatic tumors, mitral insuf GPCR polypeptide with the candidate compound; and (c) ficiency, mitral regurgitation, mitral Stenosis, mitral valve measuring biological activity of the GPCR polypeptide, prolapse, mucopolysaccharidoses, multifocal atrial tachycar wherein altered biological activity, relative to that of the dia, myocardial infarction, myocardial ischemia, myocardial GPCR polypeptide not contacted with the compound, indi rupture, myocarditis, myxomatuos degeneration, nonathero cates that the candidate compound may be useful for the matous coronary artery disease, nonbacterial thrombotic treatment of a disease or disorder of the intestine. The GPCR endocarditis, noninfectious acute pericarditis, nonviral infec tious pericarditis, oblitaerative cardiomyopathy, patent duc polypeptide can be in a cell or in a cell-free assay System. tus arteriosus, pericardial effusion, pericardial tumors, peri 0093. In yet another aspect, the invention features a carditis, persistent truncus arteriosis, premature ventricular method for determining whether a candidate compound is a contraction, progressive infarction, pulmonary atresia with compound that may be useful for the treatment of a disease or intact ventricular septum, pulmonary atresia with Vertricular disorder of the intestine. This method includes the steps of (a) septal defect, pulmonary insufficiency, pulmonary regurgita providing a transgenic non-human mammal (e.g., a knock tion, pulmonary Stenosis, pulmonary valve lesions, pulmo out mouse) having a disruption in a nucleic acid molecule nary valve Stenosis, pyogenic pericarditis, Q fever, radiations encoding a GPCR polypeptide substantially identical to a myocarditis, restrictive cardiomyopathy, rhabdomyoma, polypeptide listed in Tables 18 and 33; (b) contacting the rheumatic aortic Stenosis, rheumatic heart disease, rocky transgenic non-human mammal with the candidate com mountain 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 0094. 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, tuberculuos 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 Tables 18 and 33; (b) contacting the transgenic non-human I0086. 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 17. relative to that of the transgenic non-human mammal not 0087. 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 intestine. stantially identical to a polypeptide listed in Table 17. 0.095 Instill another aspect, the invention features another 0088. 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 0089. 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, US 2011/O 185439 A1 Jul. 28, 2011
relative to a nucleic acid molecule not contacted with the developing a disease or disorder of the intestine. Preferably, compound, indicates that the candidate compound may be the expression levels are determined by measuring levels of useful for the treatment of a disease or disorder of the intes polypeptide or mRNA. tine. 0103 Diseases of the intestine that can be treated or diag 0096. 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 abdominal hernia, abetalipoproteinemia, abnormal rotation, intestine. This method includes the steps of: (a) providing a acute hypotensive hypoperfusion, acute intestinal ischemia, GPCR polypeptide substantially identical to a polypeptide acute Small intestinal infarction, adenocarcinoma, adenoma, listed in Tables 18 and 33; (b) contacting the polypeptide with adhesions, amebiasis, anemia, arterial occlusion, atypical the candidate compound; and (c) measuring interaction of the mycobacteriosis, bacterial diarrhea, bacterial overgrowild candidate compound to the polypeptide. Interaction of the typeh Syndromes, botulism, Campylobacter fetus infection, compound to the polypeptide indicates that the candidate Campylobacter jejuni, carbohydrate absorption defects, car compound may be useful for the treatment of a disease or cinoid tumors, celiac disease (nontropical sprue, gluten-in disorder of the intestine. duced enteropathy), cholera, Chrohn's disease, chronic intes 0097. In still another aspect, the invention features another tinal ischemia, Clostridium difficile pseudomembranous method for determining whether a candidate compound may enterocolitis, Clostridium perfiringens, congenital umbilical be useful for the treatment of a disease or disorder of the hernia, Cronkhite-Canada syndrome, cytomegalovirus intestine. This method includes (a) providing a GPCR enterocolitis, diarrhea, diarrhea caused by invasive bacteria, polypeptide Substantially identical to a polypeptide listed in diverticulitits, diverticulosis, dysentery, enteroinvasive and Tables 18 and 33; (b) contacting the polypeptide with the enterohemorrhagic Escherichia coli infection, eosinophilic candidate compound; and (c) measuring the half-life of the gastroenteritis, failure of peristalsis, familial polyposis Syn polypeptide, wherein an alteration in the half-life of the dromes, food poisoning, fungal enteritis, gangliocytic polypeptide, relative to that of the polypeptide not contacted paragangliomas, Gardner's syndrome, gastrointestinal stro with the compound, indicates that the candidate compound mal neoplasms, giardiasis, hemorroids, hernia, hyperplastic 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 0098. 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, 0099. 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 0100. 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 0101. 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 a polypeptide listed in Tables 18 and 33, wherein increased or enteritis, visceral myopathy, visceral neuropathy, Vitelline decreased levels in the GPCR biological activity, relative to duct remnants, Volvulus, Western-type intestinal lymphoma, normal levels, indicate that the patient may have an increased Whipple's disease (intestinal lipopy strophy), Yersinia entero risk for developing a disease or disorder of the intestine. colitica & Yersinia pseudotuberculosis infection, and 0102. In still another aspect, the invention features yet Zollinger-Ellison syndrome. another method for determining whether a patient has an 0104. 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 0105. 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 US 2011/O 185439 A1 Jul. 28, 2011
nucleic acid molecule encoding a GPCR polypeptide sub contacted with the compound, indicates that the candidate stantially identical to a polypeptide listed in Table 18. compound may be useful for the treatment of a disease or 0106. In a related aspect, the invention features a cell from disorder of the kidney. a non-human mammal having a transgene that includes a 0113 Instill another aspect, the invention features another nucleic acid molecule encoding a GPCR polypeptide sub method for determining whether a candidate compound may stantially identical to a polypeptide listed in Table 18. be useful for the treatment of a disease or disorder of the kidney. This method includes (a) providing a nucleic acid 0107. 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 19 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 18. nucleic acid molecule with the candidate compound; and (c) 0108. In another aspect, the invention features a method of measuring reporter activity, wherein altered reporter activity, preventing or treating a disease of the kidney 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 kidney. stantially identical to a polypeptide listed in Tables 19 and 33, 0114. In another aspect, the invention features yet another operably linked to a promoter. method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the 0109. In still another aspect, the invention features a kidney. This method includes the steps of: (a) providing a method of treating or preventing a disease of the kidney GPCR polypeptide substantially identical to a polypeptide including administering to an animal (e.g., a human) a com listed in Tables 19 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 19 and 33. compound to the polypeptide indicates that the candidate 0110. 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 kidney. compound that may be useful for the treatment of a disease or 0115 Instill another aspect, the invention features another disorder of the kidney. 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 19 and 33; (b) contacting the kidney. 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 19 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 kidney. 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 kidney. Pref 0111. 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 0116. 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 0117. 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 0112. 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) 0118. 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 0119. 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 US 2011/O 185439 A1 Jul. 28, 2011
a polypeptide listed in Tables 19 and 33, wherein increased or lointerstitial disease in multiple myeloma, urate nephropathy, decreased levels in the GPCR biological activity, relative to urinary obstruction, and vasculitis. normal levels, indicate that the patient may have an increased I0122. In another aspect, the invention features a non-hu risk for developing a disease or disorder of the kidney. man mammal (e.g., a mouse), having a transgene that 0120 In still another aspect, the invention features yet includes a nucleic acid molecule encoding a GPCR polypep another method for determining whether a patient has an tide substantially identical to a polypeptide listed in Table 19. increased risk for developing a disease or disorder of the I0123. In yet another aspect, the invention features a non kidney. The method includes the step of measuring the human mammal (e.g., a mouse), having a mutation in a patient's expression levels of a polypeptide listed in Tables 19 nucleic acid molecule encoding a GPCR polypeptide sub and 33, wherein altered levels in the expression, relative to stantially identical to a polypeptide listed in Table 19. normal, indicate that the patient has an increased risk for 0.124. In a related aspect, the invention features a cell from developing a disease or disorder of the kidney. Preferably, the a non-human mammal having a transgene that includes a expression levels are determined by measuring levels of nucleic acid molecule encoding a GPCR polypeptide sub polypeptide or mRNA. stantially identical to a polypeptide listed in Table 19. 0121 Diseases of the kidney that can be treated or diag 0.125. In another aspect, the invention features a cell from nosed using the methods of the invention or for which candi a non-human mammal having a mutation in a nucleic acid date therapeutic compounds may be identified include molecule encoding a GPCR polypeptide substantially identi acquired cystic disease, acute (postinfectious) glomerulone cal to a polypeptide listed in Table 19. phritis, acute infectious interstitial nephritis, acute interstitial I0126. In another aspect, the invention features a method of nephritis, acute pyelonephritis, acute renal failure, acute preventing or treating a disease of the liver including intro transplant failure, acute tubular necrosis, adult polycystic ducing into a human an expression vector that includes a kidney disease, AL amyloid, analgesic nephropathy, anti nucleic acid molecule encoding a GPCR polypeptide sub glomerular basement membrane disease (Goodpasture's stantially identical to a polypeptide listed in Tables 20 and 33, Syndrome), asymptomatic hematuria, asymptomatic pro operably linked to a promoter. teinuria, autosomal dominant polycystic kidney disease, I0127. In still another aspect, the invention features a autosomal recessive polycystic kidney disease, Bence Jones method of treating or preventing a disease of the liver includ 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 I0128. 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-cahin deposit disease, I0129. 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 0.130. 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 US 2011/O 185439 A1 Jul. 28, 2011
polypeptide Substantially identical to a polypeptide listed in 0.136. In either of these two methods, the mutation or poly Tables 20 and 33; (b) contacting the transgenic non-human morphism is preferably associated with an alteration (for mammal with the candidate compound; and (c) measuring example, a decrease) in the biological activity of the polypep biological activity of the GPCR polypeptide in the transgenic tide. non-human mammal, wherein altered biological activity, 0.137 In another aspect, the invention features another relative to that of the transgenic non-human mammal not method for determining whether a patient has an increased contacted with the compound, indicates that the candidate risk for developing a disease or disorder of the liver. The compound may be useful for the treatment of a disease or method includes measuring biological activity of a GPCR disorder of the liver. polypeptide from the patient that is substantially identical to 0131. In still another aspect, the invention features another a polypeptide listed in Tables 20 and 33, wherein increased or method for determining whether a candidate compound may decreased levels in the GPCR biological activity, relative to be useful for the treatment of a disease or disorder of the liver. normal levels, indicate that the patient may have an increased This method includes (a) providing a nucleic acid molecule risk for developing a disease or disorder of the liver. comprising a promoter from a gene encoding a GPCR 0.138. In still another aspect, the invention features yet another method for determining whether a patient has an polypeptide listed in Tables 20 and 33, the promoter operably increased risk for developing a disease or disorder of the liver. linked to a reporter system; (b) contacting the nucleic acid The method includes the step of measuring the patient's molecule with the candidate compound; and (c) measuring expression levels of a polypeptide listed in Tables 20 and 33, reporter activity, wherein altered reporter activity, relative to wherein altered levels in the expression, relative to normal, a nucleic acid molecule not contacted with the compound, indicate that the patient has an increased risk for developing a indicates that the candidate compound may be useful for the disease or disorder of the liver. Preferably, the expression treatment of a disease or disorder of the liver. levels are determined by measuring levels of polypeptide or 0.132. In another aspect, the invention features yet another mRNA. method for determining whether a candidate compound may 0.139 Diseases of the liver that can be treated or diagnosed be useful for the treatment of a disease or disorder of the liver. using the methods of the invention or for which candidate This method includes the steps of: (a) providing a GPCR therapeutic compounds may be identified include acute alco polypeptide Substantially identical to a polypeptide listed in holic hepatitis (acute Sclerosing hyaline necrosis of the liver), Tables 20 and 33; (b) contacting the polypeptide with the acute graft-Versus-host disease, acute hepatitis, acute hepato candidate compound; and (c) measuring interaction of the cellular injury associated with infectious diseases other than candidate compound to the polypeptide. Interaction of the viral hepatitis, acute liver failure, acute viral hepatitis, aden compound to the polypeptide indicates that the candidate ovirus hepatitis, Alagile syndrome, alcoholic cirrhosis, alco compound may be useful for the treatment of a disease or holic hepatitis, alcoholic liver disease, alpha1-antitrypsin disorder of the liver. deficiency, amebic abscess, angiolmyolipoma, angiosar coma, ascending cholangitis, autoimmune chronic active 0133. In still another aspect, the invention features another hepatitis (lupoid hepatitis), bile duct adenoma, bile duct cys method for determining whether a candidate compound may tadenocarcinoma, bile duct cystadenoma, biliary atresia, bil be useful for the treatment of a disease or disorder of the liver. iary cirrhosis, biliary papillomatosis, bridging necrosis, This method includes (a) providing a GPCR polypeptide Budd-Chiari syndrome, Byler disease, cardiac fibrosis of the 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 coagulation, delta hepatitis, Dubin-Johnson syndrome, epi 0134. In another aspect, the invention features a method thelioid hemangioendothelioma, erythrohepatic protopor for determining whether a patient has an increased risk for phyria, extrahepatic biliary obstruction (primary biliary cir developing a disease or disorder of the liver. The method rhosis), fatty change, fatty liver, focal necrosis, focal nodular includes the step of determining whether the patient has a hyperplasia, fulminant viral hepatitis, galactosemia, Gilbert's mutation in a gene encoding a polypeptide listed in Tables 20 syndrome, glycogen storage diseases, graft-Versus-host dis and 33, wherein presence of the mutation indicates that the ease, granulomatous hepatitis, hemangioma, hemangiosar patient may have an increased risk for developing a disease or coma, hemochromatosis, hepatic adenoma, hepatic amebia disorder of the liver. sis, hepatic encephalopathy, hepatic failure, hepatic 0135) In a related aspect, the invention features another Schistosomiasis, hepatic veno-occlusive disease, hepatitis A, method for determining whether a patient has an increased hepatitis B, hepatitis C, hepatitis D, hepatitis E. hepatoblas risk for developing a disease or disorder of the liver. This toma, hepatocellular adenoma, hepatocellular carcinoma, method includes the step of determining whether the patient hepatocellular necrosis, hepatorenal syndrome, hereditary has a polymorphism in a gene encoding a polypeptide listed in fructose intolerance, hereditary hemochromatosis, herpesvi Tables 20 and 33, wherein presence of the polymorphism rus hepatitis, hydatid cust, hyperplastic lesions, hypoalbu indicates that the patient may have an increased risk for minenia, infantile hemangioendothelioma, infarction of the developing a disease or disorder of the liver. liver, infectious mononucleosis hepatitis, inflammatory US 2011/O 185439 A1 Jul. 28, 2011
pseudotumor of the liver, intrahepatic cholangiocarcinoma, treatment of a lung disease or disorder. The GPCR polypep intrahepatic cholestasis, intrahepatic protal hypertension, tide can be in a cell or in a cell-free assay system. ischemic necrosis (ischemic hepatitis), isoniazid-induced 0.147. In yet another aspect, the invention features a necrosis, jaundice, leptospirosis, liver cell adenoma, liver method for determining whether a candidate compound is a manifestations of Rocky Mountain spotted fever, macronodu compound that may be useful for the treatment of a disease or lar cirrhosis, macrovesicular Steatosis, malignant vascular disorder of the lung. This method includes the steps of (a) neoplasts, mass lesions, massive hepatocellular necrosis, providing a transgenic non-human mammal (e.g., a knock massive necrosis, mesenchymal hamartoma, metastatic out mouse) having a disruption in a nucleic acid molecule tumors, micronodular cirrhosis, microvesicular Steatosis, neonatal (physiologic) jaundice, neonatal hepatitis, neoplas encoding a GPCR polypeptide substantially identical to a tic lesions, nodular transformation (nodular regenerative polypeptide listed in Tables 21 and 33; (b) contacting the hyperplasia, nonSuppurative infections, nutritional cirrhosis, transgenic non-human mammal with the candidate com nutritional liver disease, oriental cholangiohepatitis, parasitic pound; and (c) measuring biological activity of the transgenic infestation of the liver, peliosis hepatis, porphyria cutaneo non-human mammal, wherein altered biological activity, tarda, portal hypertension, portal vein thrombosis, posthe relative to that of the transgenic non-human mammal not patic portal hypertension, predictiable (dose-related) toxicity, contacted with the compound, indicates that the candidate prehepatic portal hypertension, primary biliary cirrhosis, pri compound may be useful for the treatment of a disease or mary Sclerosing cholangitis, pyogenic liver abcess, Q-fever disorder of the lung. hepatitis, Rotor's syndrome, Sclerosing bile duct adenoma, 0.148. In yet another aspect, the invention features a Sclerosing cholangitis, secondary hemochromatosis, Submas method for determining whether a candidate compound is a sive necrosis, syphilis, toxic liver injury, tyrosinemia, undif compound that may be useful for the treatment of a disease or ferentiated sarcoma, unpredictable (idiosyncratic) toxicity, disorder of the lung. This method includes the steps of (a) vascular lesions, virus-induced cirrhosis, Wilson's disease, providing a transgenic non-human mammal (e.g., a mouse) and Zonal necrosis. overexpressing a nucleic acid molecule encoding a GPCR 0140. In another aspect, the invention features a non-hu polypeptide Substantially identical to a polypeptide listed in man mammal (e.g., a mouse), having a transgene that Tables 21 and 33; (b) contacting the transgenic non-human includes a nucleic acid molecule encoding a GPCR polypep mammal with the candidate compound; and (c) measuring tide substantially identical to a polypeptide listed in Table 20. biological activity of the transgenic non-human mammal, wherein altered biological activity, relative to that of the 0.141. In yet another aspect, the invention features a non human mammal (e.g., a mouse), having a mutation in a transgenic non-human mammal not contacted with the com nucleic acid molecule encoding a GPCR polypeptide sub pound, indicates that the candidate compound may be useful stantially identical to a polypeptide listed in Table 20. for the treatment of a disease or disorder of the lung. 0149 Instill another aspect, the invention features another 0142. 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 lung disease or disorder. This nucleic acid molecule encoding a GPCR polypeptide sub method includes (a) providing a nucleic acid molecule com stantially identical to a polypeptide listed in Table 20. prising a promoter from a gene encoding a GPCR polypeptide 0143. In another aspect, the invention features a cell from listed in Tables 21 and 33, the promoter operably linked to a a non-human mammal having a mutation in a nucleic acid reporter system; (b) contacting the nucleic acid molecule with molecule encoding a GPCR polypeptide substantially identi the candidate compound; and (c) measuring reporter activity, cal to a polypeptide listed in Table 20. wherein altered reporter activity, relative to a nucleic acid 0144. In another aspect, the invention features a method of molecule not contacted with the compound, indicates that the preventing or treating lung disease, including introducing candidate compound may be useful for the treatment of a lung into a human an expression vector that includes a nucleic acid disease or disorder. molecule encoding a GPCR polypeptide substantially identi 0150. In another aspect, the invention features yet another cal to a polypeptide listed in Tables 21 and 33, operably linked method for determining whether a candidate compound may to a promoter. be useful for the treatment of a lung disease or disorder. This 0145. In still another aspect, the invention features a method includes the steps of: (a) providing a GPCR polypep method of treating or preventing lung disease, including tide substantially identical to a polypeptide listed in Tables 21 administering to an animal (e.g., a human) a compound that and 33; (b) contacting the polypeptide with the candidate modulates the biological activity of a GPCR polypeptide compound; and (c) measuring interaction of the candidate substantially identical to a polypeptide listed in Tables 21 and compound to the polypeptide. Interaction of the compound to 33. the polypeptide indicates that the candidate compound may 0146 In yet another aspect, the invention features a be useful for the treatment of a lung disease or disorder. method for determining whether a candidate compound is a 0151. In still another aspect, the invention features another compound that may be useful for the treatment of a lung method for determining whether a candidate compound may disease or disorder. This method includes the steps of (a) be useful for the treatment of a lung disease or disorder. This providing a GPCR polypeptide substantially identical to a method includes (a) providing a GPCR polypeptide substan polypeptide listed in Tables 21 and 33; (b) contacting the tially identical to a polypeptide listed in Tables 21 and 33; (b) GPCR polypeptide with the candidate compound; and (c) contacting the polypeptide with the candidate compound; and measuring biological activity of the GPCR polypeptide, (c) measuring the half-life of the polypeptide, wherein an wherein altered biological activity, relative to that of the alteration in the half-life of the polypeptide, relative to that of GPCR polypeptide not contacted with the compound, indi the polypeptide not contacted with the compound, indicates cates that the candidate compound may be useful for the that the candidate compound may be useful for the treatment US 2011/O 185439 A1 Jul. 28, 2011
of a lung disease or disorder. Preferably, the GPCR polypep blastomycosis, bronchialatresia, bronchial asthma, bronchial tide is in a cell or a cell free assay system. carcinoid tumor, bronchial isomerism, bronchial obstruction, 0152. In another aspect, the invention features a method bronchial Stenosis, bronchiectasis, bronchiolalveolar carci for determining whether a patient has an increased risk for noma, bronchiolitis, bronchiolitis obliterans-organizing developing a lung disease or disorder. The method includes pneumonia, bronchocentric granulomatosis, bronchogenic the step of determining whether the patient has a mutation in cyst, bronchopneumonia, bronchopulmonary dysplasia, a gene encoding a polypeptide listed in Tables 21 and 33. bronchopulmonary sequestration, bullae, bullous emphy wherein presence of the mutation indicates that the patient sema, cancer, carcinoid tumors, carcinoma of the lung (bron may have an increased risk for developing a lung disease or chogenic carcinoma), central (bronchogenic) carcinoma, disorder. central cyanosis, centriacinar emphysema, cetrilobular 0153. In a related aspect, the invention features another emphysema, chest pain, Chlamydial pneumonia, chondroid method for determining whether a patient has an increased hamartoma, chronic airflow obstruction, chronic bronchitis, risk for developing a lung disease or disorder. This method chronic diffuse interstitial lung disease, chronic idiopathic includes the step of determining whether the patient has a pulmonary fibrosis, chronic lung abscess, chronic obstructive polymorphism in a gene encoding a polypeptide listed in pulmonary diseases, chronic radiation pneumonitis, chronic Tables 21 and 33, wherein presence of the polymorphism silicosis, chylothorax, ciliary dyskinesia, coal worker's pneu indicates that the patient may have an increased risk for moconiosis (anthracosis), coccidioidomycosis, collagen-vas developing a lung disease or disorder. cular diseases, common cold, compensatory emphysema, 0154) In either of these two methods, the mutation or poly congenital acinar dysplasia, congenital alveolar capillary morphism is preferably associated with an alteration (for dysplasia, congenital bronchobiliary fistula, congenital bron example, a decrease) in the biological activity of the polypep choesophageal fistula, congenital cystic adenomatoid malfor tide. mation, congenital pulmonary lymphangiectasis, congenital 0155. In another aspect, the invention features another pulmonary overinflation (congenital emphysema), conges method for determining whether a patient has an increased tion, cough, cryptococcosis, cyanosis, cystic fibrosis, cys risk for developing a lung disease or disorder. The method ticercosis, cytomegalovirus, descquamative interstitial pneu includes measuring biological activity of a GPCR polypep monitis, destructive lung disease, diatomaceous earth tide from the patient that is substantially identical to a pneumoconiosis, diffuse alveolar damage, diffuse pulmonary polypeptide listed in Tables 21 and 33, wherein increased or hemorrhage, diffuse septal amyloidosis, difuse panbronchi decreased levels in the GPCR biological activity, relative to olitis, Dirofilaria immitis, diseases of the pleura, distalacinar 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 0156. 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 0157 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, apiration 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. US 2011/O 185439 A1 Jul. 28, 2011
Legionella pneumonia, lipid pneumonia, lobar pneumonia, tial pneumonitis, varicella, viral pneumonia, visceral pleural localized emphysema, long-standing bronchial obstruction, thickening, Wegener's granulomatosis, and whooping cough lung abscess, lung collapse, lung fluke, lung transplantation (pertussis). implantation response, lymphangiomyomatosis, lympho 0158. In another aspect, the invention features a non-hu cytic interstitial pneumonitis (pseudolymphoma, lymphoma, man mammal (e.g., a mouse), having a transgene that lymphomatoid granulomatosis, malignant mesothelioma, includes a nucleic acid molecule encoding a GPCR polypep massive pulmonary hemorrhage in the newborn, measles, tide substantially identical to a polypeptide listed in Table 21. meconium aspiration syndrome, mesenchymal cystic hama 0159. In yet another aspect, the invention features a non rtomas, mesenchymal tumors, mesothelioma, metal-induced human mammal (e.g., a mouse), having a mutation in a lung diseases, metastatic calcification, metastatic neoplasms, nucleic acid molecule encoding a GPCR polypeptide sub metastatic ossification, mica pneumoconiosis, mixed dust stantially identical to a polypeptide listed in Table 21. fibrosis, mixed epithelial-mesenchymal tumors, mixed type 0160. In a related aspect, the invention features a cell from a non-human mammal having a transgene that includes a neoplasms, mucoepidermoid tumor, mucoviscidosis (fibro nucleic acid molecule encoding a GPCR polypeptide sub cystic disease of the pancreas), mycoplasma pneumoniae, stantially identical to a polypeptide listed in Table 21. necrotizing bacterial pneumonia, necrotizing sarcoid granu 0.161. In another aspect, the invention features a cell from lomatosis, neonatal respiratory distress syndrome, neoplasms a non-human mammal having a mutation in a nucleic acid of the pleura, neuromuscular syndromes, nocardiosis, nonde molecule encoding a GPCR polypeptide substantially identi structive lung disease, North American blastomycosis, occu cal to a polypeptide listed in Table 21. pational asthma, organic dust disease, panacinar emphysema, 0162. In another aspect, the invention features a method of Pancoast's syndrome, paracoccidioidomycosis, parainflu preventing or treating muscular disease, including introduc enza, paraneoplastic syndromes, paraseptal emphysema ing into a human an expression vector that includes a nucleic (paracicatricial), parasilicosis syndromes, parasitic infec acid molecule encoding a GPCR polypeptide substantially tions of the lung, peripheral cyanosis, peripheral lung carci identical to a polypeptide listed in Tables 22 and 33, operably noma, persistent pulmonary hypertension of the newborn, linked to a promoter. pleural diseases, pleural effusion, pleural plaques, pneumo 0163. In still another aspect, the invention features a coccal pneumonia, pneumoconioses (inorganic dust dis method of treating or preventing muscular disease, including eases), Pneumocystis carinii pneumonia, pneumocystosis, administering to an animal (e.g., a human) a compound that pneumonitis, pneumothorax, precapillary pulmonary hyper modulates the biological activity of a GPCR polypeptide tension, primary (childhood) tuberculosis, primary (idio substantially identical to a polypeptide listed in Tables 22 and pathic) pulmonary hypertension, primary mesothelial neo 33. plasms, primary pulmonary hypertensions, progressive 0164. In yet another aspect, the invention features a massive fibrosis, psittacosis, pulmonary actinomycosis, pull method for determining whether a candidate compound is a monary air-leak syndromes, pulmonary alveolar proteinosis, compound that may be useful for the treatment of a muscular pulmonary arteriovenous malformation, pulmonary blas disease or disorder. This method includes the steps of (a) toma, pulmonary capillary hemangiomatosis, pulmonary car providing a GPCR polypeptide substantially identical to a cinosarcoma, pulmonary edema, pulmonary embolism, pull polypeptide listed in Tables 22 and 33; (b) contacting the monary eosinophilia, pulmonary fibrosis, pulmonary GPCR polypeptide with the candidate compound; and (c) hypertension, pulmonary hypoplasia, pulmonary infarction, measuring biological activity of the GPCR polypeptide, pulmonary infiltration and eosinophilia, pulmonary intersti wherein altered biological activity, relative to that of the tial air (pulmonary interstitial emphysema), pulmonary GPCR polypeptide not contacted with the compound, indi lesions, pulmonary nocardiosis, pulmonary parenchymal cates that the candidate compound may be useful for the anomalies, pulmonary thromboembolism, pulmonary tuber treatment of a muscular disease or disorder. The GPCR culosis, pulmonary vascular disorders, pulmonary vasculiti polypeptide can be in a cell or in a cell-free assay System. des, pulmonary veno-occlusive disease, pyothorax, radiation 0.165. In yet another aspect, the invention features a pneumonitis, recurrent pulmonary emboli, red hepatization, method for determining whether a candidate compound is a respiration failure, respiratory syncytial virus, Reye's Syn compound that may be useful for the treatment of a muscular drome, rheumatoid lung disease, Rickettsial pneumonia, rup disease or disorder. This method includes the steps of (a) ture of pulmonary arteries, sarcoidosis, scar cancer, Scimitar providing a transgenic non-human mammal (e.g., a knock syndrome, Scleroderma, Sclerosing hemangioma, secondary out mouse) having a disruption in a nucleic acid molecule (adult) tuberculosis, secondary bacterial pneumonia, second encoding a GPCR polypeptide substantially identical to a ary pleural neoplasms, secondary pulmonary hypertension, polypeptide listed in Tables 22 and 33; (b) contacting the senile emphysema, siderosis, silicate pneumoconiosis asbes transgenic non-human mammal with the candidate com tosis, silicatosis, silicosis, simple nodular silicosis, Sjögren's pound; and (c) measuring biological activity of the GPCR syndrome, Small airway lesions, Small cell carcinoma, Small polypeptide in the transgenic non-human mammal, wherein cell undifferentiated (oat cell) carcinoma, spontaneous pneu altered biological activity, relative to that of the transgenic mothorax, sporotrichosis, sputum production, Squamous non-human mammal not contacted with the compound, indi (epidermoid) carcinoma, Stannosis, Staphlococcal pneumo cates that the candidate compound may be useful for the nia, Suppuration (abscess formation), Systemic lupus erythe treatment of a muscular disease or disorder. matosus, talcosis, tension pneumothorax, tracheal agenesis, 0166 In yet another aspect, the invention features a tracheal Stenosis, tracheobronchial amyloidosis, tracheo method for determining whether a candidate compound is a bronchomegaly, tracheoesophageal fistula, transient tachyp compound that may be useful for the treatment of a muscular nea of the newborn (neonatal wet lung), tungsten carbide disease or disorder. This method includes the steps of (a) pneumoconiosis, usual interstitial pneumonia, usual intersti providing a transgenic non-human mammal (e.g., a mouse) US 2011/O 185439 A1 Jul. 28, 2011 20 overexpressing a nucleic acid molecule encoding a GPCR 0172. In either of these two methods, the mutation or poly polypeptide Substantially identical to a polypeptide listed in morphism is preferably associated with an alteration (for Tables 22 and 33; (b) contacting the transgenic non-human example, a decrease) in the biological activity of the polypep mammal with the candidate compound; and (c) measuring tide. biological activity of the GPCR polypeptide in the transgenic 0173. In another aspect, the invention features another non-human mammal, wherein altered biological activity, method for determining whether a patient has an increased relative to that of the transgenic non-human mammal not risk for developing a muscular disease or disorder. The contacted with the compound, indicates that the candidate method includes measuring biological activity of a GPCR compound may be useful for the treatment of a muscular polypeptide from the patient that is substantially identical to disease or disorder. a polypeptide listed in Tables 22 and 33, wherein increased or 0167. In still another aspect, the invention features another decreased levels in the GPCR biological activity, relative to method for determining whether a candidate compound may normal levels, indicate that the patient may have an increased be useful for the treatment of a muscular disease or disorder. risk for developing a muscular disease or disorder. 0.174. In still another aspect, the invention features yet This method includes (a) providing a nucleic acid molecule another method for determining whether a patient has an comprising a promoter from a gene encoding a GPCR increased risk for developing a muscular disease or disorder. polypeptide listed in Tables 22 and 33, the promoter operably The method includes the step of measuring the patient's linked to a reporter system; (b) contacting the nucleic acid expression levels of a polypeptide listed in Tables 22 and 33, molecule with the candidate compound; and (c) measuring 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, muscular disease or disorder. Preferably, the expression lev indicates that the candidate compound may be useful for the els are determined by measuring levels of polypeptide or treatment of a muscular disease or disorder. mRNA. 0.168. In another aspect, the invention features yet another (0175 Preferred muscular diseases 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 muscular disease or disorder. candidate therapeutic compounds may be identified include This method includes the steps of: (a) providing a GPCR abnormalities of ion channel closure, acetylcholine receptor polypeptide Substantially identical to a polypeptide listed in deficiency, acetylcholinesterase deficiency, acid maltase defi Tables 22 and 33; (b) contacting the polypeptide with the ciencies (type 2 glycogenosis), acquired myopathies, candidate compound; and (c) measuring interaction of the acquired myotonia, adult myotonic dystrophy, alveolar rhab candidate compound to the polypeptide. Interaction of the domyosarcoma, aminoglycoside drugs, amyloidosis, amyo compound to the polypeptide indicates that the candidate trophic lateral Sclerosis, antimyelin antibodies, bacteremic compound may be useful for the treatment of a muscular myositis, Batten's disease (neuronal ceroid lipofuscinoses), Becker's muscular dystrophy, benign neoplasms, Bornholm disease or disorder. disease, botulism, branching enzyme deficiency (type 4 gly 0169. In still another aspect, the invention features another cogenosis), carbohydrate storage diseases, carnitine deficien method for determining whether a candidate compound may cies, carnitine palmitoyltransferase deficiency, central core be useful for the treatment of a muscular disease or disorder. disease, centronuclear (myotubular) myopathy, Chagas dis This method includes (a) providing a GPCR polypeptide ease, chondrodystrophic myotonia, chronic renal disease, substantially identical to a polypeptide listed in Tables 22 and congenital fibertype disproportion, congenital muscular dys 33; (b) contacting the polypeptide with the candidate com trophy, congenital myopathies, congenital myotonic dystro pound; and (c) measuring the half-life of the polypeptide, phy, congenital paucity of synaptic clefts, cysticercosis, cyto wherein an alteration in the half-life of the polypeptide, rela plasmic body myopathy, debranching enzyme deficiency 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 myopathy, Duchenne muscular dystrophy, embryonal rhab 0170 In another aspect, the invention features a method domyosarcoma, Emery-Dreifuss muscular dystrophy, exo for determining whether a patient has an increased risk for toxic bacterial infections, facioscapulohumeral muscular developing a muscular disease or disorder. The method dystrophy, failure of neuromuscular transmission, fiber includes the step of determining whether the patient has a necrosis, fibromyalgia, fingerprint body myopathy, Forbe's mutation in a gene encoding a polypeptide listed in Tables 22 disease, gas gangrene, Guillain-Barré syndrome, inclusion and 33, wherein presence of the mutation indicates that the body myositis, infantile spinal muscularatrophies, infectious patient may have an increased risk for developing a muscular myositis, inflammatory myopathies, influenza, Isaac's Syn disease or disorder. drome, ischemia, Kearns-Sayre syndrome, lactase dehydro 0171 In a related aspect, the invention features another genase deficiency, Lambert-Eaton syndrome, Leigh's dis method for determining whether a patient has an increased ease, leuknock outdystrophies, limb girdle muscular risk for developing a muscular disease or disorder. This dystrophy, lipid storage myopathies, Luft's disease, lysoso method includes the step of determining whether the patient mal glycogen storage disease with normal acid maltase activ has a polymorphism in a gene encoding a polypeptide listed in ity, maignant neoplasms, malignant hyperthermia, McAr Tables 22 and 33, wherein presence of the polymorphism dle's disease, MELAS syndrome (mitochondrial myopathy, indicates that the patient may have an increased risk for encephalopathy, lacticacidosis, and strokes), MERRF syn developing a muscular disease or disorder. drome (myoclonus epilepsy with ragged-red fibers), meta US 2011/O 185439 A1 Jul. 28, 2011 bolic myopathies, microfiber myopathy, mitochondrial myo cates that the candidate compound may be useful for the pathies, multicore disease (minicore disease), multisystem treatment of a disease or disorder of the ovary. The GPCR triglyceride storage disease, muscle wasting from diabetes, polypeptide can be in a cell or in a cell-free assay System. muscular dystrophies, myasthenia gravis, myasthenic Syn 0183 In yet another aspect, the invention features a drome (Eaton-Lambert syndrome), myoadenylate deaminase method for determining whether a candidate compound is a deficiency, myoglobinuria, myopathies, myophosphorylase compound that may be useful for the treatment of disease or deficiency (type 5 glycogenosis), myositis, myositis ossifi disorder of the ovary. This method includes the steps of (a) cans, myotonia congenita, myotonic muscular dystrophy, providing a transgenic non-human mammal (e.g., a knock nemaline myopathy, ocular muscular dystrophy, oculopha out mouse) having a disruption in a nucleic acid molecule ryngeal muscular dystrophy, paramyotonia, parasytic myo encoding a GPCR polypeptide substantially identical to a pathies, periodic paralysis, peripheral neuropathies, phos polypeptide listed in Tables 23 and 33; (b) contacting the phofructokinase deficiency (type 7 glycogenosis), transgenic non-human mammal with the candidate com phosphoglycerate kinase deficiency, phosphoglycerate pound; and (c) measuring biological activity of the GPCR mutase deficiency, pleomorphic rhabdomyosarcoma, poly polypeptide in the transgenic non-human mammal, wherein myositis, Pompe's disease, progressive muscular atrophy, altered biological activity, relative to that of the transgenic progressive systemic sclerosis, reducing body myopathy, non-human mammal not contacted with the compound, indi RefSum's disease, rhabdomyolysis, rhabdomyoma, rhab cates that the candidate compound may be useful for the domyosarcoma, sarcoidosis, sarcoma botryoides, sarcotubu treatment of a disease or disorder of the ovary. lar myopathy, secondary congenital myopathies, slow chan 0184. In yet another aspect, the invention features a nel syndrome, spasmodic torticollis, spheroid body method for determining whether a candidate compound is a myopathy, spinal muscular atrophy, Steroid myopathy, stiff compound that may be useful for the treatment of a disease or person syndrome, systemic lupus erythematosus, Tauri's dis disorder of the ovary. This method includes the steps of (a) ease, tick paralysis, toxic myopathies, toxoplasmosis, trichi providing a transgenic non-human mammal (e.g., a mouse) nosis, trilaminar fiber myopathy, type 2 myofiber atrophy, overexpressing a nucleic acid molecule encoding a GPCR typhoid fever, vasculitis, viral myositis, and Zebra body polypeptide Substantially identical to a polypeptide listed in myopathy. Tables 23 and 33; (b) contacting the transgenic non-human 0176). 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 22. relative to that of the transgenic non-human mammal not 0177. 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. 0185. In still another aspect, the invention features another 0178. 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 0179. 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, 0180. 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 0186. 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 0181. 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 0182. 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 0187. In still 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 US 2011/O 185439 A1 Jul. 28, 2011 22 tive to that of the polypeptide not contacted with the com atoma, theca lutein cysts, thecomas, transitional cell carci pound, indicates that the candidate compound may be useful noma, undifferentiated carcinoma, and yolk sac carcinoma for the treatment of a disease or disorder of the ovary. Pref (endodermal sinus tumor). erably the GPCR polypeptide is in a cell or a cell free assay 0194 In another aspect, the invention features a non-hu system. man mammal (e.g., a mouse), having a transgene that 0188 In another aspect, the invention features a method includes a nucleic acid molecule encoding a GPCR polypep for determining whether a patient has an increased risk for tide substantially identical to a polypeptide listed in Table 23. 0.195. In yet another aspect, the invention features a non developing a disease or disorder of the ovary. The method human mammal (e.g., a mouse), having a mutation in a includes the step of determining whether the patient has a nucleic acid molecule encoding a GPCR polypeptide sub mutation in a gene encoding a polypeptide listed in Tables 23 stantially identical to a polypeptide listed in Table 23. and 33, wherein presence of the mutation indicates that the 0196. In a related aspect, the invention features a cell from patient may have an increased risk for developing a disease or a non-human mammal having a transgene that includes a disorder of the ovary. nucleic acid molecule encoding a GPCR polypeptide sub 0189 In a related aspect, the invention features another stantially identical to a polypeptide listed in Table 23. method for determining whether a patient has an increased 0.197 In another aspect, the invention features a cell from risk for developing a disease or disorder of the ovary. This a non-human mammal having a mutation in a nucleic acid method includes the step of determining whether the patient molecule encoding a GPCR polypeptide substantially identi has a polymorphism in a gene encoding a polypeptide listed in cal to a polypeptide listed in Table 23. Tables 23 and 33, wherein presence of the polymorphism 0.198. In another aspect, the invention features a method of indicates that the patient may have an increased risk for preventing or treating blood disease, including introducing developing a disease or disorder of the ovary. into a human an expression vector that includes a nucleic acid 0190. In either of these two methods, the mutation or poly molecule encoding a GPCR polypeptide substantially identi morphism is preferably associated with an alteration (for cal to a polypeptide listed in Tables 24 and 33, operably linked example, a decrease) in the biological activity of the polypep to a promoter. tide. 0199. In still another aspect, the invention features a 0191 In another aspect, the invention features another method of treating or preventing blood disease, including method for determining whether a patient has an increased administering to an animal (e.g., a human) a compound that risk for developing a disease or disorder of the ovary. The modulates the biological activity of a GPCR polypeptide method includes measuring biological activity of a GPCR substantially identical to a polypeptide listed in Tables 24 and polypeptide from the patient that is substantially identical to 33. a polypeptide listed in Tables 23 and 33, wherein increased or 0200. 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) 0.192 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 cates that the candidate compound may be useful for the developing a disease or disorder of the ovary. Preferably, the treatment of a blood disease or disorder. The GPCR polypep expression levels are determined by measuring levels of tide can be in a cell or in a cell-free assay system. polypeptide or mRNA. 0201 In yet another aspect, the invention features a 0193 Diseases of the ovary that can be treated or diag method for determining whether a candidate compound is a nosed using the methods of the invention or for which candi compound that may be useful for the treatment of a blood date therapeutic compounds may be identified include disease or disorder. This method includes the steps of (a) autoimmune oophoritis, brenner tumors, choriocarcinoma, providing a transgenic non-human mammal (e.g., a knock clear cell adenocarcinoma, clear cell carcinoma, corpus luteal out mouse) having a disruption in a nucleic acid molecule cysts, decidual reaction, dysgerminoma, embryonal carci encoding a GPCR polypeptide substantially identical to a noma, endometrioid tumors, endometriosis, endometriotic polypeptide listed in Tables 24 and 33; (b) contacting the cysts, epithelial inclusion cysts, fibrothecoma, follicular transgenic non-human mammal with the candidate com cysts, gonadoblastoma, granulosa-stroma cell tumors, granu pound; and (c) measuring biological activity of the GPCR losa-theca cell tumor, gynandroblastoma, hilum cell hyper polypeptide in the transgenic non-human mammal, wherein plasia, luteal cysts, luteal hematomas, luteoma of pregnancy, altered biological activity, relative to that of the transgenic massive ovarian edema, metastatic neoplasm, mixed germ non-human mammal not contacted with the compound, indi cell tumors, monodermal tumors, mucinous tumors, neoplas cates that the candidate compound may be useful for the tic cysts, ovarian changes secondary to cytotoxic drugs and treatment of a blood disease or disorder radiation, ovarian fibroma, polycystic ovary syndrome, preg 0202 In yet another aspect, the invention features a nancy luteoma, premature follicle depletion, pseudomyxoma method for determining whether a candidate compound is a peritonei, resistant ovary, serous tumors, Sertoli-Leydig cell compound that may be useful for the treatment of a blood tumor, sex-cord tumor with annular tubules, steroid (lipid) disease or disorder. This method includes the steps of (a) cell tumor, stromal hyperplasia, Stromal hyperthecosis, ter providing a transgenic non-human mammal (e.g., a mouse) US 2011/O 185439 A1 Jul. 28, 2011
overexpressing a nucleic acid molecule encoding a GPCR 0209. 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 24 and 33; (b) contacting the transgenic non-human risk for developing a blood 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 GPCR polypeptide in the transgenic tide from the patient that is substantially identical to a non-human mammal, wherein altered biological activity, polypeptide listed in Tables 24 and 33, wherein increased or relative to that of the transgenic non-human mammal not decreased levels in the GPCR biological activity, relative to contacted with the compound, indicates that the candidate normal levels, indicate that the patient may have an increased compound may be useful for the treatment of a blood disease risk for developing a blood disease or disorder. or disorder. 0210. In still another aspect, the invention features yet 0203 Instill another aspect, the invention features another another method for determining whether a patient has an method for determining whether a candidate compound may increased risk for developing a blood disease or disorder. The be useful for the treatment of a blood disease or disorder. This method includes the step of measuring the patient's expres method includes (a) providing a nucleic acid molecule com sion levels of a polypeptide listed in Tables 24 and 33, prising a promoter from a gene encoding a GPCR polypeptide wherein altered levels in the expression, relative to normal, listed in Tables 24 and 33, the promoter operably linked to a indicate that the patient has an increased risk for developing a reporter system; (b) contacting the nucleic acid molecule with blood disease or disorder. Preferably, the expression levels the candidate compound; and (c) measuring reporter activity, are determined by measuring levels of polypeptide or mRNA. wherein altered reporter activity, relative to a nucleic acid 0211 Preferred blood diseases that can be treated or diag molecule not contacted with the compound, indicates that the nosed using the methods of the invention or for which candi candidate compound may be useful for the treatment of a date therapeutic compounds may be identified include abnor blood disease or disorder. mal hemoglobins, abnormalities in granulocyte count, 0204. In another aspect, the invention features yet another abnormalities in lymphocyte count, abnormalities in mono method for determining whether a candidate compound may cyte count, abnormalities of blood platelets, abnormalitites of be useful for the treatment of a blood disease or disorder. This platelet function, acanthocytosis, acquired neutropenia, acute method includes the steps of: (a) providing a GPCR polypep granulocytic leukemia, acute idiopathic thrombocytopenic tide substantially identical to a polypeptide listed in Tables 24 purpura, acute infections, acute lymphoblastic leukemia, and 33; (b) contacting the polypeptide with the candidate acute lymphocytic leukemia, acute myeloblastic leukemia, compound; and (c) measuring interaction of the candidate acute myelocytic leukemia, acute myeloid leukemia, acute compound to the polypeptide. Interaction of the compound to pyogenic bacterial infections, acute red cell aplasia, acute 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 0205 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 0206. 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, 0207. 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 0208. 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 US 2011/O 185439 A1 Jul. 28, 2011 24 dehydrogenase deficiency, granulated T-cell lymphocyte leu includes a nucleic acid molecule encoding a GPCR polypep kemia, granulocytic sarcoma, granulocytosis, Hageman trait, tide substantially identical to a polypeptide listed in Table 24. hairy cell leukemia (leukemic reticuloendotheliosis), Hand 0213. In yet another aspect, the invention features a non Schiller-Christian disease, heavy-chain disease, hemoglobin human mammal (e.g., a mouse), having a mutation in a C disease, hemoglobin constant spring, hemoglobin S, hemo nucleic acid molecule encoding a GPCR polypeptide sub globinopathies, hemolysis caused by infectious agents, stantially identical to a polypeptide listed in Table 24. hemolytic anemia, hemolytic anemia secondary to mechani 0214. In a related aspect, the invention features a cell from cal erythrocyte destruction, hemolytic blood transfusion a non-human mammal having a transgene that includes a reactions, hemolytic disease of the newborn, hemophago nucleic acid molecule encoding a GPCR polypeptide sub cytic disorders, hemophilia A, hemophilia B (Christmas dis stantially identical to a polypeptide listed in Table 24. ease, factor 9 deficiency, hepatitis, hereditary elliptocytosis, 0215. In another aspect, the invention features a cell from hereditary spherocytosis, heterozygous beta thalassemia a non-human mammal having a mutation in a nucleic acid (Cooley's trait), homozygous betathalassemia (Cooley's ane molecule encoding a GPCR polypeptide substantially identi mia), hypereosinophilic syndrome, hypoxia, idiopathic cold cal to a polypeptide listed in Table 24. 0216. In another aspect, the invention features a method of hemagglutinin disease, idiopathic thrombocytopenic pur preventing or treating a disease of the prostate including pura, idiopathic warm autoimmune hemolytic anemia, introducing into a human an expression vector that includes a immune drug induced hemolysis, immune-mediated nucleic acid molecule encoding a GPCR polypeptide sub hemolytic anemias, immunodeficiency disease, infantile neu stantially identical to a polypeptide listed in Tables 25 and 33, tropenia (Knock outstmann), instability of the hemoglobin operably linked to a promoter. molecule, iron deficiency anemia, isoimmune hemolytic ane 0217. In still another aspect, the invention features a mia,juvenile chronic myeloid leukemia, Langerhans cell his method of treating or preventing a disease of the prostate tiocytosis, large granular lymphocyte leukemia, lazy leu including administering to an animal (e.g., a human) a com knock outcyte syndrome, Letterer-Siwe disease, leukemias, pound that modulates the biological activity of a GPCR leukemoid reaction, leuknock outerythroblastic anemia, lipid polypeptide Substantially identical to a polypeptide listed in storage diseases, lymphoblastosis, lymphocytopenia, lym Tables 25 and 33. phocytosis, lymphoma, lymphopenia, macroangiopathic 0218. In yet another aspect, the invention features a hemolytic anemia, malaria, marrow aplasia, May-Hegglin method for determining whether a candidate compound is a anomaly, measles, megaloblastic anemia, metabolic diseases, compound that may be useful for the treatment of a disease or microangiopathic hemolytic anemia, microcytic anemia, mil disorder of the prostate. This method includes the steps of (a) iary tuberculosis, mixed phenotupe acute leukemia, mono providing a GPCR polypeptide substantially identical to a 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, 0219. 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 0220. 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 0212. 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 US 2011/O 185439 A1 Jul. 28, 2011 transgenic non-human mammal, wherein altered biological method includes measuring biological activity of a GPCR activity, relative to that of the transgenic non-human mammal polypeptide from the patient that is substantially identical to not contacted with the compound, indicates that the candidate a polypeptide listed in Tables 25 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 prostate. normal levels, indicate that the patient may have an increased 0221. In still another aspect, the invention features another risk for developing a disease or disorder of the prostate. method for determining whether a candidate compound may be useful for the treatment of a disease or disorder of the 0228. In still another aspect, the invention features yet prostate. 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 Tables 25 and 33, the promoter prostate. The method includes the step of measuring the operably linked to a reporter system; (b) contacting the patient's expression levels of a polypeptide listed in Tables 25 nucleic acid molecule with the candidate compound; and (c) and 33, wherein altered levels in the expression, relative to measuring reporter activity, wherein altered reporter activity, normal, indicate that the patient has an increased risk for relative to a nucleic acid molecule not contacted with the developing a disease or disorder of the prostate. Preferably, compound, indicates that the candidate compound may be the expression levels are determined by measuring levels of useful for the treatment of a disease or disorder of the prostate. polypeptide or mRNA. 0222. In another aspect, the invention features yet another 0229. Diseases of the prostate that can be treated or diag method for determining whether a candidate compound may nosed using the methods of the invention or for which candi be useful for the treatment of a disease or disorder of the date therapeutic compounds may be identified include acute prostate. This method includes the steps of: (a) providing a bacterial prostatitis, acute prostatitis, adenoid basal cell GPCR polypeptide substantially identical to a polypeptide tumor (adenoid cystic-like tumor), allergic (eosinophilic) listed in Tables 25 and 33; (b) contacting the polypeptide with granulomatous prostatitis, atrophy, atypical adenomatous the candidate compound; and (c) measuring interaction of the hyperplasia, atypical basal cell hyperplasia, basal cell candidate compound to the polypeptide. Interaction of the adenoma, basal cell hyperplasia, BCG-induced granuloma compound to the polypeptide indicates that the candidate tous prostatitis, benign prostatic hyperplasia, benign prostatic compound may be useful for the treatment of a disease or hypertrophy, blue nevus, carcinosarcoma, chronic abacterial disorder of the prostate. prostatitis, chronic bacterial prostatitis, cribriform hyperpla 0223) In still another aspect, the invention features another sia, ductal (endometrioid) adenocarcinoma, granulomatous method for determining whether a candidate compound may prostatitis, hematuria, iatrogenic granulomatous prostatitis, be useful for the treatment of a disease or disorder of the idiopathic (nonspecific) granulous prostatitis, impotence, prostate. This method includes (a) providing a GPCR infectious granulomatous prostatitis, inflammatory polypeptide Substantially identical to a polypeptide listed in pseudotumor, leiomyosarcoma, leukemia, lymphoepithe Tables 25 and 33; (b) contacting the polypeptide with the lioma-like carcinoma, malaknock outplakia, malignant lym candidate compound; and (c) measuring the half-life of the phoma, mucinous (colloid) carcinoma, nodular hyperplasia polypeptide, wherein an alteration in the half-life of the (benign prostatic hyperplasia), nonbacterial prostatitis, polypeptide, relative to that of the polypeptide not contacted obstruction of urinary outflow, phyllodes tumor, postatrophic with the compound, indicates that the candidate compound hyperplasia, postirradiation granulomatous prostatitis, post may be useful for the treatment of a disease or disorder of the operative spindle cell nodules, postSurgical granulomatous prostate. Preferably the GPCR polypeptide is in a cellor a cell prostatitis, prostatic adenocarcinoma, prostatic carcinoma, free assay system. prostatic intraepithelial neoplasia, prostatic melanosis, pros 0224. In another aspect, the invention features a method tatic neoplasm, prostatitis, rhabdomyosarcoma, sarcomatoid for determining whether a patient has an increased risk for carcinoma of the prostate, Sclerosing adenosis, signet ring developing a disease or disorder of the prostate. The method cell carcinoma, Small-cell, undifferentiated carcinoma (high includes the step of determining whether the patient has a grade neuroendocrine carcinoma), Squamous cell carcinoma mutation in a gene encoding a polypeptide listed in Tables 25 of the prostate, Stromal hyperplasia with atypia, transitional and 33, wherein presence of the mutation indicates that the cell carcinoma of the prostate, Xanthogranulomatous prostati patient may have an increased risk for developing a disease or tis, and Xanthoma. disorder of the prostate. 0230. In another aspect, the invention features a non-hu 0225. In a related aspect, the invention features another man mammal (e.g., a mouse), having a transgene that method for determining whether a patient has an increased includes a nucleic acid molecule encoding a GPCR polypep risk for developing a disease or disorder of the prostate. This tide substantially identical to a polypeptide listed in Table 25. method includes the step of determining whether the patient 0231. In yet another aspect, the invention features a non has a polymorphism in a gene encoding a polypeptide listed in human mammal (e.g., a mouse), having a mutation in a Tables 25 and 33, wherein presence of the polymorphism nucleic acid molecule encoding a GPCR polypeptide sub indicates that the patient may have an increased risk for stantially identical to a polypeptide listed in Table 25. developing a disease or disorder of the prostate. 0232. In a related aspect, the invention features a cell from 0226. In either of these two methods, the mutation or poly a non-human mammal having a transgene that includes a morphism is preferably associated with an alteration (for nucleic acid molecule encoding a GPCR polypeptide sub example, a decrease) in the biological activity of the polypep stantially identical to a polypeptide listed in Table 25. tide. 0233. In another aspect, the invention features a cell from 0227. In another aspect, the invention features another a non-human mammal having a mutation in a nucleic acid method for determining whether a patient has an increased molecule encoding a GPCR polypeptide substantially identi risk for developing a disease or disorder of the prostate. The cal to a polypeptide listed in Table 25. US 2011/O 185439 A1 Jul. 28, 2011 26
0234. In another aspect, the invention features a method of molecule not contacted with the compound, indicates that the preventing or treating skin disease, including introducing into candidate compound may be useful for the treatment of a skin a human an expression vector that includes a nucleic acid disease or disorder. molecule encoding a GPCR polypeptide substantially identi 0240. In another aspect, the invention features yet another cal to a polypeptide listed in Tables 26 and 33, operably linked method for determining whether a candidate compound may to a promoter. be useful for the treatment of a skin disease or disorder. This 0235. In still another aspect, the invention features a method includes the steps of: (a) providing a GPCR polypep method of treating or preventing skin disease, including tide substantially identical to a polypeptide listed in Tables 26 administering to an animal (e.g., a human) a compound that and 33; (b) contacting the polypeptide with the candidate modulates the biological activity of a GPCR polypeptide compound; and (c) measuring interaction of the candidate substantially identical to a polypeptide listed in Tables 26 and compound to the polypeptide. Interaction of the compound to 33. the polypeptide indicates that the candidate compound may 0236. In yet another aspect, the invention features a be useful for the treatment of a skin disease or disorder. method for determining whether a candidate compound is a 0241. In still another aspect, the invention features another compound that may be useful for the treatment of a skin method for determining whether a candidate compound may disease or disorder. This method includes the steps of (a) be useful for the treatment of a skin disease or disorder. This providing a GPCR polypeptide substantially identical to a method includes (a) providing a GPCR polypeptide substan polypeptide listed in Tables 26 and 33; (b) contacting the tially identical to a polypeptide listed in Tables 26 and 33; (b) GPCR polypeptide with the candidate compound; and (c) contacting the polypeptide with the candidate compound; and measuring biological activity of the GPCR polypeptide, (c) measuring the half-life of the polypeptide, wherein an wherein altered biological activity, relative to that of the alteration in the half-life of the polypeptide, relative to that of GPCR polypeptide not contacted with the compound, indi the polypeptide not contacted with the compound, indicates cates that the candidate compound may be useful for the that the candidate compound may be useful for the treatment treatment of a skin disease or disorder. The GPCR polypep of a skin disease or disorder. Preferably 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. 0237. In yet another aspect, the invention features a method for determining whether a candidate compound is a 0242. In another aspect, the invention features a method compound that may be useful for the treatment of a skin for determining whether a patient has an increased risk for disease or disorder. This method includes the steps of (a) developing a skin disease or disorder. The method includes providing a transgenic non-human mammal (e.g., a knock the step of determining whether the patient has a mutation in out mouse) having a disruption in a nucleic acid molecule a gene encoding a polypeptide listed in Tables 26 and 33. encoding a GPCR polypeptide substantially identical to a wherein presence of the mutation indicates that the patient polypeptide listed in Tables 26 and 33; (b) contacting the may have an increased risk for developing a skin disease or transgenic non-human mammal with the candidate com disorder. pound; and (c) measuring biological activity of the GPCR 0243 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 skin disease or disorder. This method non-human mammal not contacted with the compound, indi includes the step of determining whether the patient has a cates that the candidate compound may be useful for the polymorphism in a gene encoding a polypeptide listed in treatment of a skin disease or disorder Tables 26 and 33, wherein presence of the polymorphism 0238. 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 0244. 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 0245. 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. 0239 Instill another aspect, the invention features another 0246. 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. US 2011/O 185439 A1 Jul. 28, 2011 27
0247 Preferred skin diseases that can be treated or diag orders, melanocytic lesions, melanocytic neoplasms, mel nosed using the methods of the invention or for which candi anocytic nevus, melanocytic nevus with dysplasia, melanotic date therapeutic compounds may be identified include acan macule, reactive type, melasma, merkel cell (neuroendo thosis nigricans, acne Vulgaris, acquired epidermolysis crine) carcinoma, metastatic melanoma, miliara, mixed con bullosa, acrochordons, acrodermatitis enteropathica, acro nective tissue disease, molluscum contagiosum, morphea, pustulosis, actinic keratosis, acute cutaneous lupus erythema mucin deposition, mucocutaneous leishmaniasis, mycetoma, tosus, age spots, allergic dermatitis, alopecia greata, mycobacterial infection, Mycobacterium marinum, Myco angioedema, angiokeratoma, angioma, anthrax, apocrine bacterium ulcerans, mycosis fungoides (cutaneous T cell tumors, arthropid-bite reactions, atopic dermatitis, atypical lymphoma), myxoid cyst, necrobiosis lipoidica, necrobiosis fibroXanthoma, Bart's syndrome, basal cell carcinoma (basal lipoidica diabeticorum, necrolytic migratory erythema, cell epithelioma), Bateman's purpura, benign familial pem necrotizing fasciitis, neoplasms of dermal mesenchymal phigus (Hailey-Hailey disease), benign keratoses, Berloque cells, neoplasms of keratinocytes, neoplasms of skin append dermatitis, blue nevus, borderline leprosy, Borrelia infection ages, neoplasms of the epidermis, neural tumors, neuroendo (lyme disease), Bowen's disease (carcinoma in situ), bullous crine carcinoma of the skin, neurothekeoma, nevocellular pemphigoid, Café-au-lait spot, calcification, cellular blue nevus (melanocytic nevus), nummular dermatitis, oblitera nevus, cellulitis, Chagas disease, chickenpox (varicella), tive vasculitis, onchocerciasis, Paget's disease, pale cellacan chloasma, chondrodermatitis nodularis helicis, chondroid thoma of Degos, palisaded encapsulated neuroma, papillo Syringoma, chronic actinic dermatitis, chronic cutaneous mavirus infections, paraneoplastic pemphigus, parasitic lupus erythematosus, chronic discoid lesions, cicatricial pem infections, pemphigoid gestationis, pemphigus, pemphigus phigoid, collagen abnormalities, compount melanocytic foliaceus, pemphigus Vulgaris, perivascular infiltrates, pilar nevus, congenital melanocytic nevus, connective tissue cysts, pinta, pityriasis alba, pityriasis lichenoides chronica (of nevus, contact dermatitis, cutaneous leishmaniasis, cutis Juliusberg), pityriasis lichenoides et varioliformis acuta, laxa, cysts of the skin, dandruff, Darier's disease (keratosis pityriasis rosea, pityriasis rubra pilaris, plantar warts, poro follicularis), deep fungal infections, delayed-hypersensitivity keratosis, pressure necrosis, progressive systemic sclerosis, reaction, dermal Spitz's nevus, dermatitis, dermatitis herpe protozoal infections, pruritic urticarial papules and plasques tiformis, dermatofibroma (cutaneous fibrous histiocytoma), of pregnancy, pruritisani, pseudofolliculitis barbae, pseudox dermatofibrosarcoma protuberans, dermatomyositis, der anthoma elasticum, psoriasis Vulgaris, pyogenic granuloma, matophyte infections, dermatophytid reactions, dermoid radial growild typeh phase melanoma, recessive dystrophic cyst, dermotropic ricketsial infections, dermotropic viral epidermolysis bullosa, Reiter's syndrome, ringworm, Roch infections, desmoplastic melanoma, discoid lupus erythema alimaea henselae infection, rosacea, rubella, Sarcoidosis, Sca tosus, dominant dystrophic epidermolysis bullosa, Dowling bies, Schamberg's disease, Scleroderma, sebaceous hyperpla Meara epidermolysis bullosa, dyshidrotic dermatitis, dys sia, sebaceous tumors, seborrheic dermatitis, seborrheic plastic nevi, eccrine tumors, eethyma, 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, nodosum, erythema nodosum leprosum, fibrotic disorders, Superficial fungal infections, Superficial spreading melanoma fibrous tumors, follicular mucinosis, Fordyce's condition, in situ, Syphilis, Syringoma, systemic lupus erythematosus, fungal infections, genodermatoses, graft-Versus-host disease, systemic mastocytosis, tinea (dermatophytosis, tinea versi granuloma annulare, granulomatous vasculitis, Grover's dis color, toxic epidermal necrolysis, transient acantholytic der ease, hair follicle infections, hair follicle tumors, hair loss, matosis, tuberculoid leprosy, tuberculosis, urticaria, urticaria halo nevus, herpes simplex, herpes Zoster (shingles), hidrad pigmentosa, urticarial vasculitis, vascular tumors, Verruca enitis Suppurativa, histiocytic lesions, HIV infections, hives, Vulgaris (common wart), vertical growild typeh phase mela human papillomavirus, hyperhydrosis, ichthyosis, idiopathic noma, visceral leishmaniasis, vitiligo, warty dyskeratoma, skin diseases, impetigo, incontinentia pigmenti, intraepider Weber-Cockayne epidermolysis bullosa, Woringer-Knock 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 0248. 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 blennorrhagicum, keratosis pilaris, leiomyoma, lentigo, len includes a nucleic acid molecule encoding a GPCR polypep tigo maligna (Hutchinson's freckle), lepromatous leprosy, tide substantially identical to a polypeptide listed in Table 26. leprosy (Hansen's disease), leuknock outcytoclastic vasculi 0249. In yet another aspect, the invention features a non tis, lichen planus, lichen Sclerosus et atrophicus, lichen sim human mammal (e.g., a mouse), having a mutation in a plex chronicus, lichen striatus, lichenoid disorders, lichenoid nucleic acid molecule encoding a GPCR polypeptide sub drug reactions, light eruptions, linear bullous IgA dermatitis, stantially identical to a polypeptide listed in Table 26. lipoma, Lucio's phenomenon, lupus erythematosus, lym 0250 In a related aspect, the invention features a cell from phatic filariasis, lymphocytic vasculitis, lymphocytomacutis, a non-human mammal having a transgene that includes a lymphoid lesions, lymphomatoid papulosis, malignant blue nucleic acid molecule encoding a GPCR polypeptide sub nevus, malignant lymphomas, malignant melanoma, malig stantially identical to a polypeptide listed in Table 26. nant melanoma in situ (noninvasive malignant melanoma), 0251. In another aspect, the invention features a cell from mast cell neoplasms, mastocytosis, measles, melanocyte dis a non-human mammal having a mutation in a nucleic acid US 2011/O 185439 A1 Jul. 28, 2011 28 molecule encoding a GPCR polypeptide substantially identi nucleic acid molecule with the candidate compound; and (c) cal to a polypeptide listed in Table 26. measuring reporter activity, wherein altered reporter activity, 0252. 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 spleen 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 spleen. nucleic acid molecule encoding a GPCR polypeptide sub 0258. In another aspect, the invention features yet another stantially identical to a polypeptide listed in Tables 27 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 0253) In still another aspect, the invention features a spleen. This method includes the steps of: (a) providing a method of treating or preventing a disease of the spleen GPCR polypeptide substantially identical to a polypeptide including administering to an animal (e.g., a human) a com listed in Tables 27 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 27 and 33. compound to the polypeptide indicates that the candidate 0254. 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 spleen. compound that may be useful for the treatment of a disease or 0259 Instill another aspect, the invention features another disorder of the spleen. 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 27 and 33; (b) contacting the spleen. 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 27 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 spleen. 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 spleen. Pref 0255. 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 0260. In another aspect, the invention features a method disorder of the spleen. 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 spleen. 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 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 0261. 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 0256 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) 0262. 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 0263. 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 0257. In still another aspect, the invention features another risk for developing a disease or disorder of the spleen. method for determining whether a candidate compound may 0264. 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 US 2011/O 185439 A1 Jul. 28, 2011 29 normal, indicate that the patient has an increased risk for 0267 In yet another aspect, the invention features a non developing a disease or disorder of the spleen. Preferably, the human mammal (e.g., a mouse), having a mutation in a expression levels are determined by measuring levels of nucleic acid molecule encoding a GPCR polypeptide sub polypeptide or mRNA. stantially identical to a polypeptide listed in Table 27. 0265 Diseases of the spleen that can be treated or diag 0268. In a related aspect, the invention features a cell from 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 abnor stantially identical to a polypeptide listed in Table 27. mal immunoblastic proliferations of unknown origin, acute 0269. In another aspect, the invention features a cell from infections, acute parasitemias, agnogenic myeloid metapla a non-human mammal having a mutation in a nucleic acid sia, amyloidosis, angioimmunoblastic lymphadenopathy, molecule encoding a GPCR polypeptide substantially identi antibody-coated cells, asplenia, autoimmune diseases, cal to a polypeptide listed in Table 27. autoimmune hemolytic anemias, B-cell chronic lymphocytic 0270. In another aspect, the invention features a method of leukemia and prolymphocytic leukemia, babesiosis, bone preventing or treating a disease of the stomach including marrow involvement by carcinoma, brucellosis, carcinoma, introducing into a human an expression vector that includes a ceroid histiocytosis, chronic alcoholism, chronic granuloma nucleic acid molecule encoding a GPCR polypeptide sub tous disease, chronic hemolytic anemias, chronic hemolytic stantially identical to a polypeptide listed in Tables 28 and 33, disorders, chronic immunologic inflammatory disorders, operably linked to a promoter. chronic infections, chronic lymphocytic leukemia, chronic 0271 In still another aspect, the invention features a myelogenous leukemia, chronic parasitemias, chronic ure method of treating or preventing a disease of the stomach mia, cirrhosis, cold agglutinin disease, congestive splenom including administering to an animal (e.g., a human) a com egaly, cryoglobulinemia, disseminated tuberculosis, dyspro pound that modulates the biological activity of a GPCR teinemias, endocrine disorders, erythroblastic leukemia, polypeptide Substantially identical to a polypeptide listed in erythropoiesis, essential thrombocythemia, extramedullary Tables 28 and 33. hematopoiesis, Felty syndrome, fibrocongestive splenom 0272. In yet another aspect, the invention features a egaly, fungal infections, gamm heavy-chain disease, Gauch method for determining whether a candidate compound is a er's disease, graft rejection, granulomatous infiltration, hairy compound that may be useful for the treatment of a disease or cell leukemia, hamartomas, Hand-Schüller-Christian dis disorder of the stomach. This method includes the steps of (a) ease, hemangiomas, hemangiosarcomas, hematologic disor providing a GPCR polypeptide substantially identical to a ders, hemoglobinopathies, hemolytic anemias, hereditary polypeptide listed in Tables 28 and 33; (b) contacting the elliptocytosis, hereditary spherocytosis, histiocytic medul GPCR polypeptide with the candidate compound; and (c) lary reticulosis, histiocytosis X, Hodgkin's disease, hyper measuring biological activity of the GPCR polypeptide, sensitivity reactions, hypersplenism, hyposplenism, idio wherein altered biological activity, relative to that of the 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 0273. 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 0274. 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 0266. 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 US 2011/O 185439 A1 Jul. 28, 2011 30 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 28 and 33, wherein increased or disorder of the stomach. decreased levels in the GPCR biological activity, relative to 0275 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 stomach. be useful for the treatment of a disease or disorder of the 0282. In still another aspect, the invention features yet stomach. 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 Tables 28 and 33, the promoter stomach. The method includes the step of measuring the operably linked to a reporter system; (b) contacting the patient's expression levels of a polypeptide listed in Tables 28 nucleic acid molecule with the candidate compound; and (c) and 33, wherein altered levels in the expression, relative to measuring reporter activity, wherein altered reporter activity, normal, indicate that the patient has an increased risk for relative to a nucleic acid molecule not contacted with the developing a disease or disorder of the stomach. Preferably, compound, indicates that the candidate compound may be the expression levels are determined by measuring levels of useful for the treatment of a disease or disorder of the stom polypeptide or mRNA. ach. 0283 Diseases of the stomach that can be treated or diag 0276. 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 acute be useful for the treatment of a disease or disorder of the erosive gastropathy, acute gastric ulcers, adenocarcinomas, stomach. This method includes the steps of: (a) providing a adenomas, adenomatous polyps, advanced gastric cancer, GPCR polypeptide substantially identical to a polypeptide ampullary carcinoma, atrophic gastritis, bacterial gastritis, listed in Tables 28 and 33; (b) contacting the polypeptide with carcinoid tumors, carcinoma of the stomach, chemical gas the candidate compound; and (c) measuring interaction of the tritis, chronic (nonerosive) gastritis, chronic idiopathic gas candidate compound to the polypeptide. Interaction of the tritis, chronic nonatrophic gastritis, Chronkhite-Canada Syn compound to the polypeptide indicates that the candidate drome, congenital cysts, congenital diaphragmatic hernias, compound may be useful for the treatment of a disease or congenital diverticula, congenital duplications, congenital disorder of the stomach. pyloric Stenosis, congestive gastropathy, cyclic vomiting Syn 0277. In still another aspect, the invention features another drome, decreased mucosal resistance to acid, diffuse or infil method for determining whether a candidate compound may trating adenocarcinoma, early gastric cancer, emphysema be useful for the treatment of a disease or disorder of the tous gastritis, endocrine cell hyperplasia, environmental stomach. This method includes (a) providing a GPCR gastritis, eosinophilic gastritis, eosinophilic gastroenteritis, polypeptide Substantially identical to a polypeptide listed in epithelial polyps, erosive (acute) gastritis, fundic gland pol Tables 28 and 33; (b) contacting the polypeptide with the yps, fungal gastritis, gangliocytic paragangliomas, gastral 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, 0278. 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, 0279. 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 0280. 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. 0281. In another aspect, the invention features another 0284. 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. US 2011/O 185439 A1 Jul. 28, 2011
0285. 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 testes. stantially identical to a polypeptide listed in Table 28. 0293 Instill another aspect, the invention features another 0286. 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 testes. This method includes (a) providing a nucleic acid stantially identical to a polypeptide listed in Table 28. molecule comprising a promoter from a gene encoding a 0287. In another aspect, the invention features a cell from GPCR polypeptide listed in Tables 29 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 28. measuring reporter activity, wherein altered reporter activity, 0288. 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 testes 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 testes. nucleic acid molecule encoding a GPCR polypeptide sub 0294. In another aspect, the invention features yet another stantially identical to a polypeptide listed in Tables 29 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 0289. In still another aspect, the invention features a testes. This method includes the steps of: (a) providing a method of treating or preventing a disease of the testes includ GPCR polypeptide substantially identical to a polypeptide ing administering to an animal (e.g., a human) a compound listed in Tables 29 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 29 and candidate compound to the polypeptide. Interaction of the 33. compound to the polypeptide indicates that the candidate 0290. 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 testes. compound that may be useful for the treatment of a disease or 0295 Instill another aspect, the invention features another disorder of the testes. 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 29 and 33; (b) contacting the testes. 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 29 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 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 0291. 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 0296. 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. polypeptide in the transgenic non-human mammal, wherein 0297. 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 testes. 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 testes. has a polymorphism in a gene encoding a polypeptide listed in 0292. In yet another aspect, the invention features a Tables 29 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 testes. disorder of the testes. This method includes the steps of (a) 0298. 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 29 and 33; (b) contacting the transgenic non-human 0299. 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 testes. 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 2011/O 185439 A1 Jul. 28, 2011 32 a polypeptide listed in Tables 29 and 33, wherein increased or 0305. In another aspect, the invention features a cell from decreased levels in the GPCR biological activity, relative to a non-human mammal having a mutation in a nucleic acid normal levels, indicate that the patient may have an increased molecule encoding a GPCR polypeptide substantially identi risk for developing a disease or disorder of the testes. cal to a polypeptide listed in Table 29. 0300. In still another aspect, the invention features yet 0306 In another aspect, the invention features a method of another method for determining whether a patient has an preventing or treating a disease of the thymus including intro ducing into a human an expression vector that includes a increased risk for developing a disease or disorder of the nucleic acid molecule encoding a GPCR polypeptide sub testes. The method includes the step of measuring the stantially identical to a polypeptide listed in Tables 30 and 33, patient's expression levels of a polypeptide listed in Tables 29 operably linked to a promoter. and 33, wherein altered levels in the expression, relative to 0307. In still another aspect, the invention features a normal, indicate that the patient has an increased risk for method of treating or preventing a disease of the thymus developing a disease or disorder of the testes. Preferably, the including administering to an animal (e.g., a human) a com expression levels are determined by measuring levels of pound that modulates the biological activity of a GPCR polypeptide or mRNA. polypeptide Substantially identical to a polypeptide listed in 0301 Diseases of the testes that can be treated or diag Tables 30 and 33. nosed using the methods of the invention or for which candi 0308. In yet another aspect, the invention features a date therapeutic compounds may be identified include aber method for determining whether a candidate compound is a rant ducts of Haller, abnormal productions of hormones, compound that may be useful for the treatment of a disease or abnormalities of testicular descent, acute epididymoorhcitis, disorder of the thymus. This method includes the steps of (a) adenomatoid tumor, adenomatous hyperplasia of the rete tes providing a GPCR polypeptide substantially identical to a tis, adenovirus, administration of estrogens, adrenal rests, polypeptide listed in Tables 30 and 33; (b) contacting the alcoholic cirrhosis, amyloidosis, anorchism, appendix testes, GPCR polypeptide with the candidate compound; and (c) bacterial infections, Brucella, cachexia, carcinoma in situ, measuring biological activity of the GPCR polypeptide, carcinoma of the rete testis, chlamydia, choriocarcinoma, wherein altered biological activity, relative to that of the choristomas, chronic fibrosing epididymoorchitis, coxsackie GPCR polypeptide not contacted with the compound, indi virus B, cryptorchidism, cystic dysplasia of the rete testis, cates that the candidate compound may be useful for the cytomegalovirus, dystopia, E. coli, Echinococcus granulo treatment of a disease or disorder of the thymus. The GPCR sus, ectopic testes, embryonal carcinoma, epididymoorchitis, polypeptide can be in a cell or in a cell-free assay system. Fournier's scrotal gangrene, fungal infection, germ cell apla 0309. In yet another aspect, the invention features a sia, germ cell neoplasms, gonadal dysgenesis, gonadal stro method for determining whether a candidate compound is a mal neoplasms, granulomatous orchitis, granulosa cell compound that may be useful for the treatment of a disease or tumors, Haemophilus influenzae, HIV, hypergonadism, disorder of the thymus. This method includes the steps of (a) hypogonadotropic hypogonadism, hypopituitarism, providing a transgenic non-human mammal (e.g., a knock hypospermatogenesis, hyrocele, idiopathic granulomatous out mouse) having a disruption in a nucleic acid molecule 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 0310. 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 0302) 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 0303. 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. 0311. In still another aspect, the invention features another 0304. 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 US 2011/O 185439 A1 Jul. 28, 2011
GPCR polypeptide listed in Tables 30 and 33, the promoter patient's expression levels of a polypeptide listed in Tables 30 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 thymus. Preferably, relative to a nucleic acid molecule not contacted with the 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 thymus. 0319 Diseases of the thymus that can be treated or diag 0312. 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 acci be useful for the treatment of a disease or disorder of the dental involution, acute accidental involution, acute thymus. This method includes the steps of: (a) providing a lymphoblastic leukemia of T cell type, agenesis, age-related GPCR polypeptide substantially identical to a polypeptide involution, anaplastic carcinoma, ataxia telangiectasia, atro listed in Tables 30 and 33; (b) contacting the polypeptide with phy, bacterial infections, bacterial mediastinitis, basaloid car the candidate compound; and (c) measuring interaction of the cinoma, bone marrow transplantation, Bruton's agamma candidate compound to the polypeptide. Interaction of the globulinemia, carcinosarcoma, chronic accidental involution, compound to the polypeptide indicates that the candidate clear cell carcinoma, cortical thymoma, cytomegalovirus, compound may be useful for the treatment of a disease or DiGeorge syndrome, dysgenesis, dysplasia with pattern simi disorder of the thymus. lar to severe atrophy, dysplasia with pseudoglandular appear 0313 Instill another aspect, the invention features another ance, dysplasia with Stromal conticomedullary differentia method for determining whether a candidate compound may tion, ectopia, germ cell tumors, Grave's disease, histiocytosis be useful for the treatment of a disease or disorder of the X, HIV. Hodgkin's disease, hyperplasia, infectious mono thymus. This method includes (a) providing a GPCR nucleosis, involution, lymphoblastic lymphoma of T-cell polypeptide Substantially identical to a polypeptide listed in type, lymphoepithelioma-like carcinoma, lymphofollicular Tables 30 and 33; (b) contacting the polypeptide with the thymitis, maldescent, malignantlymphomas, malignant thy candidate compound; and (c) measuring the half-life of the moma, measles giant cell pneumonia, medullary thymoma, polypeptide, wherein an alteration in the half-life of the mixed (composite) thymoma, mucoepidermoid carcinoma, polypeptide, relative to that of the polypeptide not contacted myasthenia gravis, neonatal syphilis, neoplasms, Omenn's with the compound, indicates that the candidate compound syndrome, predominantly cortical (organoid) thymoma, pri may be useful for the treatment of a disease or disorder of the mary mediastinal B-cell lymphoma of high-grade malig thymus. Preferably the GPCR polypeptide is in a cell or a cell nancy, sarcomatoid carcinoma, seminoma, severe combined free assay system. immunodeficiency, short limb dwarfism, simple dysplasia, 0314. In another aspect, the invention features a method small cell carcinoma, small-cell B-cell lymphoma of MALT for determining whether a patient has an increased risk for type, squamous cell carcinoma, systemic lupus erythemato developing a disease or disorder of the thymus. The method Sus, teratoma, thymic carcinoid, thymic carcinoma, thymic includes the step of determining whether the patient has a cysts, thymic epithelial cysts, thymic epithelial tumor, thymic mutation in a gene encoding a polypeptide listed in Tables 30 neoplasms, thymitis with diffuse B-cell infiltrations, thymo and 33, wherein presence of the mutation indicates that the lipoma, thymoma, true thymic hyperplasia, Varicella-Zoster, patient may have an increased risk for developing a disease or viral infections, well differentiated thymic carcinoma, and disorder of the thymus. Wiscott-Aldrich syndrome. 0315. In a related aspect, the invention features another 0320 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 0321. 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. 0316. In either of these two methods, the mutation or poly 0322. 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. 0317. In another aspect, the invention features another 0323. 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 0324. 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, 0318. In still another aspect, the invention features yet operably linked to a promoter. another method for determining whether a patient has an 0325 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 US 2011/O 185439 A1 Jul. 28, 2011 34 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 31 and 33. compound to the polypeptide indicates that the candidate 0326 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 thyroid. compound that may be useful for the treatment of a disease or 0331 Instill another aspect, the invention features another disorder of the thyroid. 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 31 and 33; (b) contacting the thyroid. 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 31 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 thyroid. 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 0327. In yet another aspect, the invention features a thyroid. 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 0332. In another aspect, the invention features a method disorder of the thyroid. 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 thyroid. 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 31 polypeptide listed in Tables 31 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 transgenic disorder of the thyroid. non-human mammal, wherein altered biological activity, 0333. In a related aspect, the invention features another relative to that of the GPCR transgenic non-human mammal method for determining whether a patient has an increased not contacted with the compound, indicates that the candidate risk for developing a disease or disorder of the thyroid. This compound may be useful for the treatment of a disease or method includes the step of determining whether the patient disorder of the thyroid. has a polymorphism in a gene encoding a polypeptide listed in 0328. In yet another aspect, the invention features a Tables 31 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 thyroid. disorder of the thyroid. This method includes the steps of (a) 0334. 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 31 and 33; (b) contacting the transgenic non-human 0335. 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 thyroid. 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 31 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 thyroid. normal levels, indicate that the patient may have an increased 0329 Instill another aspect, the invention features another risk for developing a disease or disorder of the thyroid. method for determining whether a candidate compound may 0336. 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. 0337 Diseases of the thyroid that can be treated or diag 0330. 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 US 2011/O 185439 A1 Jul. 28, 2011
tis, carcinoma, C-cell hyperplasia, clear cell tumors, clear cell including administering to an animal (e.g., a human) a com variant of medullary carcinoma, colloid adenoma, columnar pound that modulates the biological activity of a GPCR variant of papillary carcinoma, congentital hypothyroidism polypeptide Substantially identical to a polypeptide listed in (cretinism), diffuse nontoxic goiter, diffuse Sclerosing variant Tables 32 and 33. of papillary carcinoma, dyshormonogenic goiter, embryonal 0344. In yet another aspect, the invention features a adenoma, encapsulated variant of papillary carcinome, method for determining whether a candidate compound is a endemic cretinism, endemic goiter, enzyme deficiency, fetal compound that may be useful for the treatment of a disease or adenoma, follicular adenoma, follicular carcinoma, follicular disorder of the uterus. This method includes the steps of (a) variant of medullary carcinoma, follicular variant of papillary providing a GPCR polypeptide substantially identical to a carcinoma, fungal infection, giant cell variant of medullary polypeptide listed in Tables 32 and 33; (b) contacting the carcinoma, goiter induced by antithyroid agents, goitrous GPCR polypeptide with the candidate compound; and (c) hypothyroidism, Graves disease, Hashimoto's autoimmune measuring biological activity of the GPCR polypeptide, thyroiditis, Hirthle cell (oncocytic) adenoma, hyalinized tra wherein altered biological activity, relative to that of the becular adenoma, hyperthyroidism, hypothyroid cretinism, GPCR polypeptide not contacted with the compound, indi hypothyroidism, iodine deficiency, juvenile thyroiditis, latro cates that the candidate compound may be useful for the genic hypothyroidism, lingual thyroid glands, malignant treatment of a disease or disorder of the uterus. The GPCR lymphoma, medullary carcinoma, melanocytic variant of polypeptide can be in a cell or in a cell-free assay System. medullary carcinoma, mesenchymal tumors, metastatic 0345. In yet another aspect, the invention features a tumors, minimally invasive follicular carcinoma, mixed med method for determining whether a candidate compound is a ullary and follicular carcinoma, mixed medullary and papil compound that may be useful for the treatment of a disease or lary carcinoma, mucinous carcinoma, mucoepidermoid car disorder of the uterus. This method includes the steps of (a) cinoma, multinodular goiter, myxedema, neoplasms, providing a transgenic non-human mammal (e.g., a knock neurologic cretinism, nonspecific lymphocytic (simple out mouse) having a disruption in a nucleic acid molecule chronic) thyroiditis, oncocytic variant of medullary carci encoding a GPCR polypeptide substantially identical to a noma, palpation thyroiditis, papillary carcinoma, papillary polypeptide listed in Tables 32 and 33; (b) contacting trans microcarcinoma, papillary variant of medullary carcinoma, genic non-human mammal with the candidate compound; partial agenesis, pituitary thyrotropic adenoma, poorly differ and (c) measuring biological activity of the GPCR transgenic entiated carcinoma, primary hypothyroidism, pseudopapil non-human mammal, wherein altered biological activity, lary variant of medullary carcinoma, Riedel's thyroiditis, relative to that of the transgenic non-human mammal not Sclerosing mucoepidermoid carcinoma with eosinophilia, contacted with the compound, indicates that the candidate silent thyroiditis, simple adenoma, Small cell variant of med compound may be useful for the treatment of a disease or ullary carcinoma, Solitary thyroid nodule, sporadic goiter, disorder of the uterus. squamous cell carcinoma, squamous variant of medullary 0346. In yet another aspect, the invention features a carcinoma, Subacute throiditis (DeCuervain, granulomatous, method for determining whether a candidate compound is a 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 0338. 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 0339. 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 uterus. stantially identical to a polypeptide listed in Table 31. 0347 Instill another aspect, the invention features another 0340. 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 uterus. This method includes (a) providing a nucleic acid stantially identical to a polypeptide listed in Table 31. molecule comprising a promoter from a gene encoding a 0341. In another aspect, the invention features a cell from GPCR polypeptide listed in Tables 32 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 31. measuring reporter activity, wherein altered reporter activity, 0342. 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 uterus 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 uterus. nucleic acid molecule encoding a GPCR polypeptide sub 0348. In another aspect, the invention features yet another stantially identical to a polypeptide listed in Tables 32 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 0343. In still another aspect, the invention features a uterus. This method includes the steps of: (a) providing a method of treating or preventing a disease of the uterus GPCR polypeptide substantially identical to a polypeptide US 2011/O 185439 A1 Jul. 28, 2011 36 listed in Tables 32 and 33; (b) contacting the polypeptide with dometriosis interna), adenosquamous carcinoma, amebiasis, the candidate compound; and (c) measuring interaction of the arias-Stella phenomenon, atrophy of the endometrium, atypi candidate compound to the polypeptide. Interaction of the cal hyperplasia, benign polypoid lesions, benign stromal nod compound to the polypeptide indicates that the candidate ule, carcinoid tumors, carcinoma in situ, cervical intraepithe compound may be useful for the treatment of a disease or lial neoplasia, chlamydia, chronic cerviciitis, chronic disorder of the uterus. nonspecific endometritis, ciliated (tubal) metaplasia, clear 0349. In still another aspect, the invention features another cell adenocarcinoma, clear cell carcinoma, clear cell meta method for determining whether a candidate compound may plasia, complex hyperplasia with atypia, complex hyperpla be useful for the treatment of a disease or disorder of the sia without atypia, condyloma aduminatum, congenital uterus. This method includes (a) providing a GPCR polypep abnormalities, corpus cancer syndrome, cystic hyperplasia, tide substantially identical to a polypeptide listed in Tables 32 dysfunctional uterine bleeding, dysmenorrhea, dysplasia of and 33; (b) contacting the polypeptide with the candidate compound; and (c) measuring the half-life of the polypeptide, the cervix (cervical intraepithelial neoplasia, squamous wherein an alteration in the half-life of the polypeptide, rela intraepithelial lesion), endocervical adenocarcinoma, tive to that of the polypeptide not contacted with the com endocervical polyp, endolymphatic stromal myosis, endome pound, indicates that the candidate compound may be useful trial adenocarcinoma, endometrial carcinoma, endometrial for the treatment of a disease or disorder of the uterus. Pref hyperplasia, endometrial polyps, endometrial stromal neo erably the GPCR polypeptide is in a cell or a cell free assay plasms, endometriosis, endometritis, endometroid (pure) system. adenocarcinoma of the endometrium, endometroid adenocar 0350. In another aspect, the invention features a method cinoma with squamous differentiation, eosinophilic metapla for determining whether a patient has an increased risk for sia, epimenorrhea, exogenous progestational hormone effect, developing a disease or disorder of the uterus. The method extrauterine endometriosis (endometriosis externa), gesta includes the step of determining whether the patient has a tional trophoplastic disease, gonorrhea, hemangioma, herpes mutation in a gene encoding a polypeptide listed in Tables 32 simplex virus type 2, high-grade squamous intraepithelial and 33, wherein presence of the mutation indicates that the lesion, human papillomavirus, hyperplasia, inadequate luteal patient may have an increased risk for developing a disease or phase, infertility, inflammatory cervical lesions, inflamma disorder of the uterus. tory lesions of the endometrium, intravenous leiomyomato 0351. In a related aspect, the invention features another sis, invasive carcinoma of cervix, invasive squamous cell method for determining whether a patient has an increased carcinoma, leiomyoma, leiomyosarcoma, lipoma, low-grade risk for developing a disease or disorder of the uterus. This squamous intraepithelial lesion, malignant mixed mesoder method includes the step of determining whether the patient mal (Millerian) tumor, menorrhagia, metaplasia, metastasiz has a polymorphism in a gene encoding a polypeptide listed in ing leiomyoma, metastatic carcinoma, microglandular hyper Tables 32 and 33, wherein presence of the polymorphism plasia, microinvasive carcinoma, microinvasive squamous cell carcinoma, mucinous adenocarcinoma, mucinous meta 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 0352. 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, 0353. 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 or mata, Verrucou carcinoma, Vestigial and heterotopic struc 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. 0354. In still another aspect, the invention features yet 0356. In another aspect, the invention features a non-hu another method for determining whether a patient has an man mammal (e.g., a mouse), having a transgene that increased risk for developing a disease or disorder of the includes a nucleic acid molecule encoding a GPCR polypep uterus. The method includes the step of measuring the tide substantially identical to a polypeptide listed in Table 32. patient's expression levels of a polypeptide listed in Tables 32 0357. In yet another aspect, the invention features a non and 33, wherein altered levels in the expression, relative to human mammal (e.g., a mouse), having a mutation in a normal, indicate that the patient has an increased risk for nucleic acid molecule encoding a GPCR polypeptide sub developing a disease or disorder of the uterus. Preferably, the stantially identical to a polypeptide listed in Table 32. expression levels are determined by measuring levels of 0358. In a related aspect, the invention features a cell from polypeptide or mRNA. a non-human mammal having a transgene that includes a 0355 Diseases of the uterus 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 Table 32. date therapeutic compounds may be identified include acute 0359. In another aspect, the invention features a cell from cervicitis, acute endometritis, adenocanthoma, adenocarci a non-human mammal having a mutation in a nucleic acid noma, adenocarcinoma in situ, adenoid cystic carcinoma, molecule encoding a GPCR polypeptide substantially identi adenomatoid tumor, adenomyoma, adenomyosis (en cal to a polypeptide listed in Table 32. US 2011/O 185439 A1 Jul. 28, 2011 37
0360. 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 pancreas including indicates that the candidate compound may be useful for the introducing into a human an expression vector that includes a treatment of a disease or disorder of the pancreas. nucleic acid molecule encoding a GPCR polypeptide sub 0366. In another aspect, the invention features yet another stantially identical to a polypeptide listed in Table 1 operably method for determining whether a candidate compound may linked to a promoter. be useful for the treatment of a disease or disorder of the 0361. In still another aspect, the invention features a pancreas. This method includes the steps of: (a) providing a method of treating or preventing a disease of the pancreas GPCR polypeptide substantially identical to a polypeptide including administering to an animal (e.g., a human) a com listed in Table 1; (b) contacting the polypeptide with the pound that modulates the biological activity of a GPCR candidate compound; and (c) measuring interaction of the polypeptide Substantially identical to a polypeptide listed in candidate compound to the polypeptide. Interaction of the Table 1. compound to the polypeptide indicates that the candidate 0362. 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 pancreas. compound that may be useful for the treatment of a disease or 0367 Instill another aspect, the invention features another disorder of the pancreas. 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 Table 1; (b) contacting the GPCR pancreas. This method includes (a) providing a GPCR polypeptide with the candidate compound; and (c) measuring polypeptide Substantially identical to a polypeptide listed in biological activity of the GPCR polypeptide, wherein altered Table 1; (b) contacting the polypeptide with the candidate biological activity, relative to that of the GPCR polypeptide compound; and (c) measuring the half-life of the polypeptide, not contacted with the compound, indicates that the candidate wherein an alteration in the half-life of the polypeptide, rela compound may be useful for the treatment of a disease or tive to that of the polypeptide not contacted with the com disorder of the pancreas. The GPCR polypeptide can be in a pound, indicates that the candidate compound may be useful cell or in a cell-free assay system. for the treatment of a disease or disorder of the pancreas. 0363. In yet another aspect, the invention features a 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 disease or disorder of the pancreas. This method includes the steps of (a) 0368. 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 pancreas. The method encoding a GPCR polypeptide substantially identical to a includes the step of determining whether the patient has a polypeptide listed in Table 1; (b) contacting the transgenic mutation in a gene encoding a polypeptide listed in Table 1, non-human mammal with the candidate compound; and (c) wherein presence of the mutation indicates that the patient measuring biological activity of the GPCR polypeptide in the has an increased risk for developing a disease or disorder of transgenic non-human mammal, wherein altered biological the pancreas. activity, relative to that of the transgenic non-human mammal 0369. In a related aspect, the invention features another not 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 pancreas. This disorder of the pancreas. method includes the step of determining whether the patient 0364. 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) 0370. 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 0371. 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 0365. 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 0372. 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, molecule with the candidate compound; and (c) measuring 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 US 2011/O 185439 A1 Jul. 28, 2011 disease or disorder of the pancreas. Preferably, the expression tical to a polypeptide listed in Table 1; (b) contacting the levels are determined by measuring levels of polypeptide or GPCR polypeptide with the candidate compound; and (c) mRNA. measuring biological activity of the GPCR polypeptide, 0373 Diseases of the pancreas that can be treated or diag wherein altered biological activity, relative to that of the nosed using the methods of the invention or for which candi GPCR polypeptide not contacted with the compound, indi date therapeutic compounds may be identified include cates that the candidate compound may be useful for the ACTHoma, acute pancreatitis, adult onset diabetes, annulare treatment of a disease or disorder of the bone and joints. The pancreas, carcinoid syndrome, carcinoid tumors, carcinoma GPCR polypeptide can be in a cell or in a cell-free assay of the pancreas, chronic pancreatitis, congenital cysts, Cush system. ing's syndrome, cystadenocarcinoma, cystic fibrosis (muco 0381. In yet another aspect, the invention features a viscidosis, fibrocystic disease), diabetes mellitus, ectopic method for determining whether a candidate compound is a pancreatic tissue, gastinoma, gastrin excess, glucagon excess, compound that may be useful for the treatment of a disease or glucagonomas, GRFomas, hereditary pancreatitis, hyperin disorder of the bone and joints. This method includes the Sulinism, impaired insulin release, infected pancreatic necro steps of (a) providing a transgenic non-human mammal (e.g., sis, insulin resistance, insulinomas, islet cell hyperplasia, islet a knock-out mouse) having a disruption in a nucleic acid cell neoplasms, juvenile onset diabetes, macroamylasemia, molecule encoding a GPCR polypeptide substantially identi maldevelopment of the pancreas, maturity-onset diabetes of cal to a polypeptide listed in Table 1; (b) contacting the the young, metastatic neoplasms, mucinous cystadenoma, transgenic non-human mammal with the candidate com neoplastic cysts, nonfunctional pancreatic endocrine tumors, pound; and (c) measuring biological activity of the GPCR pancreas divisum, pancreatic abcess, pancreatic cancer, pan polypeptide in the transgenic non-human mammal, wherein creatic cholera, pancreatic cysts, pancreatic endocrine tumor altered biological activity, relative to that of the transgenic causing carcinoid syndrome, pancreatic endocrine tumor non-human mammal not contacted with the compound, indi causing hypercalcemia, pancreatic endocrine tumors, pancre cates that the candidate compound may be useful for the atic exocrine insufficiency, pancreatic pleural effusion, pan treatment of a disease or disorder of the bone and joints. creatic polypeptide excess, pancreatic pseudocyst, pancreatic 0382. In yet another aspect, the invention features a trauma, pancreatogenous ascites, serous cystadenoma, method for determining whether a candidate compound is a Shwachman's syndrome, somatostatin excess. Somatostati compound that may be useful for the treatment of a disease or noma syndrome, traumatic pancreatitis, type 1 (insulin-de disorder of the bone and joints. This method includes the pendent) diabetes, type 2 (non-insulin-dependent) diabetes, steps of (a) providing a transgenic non-human mammal (e.g., vasoactive intestinal polypeptide excess, VIPomas, a mouse) overexpressing a nucleic acid molecule encoding a Zollinger-Ellison syndrome. GPCR polypeptide substantially identical to a polypeptide 0374. In another aspect, the invention features a non-hu listed in any one of Table 1; (b) contacting the transgenic man mammal (e.g., a mouse), having a transgene that non-human mammal with the candidate compound; and (c) 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 0375. 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. 0376. In a related aspect, the invention features a cell from 0383 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 0377. 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 0378. 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 0384. In another aspect, the invention features yet another operably linked to a promoter. method for determining whether a candidate compound may 0379. 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 0380. 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 0385 Instill another aspect, the invention features another steps of (a) providing a GPCR polypeptide substantially iden method for determining whether a candidate compound may US 2011/O 185439 A1 Jul. 28, 2011 39 be useful for the treatment of a disease or disorder of the bone drome, fibromyalgia, fibrous cortical defect, fibrous dyspla and joints. This method includes (a) providing a GPCR sia (McCune-Albright syndrome, fungal arthritis, ganglion, polypeptide Substantially identical to a polypeptide listed in giant cell tumor, gout, hematogenous osteomyelitis, hemo Table 1; (b) contacting the polypeptide with the candidate philic arthropathy, hereditary hyperphosphatasia, hyperosto compound; and (c) measuring the half-life of the polypeptide, sis, hyperostosis frontalis interna, hyperparathyroidism (os wherein an alteration in the half-life of the polypeptide, rela teitis fibrosa cystica), hypertrophic osteoarthropathy, tive to that of the polypeptide not contacted with the com infections diseases of joints, juvenile rheumatoid arthritis pound, indicates that the candidate compound may be useful (Still's disease), lyme disease, lymphoid neoplasms, for the treatment of a disease or disorder of the bone and melorheostosis, metabolic diseases of joints, metastatic car joints. Preferably the GPCR polypeptide is in a cell or a cell cinoma, metastatic neoplasms, monostatic fibrous dysplasia, free assay system. multiple exostoses (diaphyseal aclasis, osteochondromato 0386. In another aspect, the invention features a method sis), neoplasms, neuropathic joint (Charcot's joint), osteoar for determining whether a patient has an increased risk for thritis, osteoarthrosis, osteoblastoma, osteochondroma (ex developing a disease or disorder of the bone and joints. The ostosis), osteogenesis imperfecta (brittle bone disease), method includes the step of determining whether the patient osteoid osteoma, osteoma, osteomalacia, osteomyelitis, has a mutation in a gene encoding a polypeptide listed in osteomyelosclerosis, osteopetrosis (marbel bone disease, Table 1, wherein presence of the mutation indicates that the Albers-Schönberg disease), osteopoikilosis, osteoporosis patient has an increased risk for developing a disease or (osteopenia), osteosarcoma, osteosclerosis, Paget's disease disorder of the bone and joints. of bone (osteitis deformans), parasitic arthritis, parosteal 0387. In a related aspect, the invention features another osteosarcome, pigmented villonodular synovitis, polyostotic method for determining whether a patient has an increased fibrous dysplasia, postinfectious or reactive arthritis, progres risk for developing a disease or disorder of the bone and sive diaphyseal dysplasia (Camurati-Engelmann disease), joints. This method includes the step of determining whether pseudogout, psoriatic arthritis, pyknodysostosis, pyogenic the patient has a polymorphism in a gene encoding a polypep arthritis, reflex sympathetic dystrophy syndrome, relapsing tide listed in Table 1, wherein presence of the polymorphism polychondritis, rheumatoid arthritis, rickets, senile indicates that the patient may have an increased risk for osteoporosis, sickle cell disease, spondyloepiphyseal dyspla developing a disease or disorder of the bone and joints. sia, synovial chondromatosis, synovial sarcoma, syphilitic 0388. In either of these two methods, the mutation or poly arthritis, talipes calcaneovalgus, talipes equinovarus, thalas morphism is preferably associated with an alteration (for semia, Tietze's syndrome, tuberculosis of bone, tuberculous example, a decrease) in the biological activity of the polypep arthritis, unicameral bone cyst (Solitary bone cyst), viral tide. arthritis. 0389. In another aspect, the invention features another 0392. In another aspect, the invention features a method of method for determining whether a patient has an increased preventing or treating a disease of the breast including intro 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 0393. 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 0390. 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 Table 1. and joints. The method includes the step of measuring the 0394. In yet another aspect, the invention features a patient's expression levels of a polypeptide listed in Table 1, method for determining whether a candidate compound is a wherein altered levels in the expression, relative to normal, compound that may be useful for the treatment of a disease or indicate that the patient has an increased risk for developing a disorder of the breast. This method includes the steps of (a) disease or disorder of the bone and joints. Preferably, the providing a GPCR polypeptide substantially identical to a expression levels are determined by measuring levels of polypeptide listed in Table 1; (b) contacting the GPCR polypeptide or mRNA. polypeptide with the candidate compound; and (c) measuring 0391 Diseases of the bone and joints that can be treated or biological activity of the GPCR polypeptide, wherein altered diagnosed using the methods of the invention or for which biological activity, relative to that of the GPCR polypeptide candidate therapeutic compounds may be identified include not contacted with the compound, indicates that the candidate achondroplasia, acute bacterial arthritis, acute pyogenic compound may be useful for the treatment of a disease or osteomyelitis, Albright's syndrome, alkaptonuria (ochrono disorder of the breast. The GPCR polypeptide can be in a cell sis), aneurysmal bone cyst, ankylosing spondylitis, arthritic, or in a cell-free assay system. arthropathies associated with hemoglobinopathies, arthropa 0395. In yet another aspect, the invention features a thy of acromegaly, arthropathy of hemochromatosis, bone method for determining whether a candidate compound is a cysts, calcium hydroxyapatite deposition disease, calcium compound that may be useful for the treatment of a disease or pyrophosphate deposition disease, chondrocalcinosis, chon disorder of the breast. This method includes the steps of (a) droma, chondrosarcoma, choStochondritis, chrondromblas providing a transgenic non-human mammal (e.g., a knock toma, congenital dislocation of the hip, congenital disorders out mouse) having a disruption in a nucleic acid molecule of joints, echondromatosis (dyschondroplasia, Ollier's dis encoding a GPCR polypeptide substantially identical to a ease), erosive osteoarthritis, Ewing's sarcoma, Felty's Syn polypeptide listed in Table 1; (b) contacting the transgenic US 2011/O 185439 A1 Jul. 28, 2011 40 non-human mammal with the candidate compound; and (c) wherein presence of the mutation indicates that the patient measuring biological activity of the GPCR polypeptide in the has an increased risk for developing a disease or disorder of transgenic non-human mammal, wherein altered biological the breast. activity, relative to that of the transgenic non-human mammal 04.01. In a related aspect, the invention features another not 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 breast. This disorder of the breast. method includes the step of determining whether the patient has a polymorphism in a gene encoding a polypeptide listed in 0396. In yet another aspect, the invention features a Table 1, wherein presence of the polymorphism indicates that method for determining whether a candidate compound is a the patient may have an increased risk for developing a dis compound that may be useful for the treatment of a disease or ease or disorder of the breast. disorder of the breast. This method includes the steps of (a) 0402. 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. any one of Table 1; (b) contacting the transgenic non-human 0403. 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 breast. 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 Table 1, 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 breast. normal levels, indicates that the patient has an increased risk 0397. In still another aspect, the invention features another for developing a disease or disorder of the breast. method for determining whether a candidate compound may 04.04. 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 increased risk for developing a disease or disorder of the breast. This method includes (a) providing a nucleic acid breast. 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 Table 1, GPCR polypeptide listed in Table 1, the promoter operably wherein altered levels in the expression, relative to normal, linked to a reporter system; (b) contacting the nucleic acid indicate that the patient has an increased risk for developing a molecule with the candidate compound; and (c) measuring disease or disorder of the breast. Preferably, the expression reporter activity, wherein altered reporter activity, relative to levels are determined by measuring levels of polypeptide or a nucleic acid molecule not contacted with the compound, mRNA. indicates that the candidate compound may be useful for the 04.05 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 0398. 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, 0399. 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 0406. 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 0407. 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 0400. 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 0408. 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 US 2011/O 185439 A1 Jul. 28, 2011
disorder of the immune system. This method includes the 0413 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 GPCR polypeptide with the candidate compound; and (c) immune system. 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 immune system. 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 immune 04.09. In yet another aspect, the invention features a system. 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 0414. In another aspect, the invention features a method disorder of the immune system. 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 immune system. 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 immune system. polypeptide in the transgenic non-human mammal, wherein 0415. 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 immune sys cates that the candidate compound may be useful for the tem. This method includes the step of determining whether treatment of a disease or disorder of the immune system. the patient has a polymorphism in a gene encoding a polypep 0410. 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 immune system. disorder of the immune system. This method includes the 0416) 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 0417. 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 disease or disorder of the immune sys transgenic non-human mammal, wherein altered biological tem. 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 not contacted with the compound, indicates that the candidate tical to a polypeptide listed in Table 1, 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 immune system. normal levels, indicates that the patient has an increased risk 0411. In still another aspect, the invention features another for developing a disease or disorder of the immune system. method for determining whether a candidate compound may 0418. 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 immune system. This method includes (a) providing a nucleic increased risk for developing a disease or disorder of the acid molecule comprising a promoter from a gene encoding a immune system. The method includes the step of measuring GPCR polypeptide listed in Table 1, the promoter operably the patient's expression levels of a polypeptide listed in Table linked to a reporter system; (b) contacting the nucleic acid 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 immune system. Preferably, the a nucleic acid molecule not contacted with the compound, expression levels are determined by measuring levels of indicates that the candidate compound may be useful for the polypeptide or mRNA. treatment of a disease or disorder of the immune system. 0419 Diseases of the immune system that can be treated 0412. In another aspect, the invention features yet another or diagnosed using the methods of the invention or for which method for determining whether a candidate compound may candidate therapeutic compounds may be identified include be useful for the treatment of a disease or disorder of the abnormal neutrophil function, acquired immunodeficiency, immune system. This method includes the steps of: (a) pro acute rejection, Addison's disease, advanced cancer, aging, viding a GPCR polypeptide substantially identical to a allergic rhinitis, angioedema, arthrus-type hypersensitivity polypeptide listed in Table 1; (b) contacting the polypeptide reaction, ataxia-telangiectasia, autoimmune disorders, with the candidate compound; and (c) measuring interaction autoimmune gastritis, autosomal recessive agammaglobu of the candidate compound to the polypeptide. Interaction of linemia, blood transfusion reactions, Bloom's syndrome, the compound to the polypeptide indicates that the candidate Bruton's congenital agammaglobulinemia, bullous pemphig compound may be useful for the treatment of a disease or oid, Chédiak-Higashi syndrome, chronic active hepatitis, disorder of the immune system. chronic granulomatous disease of childhood, chronic rejec US 2011/O 185439 A1 Jul. 28, 2011 42 tion, chronic renal failure, common variable immunodefi wherein altered biological activity, relative to that of the ciency, complement deficiency, congenital (primary) immu GPCR polypeptide not contacted with the compound, indi nodeficiency, contact dermatitis, deficiencies of immune cates that the candidate compound may be useful for the response, deficiency of the vascular response, dermatomyo treatment of a metabolic or nutritive disease or disorder. The sitis, diabetes mellitus, disorders of microbial killing, disor GPCR polypeptide can be in a cell or in a cell-free assay ders of phagocytosis, Goodpasture's syndrome, graft rejec system. tion, graft-Versus-host disease, granulocyt deficiency, 0423. In yet another aspect, the invention features a granulocytic leukemia, Graves disease, Hashimoto's thy method for determining whether a candidate compound is a roiditis, hemolytic anemia, hemolytic disease of the newborn, compound that may be useful for the treatment of a metabolic HIV infection (AIDS), Hodgkin's disease, hyperacute rejec or nutritive disease or disorder. This method includes the tion, hyper-IgE syndrome, hypersensitivity pneumonitis, steps of (a) providing a transgenic non-human mammal (e.g., hypoparathyroidism, IgA deficiency, IgG Subclass deficien a knock-out mouse) having a disruption in a nucleic acid cies, immunodeficiency with thymoma, immunoglobulin molecule encoding a GPCR polypeptide substantially identi deficiency syndromes, immunologic hypersensitivity, immu cal to a polypeptide listed in Table 1; (b) contacting the noSupressive drug therapy, infertility, insulin-resistant diabe transgenic non-human mammal with the candidate com tes mellitus, interferon Y receptor deficiency, interleukin 12 pound; and (c) measuring biological activity of the GPCR receptor deficiency, iron deficiency, juvenile insulin-depen polypeptide in the transgenic non-human mammal, wherein dent diabetes mellitus, Kaposi's sarcoma, lazy leuknock out altered biological activity, relative to that of the transgenic cyte syndrom, localized type 1 hypersensitivity, lymphocytic non-human mammal not contacted with the compound, indi leukemia, lymphoma, maignant B cell lymphoma, major his cates that the candidate compound may be useful for the tocompatibility complex class 2 deficiency, mixed connective treatment of a metabolic or nutritive disease or disorder. tissue disease, multiple myeloma, myasthenia gravis, 0424. In yet another aspect, the invention features a myeloperoxidase deficiency, neutropenia, nude syndrome, method for determining whether a candidate compound is a pemphigus Vulgaris, pernicious anemia, postinfectious compound that may be useful for the treatment of a metabolic immunodeficiency, primary biliary cirrhosis, primary immu or nutritive disease or disorder. This method includes the nodeficiency, primary T cell immunodeficiency, progressive steps of (a) providing a transgenic non-human mammal (e.g., systemic Sclerosis, protein-calorie malnutrition, purine a mouse) overexpressing a nucleic acid molecule encoding a nucleoside phosphorylation deficiency, rheumatic fever, GPCR polypeptide substantially identical to a polypeptide rheumatoid arthritis, secondary immunodeficiency, selective listed in any one of Table 1; (b) contacting the transgenic (isolated) IgA deficiency, serum sickness type hypersensitiv non-human mammal with the candidate compound; and (c) ity reaction, severe combined immunodeficiency, Sjögren's measuring biological activity of the GPCR polypeptide in the syndrome, sympathetic ophthalmitis, Systemic lupus erythe transgenic non-human mammal, wherein altered biological matosus, systemic mastocytosis, systemic type 1 hypersensi activity, relative to that of the transgenic non-human mammal tivity, T cell receptor 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 0425 Instill 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 0420. 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 0426 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 0421. 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 0422. 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 0427. 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 US 2011/O 185439 A1 Jul. 28, 2011
Table 1; (b) contacting the polypeptide with the candidate calcium deficiency, carnitine transport defect, choline defi compound; and (c) measuring the half-life of the polypeptide, ciency, choline toxicity, chromium deficiency, chronic fat wherein an alteration in the half-life of the polypeptide, rela malabsorption, citrullinemia, classic branched-chain ketoaci tive to that of the polypeptide not contacted with the com duria, classic cystinuria, congenital chloridorrhea, congenital pound, indicates that the candidate compound may be useful erythropoietic porphyria, congenital generalized lipodystro for the treatment of a metabolic or nutritive disease or disor phy, congenital myotonia, copper deficiency, copper toxicity, der. Preferably the GPCR polypeptide is in a cell or a cell free cyStathionine B-synthase deficiency, cystathioninuria, cystic assay system. fibrosis, cystinosis, cystinuria, Darier disease, defect in trans 0428. In another aspect, the invention features a method port of long-chain fatty acids, deficiency of cobalamin coen for determining whether a patient has an increased risk for Zyme deficiency, Dent's syndrome, diatrophic dysplasia, developing a metabolic or nutritive disease or disorder. The dibasic aminoaciduria, dicarboxylic aminoaciduria, dihydro method includes the step of determining whether the patient pyrimidine dehydrogenase deficiency, distal renal tubular has a mutation in a gene encoding a polypeptide listed in acidosis, dry beriberi, Dubin-Johnson syndrome, dysbetali Table 1, wherein presence of the mutation indicates that the poproteinemia, end-organ insensitivity to vitamin D. eryth patient has an increased risk for developing a metabolic or ropoietic protoporphyria, Fabry disease, failure of intestinal nutritive disease or disorder. absorption, familial apoprotein C2 deficiency, familial com 0429. In a related aspect, the invention features another bined hyperlipidemia, familial defective Apo B100, familial method for determining whether a patient has an increased goiter, familial hypercholesterolemia, familial hypertriglyc risk for developing a metabolic or nutritive disease or disor eridemia, familial hypophosphatemic rickets, familial lipo der. This method includes the step of determining whether the protein lipase deficiency, familial partial lipodystrophy, Fan patient has a polymorphism in a gene encoding a polypeptide coni-Bickel syndrome, fluoride deficiency, folate listed in Table 1, wherein presence of the polymorphism malabsorption, folic adic deficiency, formiminoglutamic aci indicates that the patient may have an increased risk for duria, fructose 1.6 diphosphatase deficiency, galactokinase developing a metabolic or nutritive disease or disorder. deficiency, galactose 1-phosphate uridyl transferase defi 0430. In either of these two methods, the mutation or poly ciency galactosemia, Gaucher disease, Gitelman's syndrome, morphism is preferably associated with an alteration (for globoid cell leuknock outdystrophy, glucose-6-phosphatease example, a decrease) in the biological activity of the polypep deficiency, glucose-6-translocase deficiency, glucose-galac tide. tose malabsorption, glucose-transporter protein syndrome, 0431. In another aspect, the invention features another glutaric adiduria, glycogen storage disease type 2, glycogen method for determining whether a patient has an increased storage disease type Ib, glycogen storage disease type ID. risk for developing a metabolic or nutritive disease or disor glycogen synthase deficiency, gout, Hartnup disease, hawk der. The method includes measuring biological activity of a insinuria, hemochromatosis, hepatic glycogenosis with renal GPCR polypeptide from the patient that is substantially iden fanconi syndrome, hepatic lipase deficiency, hepatic porphy 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, 0432. 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 0433 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), acuired 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 outrsaknock outffs syndrome, ciency, adenosine deaminase deficiency, adenyloSuccinate kwashiorknock outr, leuknock outdystrophies, Liddle's Syn lyase deficiency, adiposis dolorosa (Dercum disease), ALA drome, lipodystrophies, lipomatosis, liver glycogenoses, dehydratase-deficient porphyria, albinism, alkaptonuria, liver phosphorylase kinase deficiency, long QT syndrome, amulopectinosis, Andersen disease, argininemia, arginino lysinuria, lysosomal storage diseases, magnesium deficiency, Succinic aciduria, astelosteogenesis type 2, Bartter's Syn malabsorptive diseases, malignant hyperphenylalaninemia, drome, benign familial neonatal epilepsy, benign fructosuria, manganese 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 US 2011/O 185439 A1 Jul. 28, 2011 44 acidemia, molybdenum deficiency, monosodiumurate gout, wherein a decrease in the biological activity of the GPCR Morquio syndrome, mucolipidoses, mucopolysaccharidoses, polypeptide identifies the candidate compound as a com multiple carboxylase deficiency syndrome, multiple symmet pound that may be useful for the treatment of a disease or ric lipomatosis (Madelung disease, muscle glycogenoses, disorder. In one embodiment, the transgenic mouse has a muscle phosphofructokinase deficiency, muscle phosphory mutation (e.g., a deletion, frameshift, insertion or a point lase deficiency, myoadenylate deaminase deficiency, nephro mutation) in a gene listed in Table 1. In a related embodiment, genic diabetes insipidus, nesidioblastosis of pancreas, niacin the mouse has a mutation in the gene that is orthologous to the deficiency, niacintoxicity, Niemann-Pick disease, obesity, transgene. orotic aciduria, osteomalacia, paramyotonia congenita, pel 0438. In a related aspect, the invention features another lagra, Pendred syndrome, phenylketonuria, phenylketonuria method for identifying a compound that may be useful for the type 1, phenylketonuria type 2, phenylketonuria type 3. phos treatment of a disease or disorder described herein. This phate deficiency, phosphoribosylpyrophosphate synthetase method includes the steps of administering a candidate com overactivity, polygenic hypercholesterolemia, Pompe dis pound to a transgenic mouse expressing a transgene encoding ease, porphyria cutanea tarda, porphyrias, primary bile acid a GPCR polypeptide in a gene listed in Table 1, and having a malabsorption, primary hyperoxaluria, primary hypoalphali disease or disorder caused by the expression of the transgene; poproteinemia, propionic acidemia, protein-energy malnutri and determining whether the candidate compound treats the tion, proximal renal tubular acidosis, purine nucleoside phos disease or disorder. phorylase deficiency, pyridoxine deficiency, pyrimidine 0439. In a related aspect, the invention features another 5'-nucleotidase deficiency, renal glycosuria, riboflavin defi method for identifying a compound that may be useful for the ciency, rickets, Rogers' Syndrome, Saccharopinuria, Sandhoff treatment of a disease or disorder described herein. This disease, Sanfilippo syndromes, sarcosinemia, Scheie disease, method includes the steps of administering a candidate com Scurvy (vitamin C deficiency), selenium deficiency, seleno pound to a transgenic mouse transgenic mouse containing a sis, sialic acid storage disease, S-Sulfo-L-cysteine, Sulfite, mutation (e.g., a deletion, frameshift, insertion or a point thiosulfaturia, Tarui disease, Tay-Sachs disease, thiamine mutation) in a gene listed in Table 1, and having a disease or deficiency, tryptophan malabsorption, tryptophanuria, type 1 disorder caused by gene disruption; and determining whether pseudohypoaldosteronism, type 3 glycogen storage disease candidate compound treats the disease or disorder. (debrancher deficiency, limit dextrinosis), tyrosinemia, 0440. In still another aspect, the invention features a tyrosinemia type 1, tyrosinemia type 2, tyrosinemia type 3. method for identifying a compound that may be useful for the uridine diphosphate galactose 4-epimerase deficiency, uro treatment of a disease or disorder described herein. This canic aciduria, variegate porphyria, Vitamin B12 deficiency, method includes the steps of contacting a candidate com vitamin C toxicity, vitamin D deficiency, vitamin D-resistant pound with a cell from a transgenic mouse expressing a rickets, vitamind-sensitive rickets, vitamin E deficiency, Vita transgene encoding a GPCR polypeptide in a gene listed in min E toxicity, Vitamin K deficiency, vitamin K toxicity, Von Table 1; and determining whether the candidate compound 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 0434 Inanother 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 0441. 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 0435. 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. 0442. The invention features another kit that includes a 0436. 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. 0437. The invention also features a method for identifying 0443) 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 US 2011/O 185439 A1 Jul. 28, 2011
GPCR polynucleotide of Table 1, wherein at least 50 different components. Accordingly, Substantially pure polypeptides polynucleotides, each capable of hybridizing under high include those that naturally occur in eukaryotic organisms but stringency conditions to a different mouse GPCR polynucle are synthesized in E. coli, yeast or other microbial system. otide listed on Table 1, are present in the kit. 0452. By “purified antibody' is meant antibody that is at 0444 The invention features another kit that includes a least 60%, by weight, free from proteins and naturally occur plurality of mice having a mutation in a GPCR polynucle ring organic molecules with which it is naturally associated. otide. In this kit, mice having a mutation in each GPCR Preferably, the preparation is at least 75%, more preferably polynucleotide listed on one of Tables 3-33 are present in the 90%, and most preferably at least 99%, by weight, antibody. kit. A purified antibody may be obtained, for example, by affinity 0445. In any of the foregoing kits, at least one of the GPCR chromatography using recombinantly-produced protein or polynucleotides is desirably a GPCR polynucleotide of Table conserved motif peptides and standard techniques. 2. 0453. By “specifically binds” is meant any small mol ecule, peptide, antibody, or polypeptide that recognizes and Definitions binds, for example, a huma GPCR polypeptide but does not 0446. By “polypeptide' is meant any chain of more than Substantially recognize and bind other molecules in a sample, two amino acids, regardless of post-translational modifica e.g., a biological sample, that naturally includes the protein. tion Such as glycosylation or phosphorylation. 0454. By “polymorphism' is meant that a nucleotide or 0447. By “substantially identical' is meant a polypeptide nucleotide region is characterized as occurring in several or nucleic acid exhibiting at least 50%, preferably 85%, more different sequence forms. A "mutation' is a form of a poly preferably 90%, and most preferably 95% identity to a refer morphism in which the expression level, stability, function, or ence amino acid or nucleic acid sequence. For polypeptides, biological activity of the encoded protein is substantially the length of comparison sequences will generally be at least altered. 16 amino acids, preferably at least 20 amino acids, more 0455 By “GPCR related polypeptide' is meant apolypep preferably at least 25 amino acids, and most preferably 35 tide having Substantial identity to any of the polypeptides amino acids or the full-length polypeptide. For nucleic acids, listed in Table 1, including polymorphic forms (e.g., the length of comparison sequences will generally be at least sequences having one or more SNPs) and splice variants. 50 nucleotides, preferably at least 60 nucleotides, more pref 0456 By “GPCR biological activity” is meant measurable erably at least 75 nucleotides, and most preferably 110 nucle effect or change in an organism or a cell resulting from the otides or the full-length polynucleotide. modulation of a GPCR at the molecular, cellular, physiologi 0448 Sequence identity is typically measured using a cal or behavioral levels or alteration in the extent of activation sequence analysis program (e.g., BLAST 2: Tatusova et al., ordeactivation that can be elicited by an agonist orantagonist. FEMS Microbiol Lett. 174:247-250, 1999) with the default 0457 “Dominant negative” means an effect of a mutant parameters specified therein. form of a gene product that dominately interferes with the 0449 By “high stringency conditions” is meant hybridiza function of the normal gene product. tion in 2xSSC at 40°C. with a DNA probe length of at least 40 0458 “Reporter system’ means any gene, compound or nucleotides. For other definitions of high Stringency condi polypeptide whose product can be assayed, measured or tions, see F. Ausubel et al., Current Protocols in Molecular monitored. Examples include, but are not limited to neomy Biology, pp. 6.3.1-6.3.6. John Wiley & Sons, New York, N.Y., cin (Kang et al., Mol. Cells: 7:502-508, 1997), luciferase 1994, hereby incorporated by reference. “Substantially iden (Welsh et al., Curr. Opin. Biotechnol. 8:617-622, 1997), lacz, tical polynucleotides also include those that hybridize under (Spergel et al., Prog. Neurobiol. 63:673-686, 2001), aequorin high stringency conditions. “Substantially identical (Deo et al., J. Anal. Chem. 369:258-266, 2001) and green polypeptides include those encoded by polynucleotides that fluorescent protein (Tsien, Annu Rev. Biochem. 67:509-544, hybridize under high Stringency conditions. 1998). 0450. By “substantially pure polypeptide' is meant a 0459. “Conditional mutant” is any gene, cell or organism polypeptide that has been separated from the components that for which the expression of the mutant phenotype can be naturally accompany it. Typically, the polypeptide is Substan controlled through alteration in the temperature, diet or other tially pure when it is at least 60%, by weight, free from the external conditions. proteins and naturally-occurring organic molecules with 0460 “Overexpression” means level of expression higher which it is naturally associated. Preferably, the polypeptide is than the physiological level of expression. a GPCR polypeptide that is at least 75%, more preferably at 0461) “Isolated' or “purified’ means altered from its natu least 90%, and most preferably at least 99%, by weight, pure. ral state, i.e., if it occurs in nature, it has been changed or A substantially pure GPCR polypeptide may be obtained, for removed from its original environment, or both. For example, example, by extraction from a natural source (e.g., a pancre a polynucleotide or a polypeptide naturally present in a living atic cell), by expression of a recombinant nucleic acid encod organism is not "isolated, but the same polynucleotide or ing a GPCR polypeptide, or by chemically synthesizing the polypeptide separated from the coexisting materials of its polypeptide. Purity can be measured by any appropriate natural state is "isolated as the term is employed herein. method, e.g., by column chromatography, polyacrylamide Moreover, a polynucleotide or polypeptide that is introduced gel electrophoresis, or HPLC analysis. into an organism by transformation, genetic manipulation, or 0451 A polypeptide is substantially free of naturally asso by any other recombinant method is "isolated even if it is still ciated components when it is separated from those contami present in the organism. nants that accompany it in its natural State. Thus, a polypep 0462 “Polynucleotide’ generally refers to any polyribo tide which is chemically synthesized or produced in a cellular nucleotide (RNA) or polydeoxyribonucleotide (DNA), which system different from the cell from which it naturally origi may be unmodified or modified RNA or DNA. Polynucle nates will be substantially free from its naturally associated otides include, without limitation, single- and double US 2011/O 185439 A1 Jul. 28, 2011 46 stranded DNA, DNA that is a mixture of single- and double 0467. “Transgene' is any exogenously added nucleic acid. Stranded regions, single- and double-stranded RNA, and 0468 Antisense' or “Reverse complement’ means a RNA that is mixture of single- and double-stranded regions, nucleic acid sequence complementary to the messenger hybrid molecules comprising DNA and RNA that may be RNA. single-stranded or, more typically, double-stranded or a mix 0469 “Single nucleotide polymorphism” or “SNP refers ture of single- and double-stranded regions. Polynucleotide to the occurrence of nucleotide variability at a single nucle can also refer to triple helix nucleic acids. otide position in the genome, within a population. An SNP 0463 “Variant” refers to a polynucleotide or polypeptide may occur within a gene or within intergenic regions of the that differs from a reference polynucleotide or polypeptide, genome. SNPs can be assayed using Allele Specific Amplifi but retains the essential properties thereof. A typical variant of cation (ASA). For this process, at least three primers are a polynucleotide differs in nucleotide sequence from the ref required. A common primer is used in reverse complement to erence polynucleotide. Changes in the nucleotide sequence of the polymorphism being assayed. This common primer can the variant may or may not alter the amino acid sequence of a be between 50 and 1500 bps from the polymorphic base. The polypeptide encoded by the reference polynucleotide. Nucle other two (or more) primers are identical to each other except otide changes may result in amino acid substitutions, addi that the final 3' base wobbles to match one of the two (or more) tions, deletions, fusions and truncations in the polypeptide alleles that make up the polymorphism. Two (or more) PCR encoded by the reference sequence, as discussed below. A reactions are then conducted on sample DNA, each using the typical variant of a polypeptide differs in amino acid common primer and one of the Allele Specific Primers. sequence from the reference polypeptide. Generally, alter 0470 “Splice variant” as used herein refers to cDNA mol ations are limited so that the sequences of the reference ecules produced from RNA molecules initially transcribed polypeptide and the variant are closely similar overall and, in from the same genomic DNA sequence but which have under many regions, identical. A variant and reference polypeptide gone alternative RNA splicing. Alternative RNA splicing may differ in amino acid sequence by one or more substitu occurs when a primary RNA transcript undergoes splicing, tions, insertions, or deletions in any combination. A Substi generally for the removal of introns, which results in the tuted or inserted amino acid residue may or may not be one production of more than one distinct mRNA molecules each encoded by the genetic code. Typical conservative Substitu of which may encode different amino acid sequences. The tions include Gly, Ala; Val, Ile, Leu: Asp, Glu: Asn., Gln: Ser, term splice variant also refers to the polypeptides encoded by Thr; Lys, Arg; and Phe and Tyr. A variant of a polynucleotide the above mRNA molecules. or polypeptide may be naturally occurring such as an allele, or 0471) “Fusion protein’ refers to a polypeptide encoded by it may be a variant that is not known to occur naturally. two, often unrelated, fused genes or fragments thereof. Non-naturally occurring variants of polynucleotides and 0472. By “candidate compound' or “test compound is polypeptides may be made by mutagenesis techniques or by meant a chemical, be it naturally-occurring or artificially direct synthesis. Also included as variants are polypeptides derived, that is assayed for its ability to modulate gene activ having one or more post-translational modifications, for ity or protein stability or binding, expression levels, or activ instance glycosylation, phosphorylation, methylation, ADP ity, by employing any standard assay method. Test ribosylation and the like. Embodiments include methylation compounds may include, for example, peptides, polypep of the N-terminal amino acid, phosphorylations of serines and tides, synthesized organic molecules, naturally occurring threonines and modification of C-terminal glycines. organic molecules, polynucleotide molecules, and compo 0464 Allele” refers to one of two or more alternative nents thereof. forms of a gene occurring at a given locus in the genome. 0473 By “promoter is meant a minimal sequence suffi cient to direct transcription. Also included in the invention are 0465. A “transgenic organism as used herein, is any those promoter elements which are sufficient to render pro organism, including but not limited to animals and plants, in moter-dependent gene expression controllable for cell type which one or more of the cells of the organism contains specific, tissue-specific, temporal-specific, or inducible by heterologous nucleic acid introduced by way of human inter external signals or agents; Such elements may be located in vention, Such as by transgenic techniques well known in the the 5' or 3' or intron sequence regions of the native gene. art. The nucleic acid is introduced into the cell, directly or 0474 By “operably linked' is meant that a gene and one or indirectly by introduction into a precursor of the cell, by way more regulatory sequences are connected in Such a way as to of deliberate genetic manipulation, such as by microinjection, permit gene expression. transfection or by infection with a recombinant virus. The transgenic organisms contemplated in accordance with the 0475 Other features and advantages of the invention will present invention include mice, bacteria, cyanobacteria, be apparent from the following description of the preferred fungi, plants and animals. The isolated DNA of the present embodiments thereof and from the claims. invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation BRIEF DESCRIPTION OF THE DRAWINGS or transconjugation. 0476 FIG. 1 is a list of GPCR polynucleotides of the 0466. A “transgenic mice, as used herein, is a mouse, in invention in human and mouse. Polynucleotides are divided which one or more of the cells of the organism contains into four classes, A, B, C, and F/S, according to conventional nucleic acid introduced by way of human intervention, Such classification of the GPCR superfamily. The “No Class” as by transgenic techniques well known in the art. The nucleic group includes five polynucleotides that cannot be assigned acid is introduced into the cell, directly or indirectly by intro to any of the above four classes. Within each class, polynucle duction into a precursor of the cell, by way of deliberate otides are further grouped into Small families based on ligand genetic manipulation, by methods known in the art, for specificity or, in the case of orphan receptors, significant example microinjection, infection, transfection, or transfor sequence homology (24.0%) within each family. Orphan mation. receptors that cannot be grouped by this criterion are alpha US 2011/O 185439 A1 Jul. 28, 2011 47 betically listed at the end of each class. Whenever available, effects of ethanol as measured by the difference before and 30 names are adopted from the official gene names of the NCBI minutes after an i.p. injection of 2.5 g/kg ethanol on two LocusLink database. Orphan GPCRs are indicated with an consecutive treatment days. GPR85 knockout mice display a asterisk. Abbreviations: H, human; M, mouse; FMLP, fMet decreased initial sensitivity to the effects of ethanol. FIG.9B. Leu-Phe: GNRH; gonadotropin-releasing hormone: PAF, Tolerance to the hypothermic effects of ethanol as shown by platelet-activating factor: INSL3, insulin-like 3: SPC, sphin the difference in the change of core body temperature for day gosylphosphorylcholine; LPC, lysophosphatidylcholine; 1 and day 2. TRH, thyrotropin-releasing hormone: LGR, leucine-rich repeat-containing G protein-coupled receptor, SREB, Super conserved receptor expressed in brain; GIP, gastric inhibitory DETAILED DESCRIPTION OF THE INVENTION polypeptide; GHRH, growild typeh hormone-releasing hor 0485 G protein coupled receptors (GPCRs) include mone, PACAP, pituitary adenylate cyclase activating receptors for neurotransmitters, light, odors, hormones, and polypeptide: DAF, decay accelerating factor; GPRC5, G pro molecules used for communication in the immune system. tein-coupled receptor family C group 5. GPCRs are by far the largest family of receptors known. It is 0477 FIG. 2 is a series of phylogenetic trees of human believed that there are as many as 1,000 different GPCRs for GPCRs. Lines corresponding to individual polynucleotides odor recognition alone. are colored black for those with known ligands, red for orphan genes, and blue for genes with 7 trans-membrane domains but no homology to known GPCRs. The Class A tree was split Identification of GPCR Polypeptides and Polynucleotides into two parts due to size considerations (arrow line indicates 0486 To identify the full complement of GPCRs in human the connection). Families are defined as described in FIG. 1. and mouse, we embarked on a multi-step process; the first Clusters of GPCRs with significant predictive value as to step was to identify previously known GPCR genes and then ligands are highlighted in purple on these bootstrap consen the Subsequent identification of novel genes. To identify sus trees (bootstrap values not shown). The ruler at the bottom known genes we searched the public literature and sequence of each tree indicates the horizontal distance equal to 10% databases of the National Center for Biotechnology Informa sequence divergence. tion for human and mouse GPCRs and then performed 0478 FIG. 3 is a photograph showing the expression pro sequence comparisons. This procedure defined a unique gene files of nine GPCRs as identified by RT-PCR. set of GPCRs for both human and mouse and identified the 0479 FIG. 4 is schematic summary of tissue expression in human and mouse orthologs. In total, 340 GPCRs were iden 100 GPCR polynucleotides. Polynucleotides were analyzed tified in human and 304 in mouse. Sequence alignments indi individually by RT-PCR, as shown in FIG.3, and the intensity cated that 260 of these molecules were common to both of the observed bands determined by Scanning. Each gene is species (FIG. 1). represented by a single row of colored boxes, with four dif 0487. We then asked whether the remaining GPCR genes ferent expression levels: no expression—blue; low expres (80 human and 44 in mouse), which did not show a counter sion purple; moderate expression—dark red; strong expres part in the other species, might have undiscovered orthologs. sion pure red. Polynucleotides and tissues, as well as Using the non-shared GPCRs as queries, the public human groups of expression patterns, are indicated. and mouse genome sequence databases were searched for 0480 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. 0488 We subsequently undertook an exhaustive search 0481 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 0482 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 0483 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. 0484 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. US 2011/O 185439 A1 Jul. 28, 2011 48
0489. In a second discovery method, a search was con and mouse GPCR was first assigned to one of the four distinct ducted for proteins with sequence motifs characteristic of the classes of GPCRs (A, B, C, F/S) by comparing with HMM four different classes of GPCRs. The Hidden Markov Model models. All but five of the receptors (TPRA40, TM7SF1, (HMM) profile-based approach was used to search the human TM7SF1L1, TM7SF1L2 and TM7SF3) could be assigned to proteome. This method yielded 1,100 potential matches. one of the four classes by this method. These assignments Among these hits 331 of the 342 known GPCRs were repre indicate that of 370 human GPCRs. 287 belong to Class A, 50 sented, confirming the validity of the search strategy. Follow to Class B, 17 to Class C, and 11 to Class F/S. Of 393 mouse ing elimination of known genes, three novel genes were iden GPCRs, 311, 50, 17, and 10 belong to Classes A, B, C, and tified. The combination of both genomic search strategies F/S, respectively. revealed 28 GPCR genes that have not been previously described. These genes are referred to as PGR1 to PGR28 0495. The GPCRs were next catalogued according to (FIG. 1). Searches of the mouse genome sequence database, ligand specificities reported in the literature. This effort iden together with RT-PCR analyses, identified orthologs for 25 of tified 229 human and 215 mouse GPCRs with known ligands. the 28 novel genes in the mouse. The remaining 145 human and 178 mouse GPCRs have no 0490 Altogether, these searches identified a total of 383 known ligands and are therefore orphan receptors. Among the GPCRs in human and 391 in mouse; 358 of the GPCRs were orphan receptors, 100 human and 133 mouse receptors common to the two species. belong to Class A, 34 human and 34 mouse receptors to Class B, 6 human and 6 mouse receptors to Class C, none to Class Methods F/S, and 5 human and 5 mouse receptors could not be 0491. The 254 GPCRs used as queries were aligned using assigned to a specific class (FIG. 1). the Clustal W program. The amino acid sequence of the seven-transmembrane region of each GPCR was extracted 0496 The GPCRs were subsequently divided into a series and used to search through the public human genome (HG) of families of related receptors that either recognize the same/ database (downloaded in August, 2001) using TBLASTN at similar ligand(s) or are highly likely to do so. Sequence com an E-value of 10. The resulting hits (500,000) were combined parisons and phylogenetic analyses (see below) showed that and sorted according to contig and position numbers. Only GPCRs with highly related ligand specificities that are tradi the hit with the best E-value was selected among the group of tionally classed as belonging to the same “family' are at least hits within 1 kb from each other on the same contig. Each of 40% homologous in protein sequence. We therefore assigned the ~50,000 unique hits generated were used to search against GPCRs to specific families using the criteria that members of nr protein database using BLASTP. From this search, 10,000 a family either recognize the same/similar ligand or show at hits appeared to be most homologous to GPCRs. Almost 2000 least 40% sequence homology. In this manner, 93 different of these hits were determined to be parts of various known families of GPCRs were identified, including 16 families of GPCRs and were excluded from further consideration. The orphan receptors that have not been previously described best 500 of the remaining hits were subjected to full-length (FIG. 1). These studies assigned 12 of 145 human and 47 of gene structure prediction. This process involved comparison 178 mouse orphan GPCRs to seven different families of of 200kb genomic DNA sequence surrounding each hit with receptors that interact with known ligands. The orphan recep the full-length sequence of its most homologous known tors in these families can be predicted to recognize ligands GPCR using BLAST2. Twenty-five candidate novel GPCRs similar to those detected by other members of the same fam were obtained. Their nucleotide sequences were then used to ily. search the EST database for the identification of human and/ 0497 To further investigate sequence-ligand relationships or mouse ESTs. among human GPCRs, we conducted a phylogenetic analy 0492 For the HMM profile-based approach, GPCR Class sis. GPCRs were aligned to the class specific HMM profile A, B and C HMM models were downloaded from the Pfam model using the HMMALIGN program of the HMMER database and were used as queries in the HMMSEARCH package. These alignments were used for the construction of program (HMMER package) to search against the Interna phylogenetic trees, using the ClustalW program. The phylo tional Protein Index (IPI) proteome database. All hits with 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 0498. 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 0493 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 0499. 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 0494 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 US 2011/O 185439 A1 Jul. 28, 2011 49 ligands were clustered in four large branches, three in the using the reagents in the kit. 1-5ug total RNA was used in a class A tree and one in the class B tree. This organization is of total volume of 10ul with 10xRNase0ut and CIP (10 U). The predictive value for numerous orphan GPCRs. For example, reaction was incubated at 50° C. for 1 hour. After incubation, GPCRs such as PGR2, PGR3, PGR11, GPR19, GPR37, the RNA was precipitated with ethanol. GPR39, GPR45, GPR63 and GPR103 could be predicted to 0515 2. Treat dephosphorylated RNA with tobacco acid have peptide ligands since they were grouped with other pyrophosphatase (TAP) to remove the 5' cap structure from receptors activated by peptides. Other orphan receptors. Such intact, full-length mRNA. This treatment leaves a 5" phos as GPR21 and GPR52 could conceivably be activated by phate required for ligation to the GeneRacer RNA Oligo. amine neuromodulators, as they clustered phylogenetically 0516. The reaction was set up on ice the using the reagents with amine-type molecules in the large neurotransmitter in the kit. branch of the class A tree. Dephosphorylated RNA 7 ul Full-Length Sequence for Novel Human GPCR Genes 10XTAP Buffer 1 ul Methods RNase0ut (40 U/1) 1 ul 0500. To identify full-length clones for the novel human GPCR genes that were discovered by the gene-mining effort, TAP (0.5 U/ul) 1 ul the following methods were used: Total Volume 10 ul First-Strand cDNA Synthesis 0501 First strand cDNA Synthesis was performed as 0517. The reaction was incubated at 37° C. for 1 hour. essentially described in the following kit, CLONTECH Labo After incubation, the RNA was precipitated with ethanol. ratories, Inc., Protocol HPT3269-1 16 Version HPR14596. 0518. 3. Ligate the GeneRacer RNA Oligo to the 5' end of 0502. Two 10 ul reactions described below convert 50 the mRNA using T4 RNA ligase. The GeneRacer RNA Oligo ng-1 lug of total or poly A+ RNA into RACE-Ready first will provide a known priming site for GeneRacer. 7 ul of strand cDNA. For optimal results, use 1 lug of poly A+ RNA dephosphorylated, decapped RNA was incubated at 65° C. or 1 lug of total RNA in the reactions below. for 5 minutes. Then the following were added: 1. Combined the following in separate 0.5-ml microcentri fuge tubes: 10x Ligase Buffer 1 ul For preparation of 5'-RACE-Ready or cDNA 3’-RACE 10 mM ATP 1 ul Ready cDNA (0503) 1-3 ul RNA sample 1-3 ul RNA sample RNase0ut. (40 U/ul) 1 ul (0504) 1 Jul 5'-CDS primer 1 ul 3'-CDS primer A 0519 T4 RNA ligase (5 U?ul) 1 ul 0505] 1 ul SMART II A oligo 2. Add sterile HO to a final volume of 5ul for each reaction. Total Volume 10 ul 3. Mix contents and spin the tubes briefly in a microcentri 0520. After incubation, 90 ul of DEPC treated water was fuge. added and the reaction was extracted with phenol/chloro 4. Incubate the tubes at 70° C. for 2 min. form, and precipitated with the addition of 2 ul of 10 mg/ml 5. Cool the tubes on ice for 2 min. mussel glycogen, 10ul 3M sodium acetate, pH 5.2 and 220 ul 6. Spin the tubes briefly to collect the contents at the bottom. of 95% ethanol. 7. Add the following to each reaction tube (already containing 0521. 4. Reverse-transcribe the ligated mRNA using (0506) 2 ul 5x First-Strand buffer Cloned AMV RT or SuperScript II RT and the GeneRacer. 0507 1 ul DTT (20 mM) OligodT Primer to create RACE-ready first-strand cDNA 0508) 1 ul dNTP Mix (10 mM) with known priming sites at the 5' and 3' ends. (0509 1 ul PowerScript Reverse Transcriptase 0522 To 10 ul ligated mRNA, 1 ul of the desired primer 0510) 10 ul Total volume was added and 1 ul of dNTP Mix (25 mM each) to the ligated 8. Mix the contents of the tubes by gently pipetting. RNA. Then the mixture was incubated at 65° C. for 5 minutes 9. Spin the tubes briefly to collect the contents at the bottom. to remove any RNA secondary structure, chilled on ice for 2 10. Incubate the tubes at 42°C. for 1.5 hr in an air incubator. minutes and added the following reagents to the ligated RNA 11. Dilute the first-strand reaction product with Tricine and primer mixture: EDTA Buffer: 0511. Added 20 ul if started with <200 ng of total RNA. 5xRT Buffer 4 ul 0512. Added 100 ul if started with >200 ng of total RNA. Cloned AMV RT (15 U?ul) 1 ul 0513. Added 250 ul if started with poly A RNA. 12. Heat tubes at 72° C. for 7 min. 0523 Sterile water 2 ul 13. Samples can be stored at -20°C. for up to three months. Now have 3'- and 5'-RACE-Ready cDNA samples. RNase0ut (40 U/ul) 1 ul Total Volume 20 ul 3' and 5 RACE 0524. The reaction was incubated at 45° C. for 1 hour and 0514 1. Treat total RNA or mRNA with calf intestinal then at 85°C. for 15 minutes to inactivate the cloned AMV phosphatase (CIP) to remove the 5' phosphates. This elimi RT. nates truncated mRNA and non-mRNA from subsequent 0525 5. To obtain 5' ends, amplify the first-strand cDNA ligation with the GeneRacer RNA Oligo. Dephosphorylation using a reverse gene specific primer (Reverse GSP) and the reaction was set up in a 1.5 ml sterile microcentrifuge tube GeneRacer 5' Primer. Only mRNA that has the GeneRacer US 2011/O 185439 A1 Jul. 28, 2011 50
RNA Oligo ligated to the 5' end AND is completely reverse (0543. The following cDNA primers were used: transcribed will be amplified using PCR. If needed, perform additional PCR with nested primers. HPG5dnO1, 0526 6. To obtain 3' ends, amplify the first-strand cDNA (SEQ ID NO: 1561) using a forward gene-specific primer (Forward GSP) and the GCCGCGCTGCAGGTGCACGATG, GeneRacer 3' Primer. Only mRNA that has a polyA tail and is reverse-transcribed will be amplified using PCR. If needed, HPGS-36 oup, (SEQ ID NO: 1562) perform additional PCR with nested primers. TGCCACCTGCTCTTCTACGTGATG, PCR Conditions Used for 3' or 5' Race or Internal Fragment HPG5 - 6 Oldn Amplification (SEQ ID NO: 1563) GCAAATCAGTGTGCAAATCGAAA 0527 PCR was performed using the following cycle HPGS-629up parameters, 94 C for 2 minutes for melting, then (94 C for 30 (SEQ ID NO: 1564) sec; 67 C for 1 minute; 72 C for 1.5 minutes) for 6 cycles, then CATTCCTGGAGAGATCTCGTGGGA (94 Cfor 30 seconds, 60C for 1 minute, 72C for 1.5 minutes) HPG5-1183din for 38 cycles, then 72 C for 7 minutes and then hold at 4 C. (SEO ID NO : 1565) 0528 7. Purify RACE PCR products using the S.N.A.P. GGTGCCACTGATGGAGGGTACTG, columns included in the kit. HPG5-755up Rapid Amplification of cDNA Ends (RACE) (SEQ ID NO: 1566) 0529. This procedure describes the 5'-RACE and GGTAAGCCTGGCCTACTCGGAGAG, 3'-RACE PCR reactions that generate the 5' and 3' cDNA fragments. HPGsMaxDN (SEO ID NO : 1567) 0530 1. For each 50-ul reaction, mix the following TGCACCTGGCCAACAAATCCTTTT, reagents: HPGSMaxUP 0531. 34.5 ul PCR-Grade Water (SEQ ID NO: 1568) 0532 5ul 10x Advantage 2 PCR Buffer GGTAAGCCTGGCCTACTCGGAGAG, 0533. 1 ul dNTP Mix (10 mM) HPGgMax5up18 0534 1 ul 50x Advantage 2 Polymerase Mix (SEO ID NO : 1569) 0535) 41.5 ul Total volume GGGCCAGAGGCGAGATGT, 0536 Mix well by vortexing (without introducing HPGSgMaxSdn bubbles) and briefly spin the tube in a microcentrifuge. (SEO ID NO : 1570) GCAGGTCCGCGCAGAA, 0537 2. For 5'-RACE: PCR reactions as shown in Table III used for 5 RACE of Clontech's RACE kit. HPGSgMax3up 0538 For 3'-RACE: PCR reactions as shown in Table IV (SEO ID NO : 1571) of Clontech's RACE kit. CCACCAGATCCGCGTGTC; 0539 PCR Cycle conditions: as described in the Clon used for 3 RACE tech's RACE kit. HPG5gMax3end 0540 Complete reactions were then run on gel to visualize (SEO ID NO : 1572) PCR products. If the gel showed nothing then the reaction GTTGGTCAGGTTGGTCTCGAAC, would be amplified for additional cycles (total of 40). PGR4 cDNA sequence (SEQ ID NO: 88) Human PGR4 ATGGACTCATTACAAGTTGTTTTAGGATCTAC CTCCAGACCCATGGAGT 0541 Full length cDNA was isolated from human Pitu TTCTTTAGTAAAGCCTGAACGACACAGGCCAAAATAATCTCCAAAGGCC itary by a combination of 5' and 3' Rapid Amplification of cDNA Ends (RACE) and internal RT-PCR experiments using AGCTCTGACCCTTTTAAATCAATTTTAGCTAAATCCGTTCACAAAAGGC the methods described above. RACE pituitary was prepared TTCGCACATCCAGTGTCCCTGAAAAATAAAGGAGGTTGGGCAGGCCCTG using the Invitrogen GeneRacer Kit (Cat it L1500-01). 0542. The following RACE primers were used: CGGGGGCTCGAGGAATTCGCTAAGTGAGTTTTCTGGCTTCTGGATACAC TTTCAAAGGGCCAGAGGGCACGAGGCTTCCGCCTTGGCCGCCACCTCCC
5' RACE (Invitrogen) CGGCCAGCTGCGGTGTTCGCGGCCAGTGTTGCCGGGCACTTCCTGGTTC CGACTGGAGCACGAGGACACTGA (SEO ID NO : 1557) TCCGCGCGCCCCGGGTGCAGCCCCTGCACCCAGTGCTGGCGCTCCTCAG 3' RACE (Invitrogen) : GCTGTCAACGATACGCTACGTAACG (SEO ID NO : 1558) AAGGGAGGGGGCCAGAGGCGAGATGTCGCAACCGCCTCCCTCCCTCTTT
5' nested RACE primer: CCCCGCCTTGGCACTCAGTCGCCTCCCAGATGAGCACTCTCTCAGACCG GGACACTGACATGGACTGAAGGAGTA (SEO ID NO : 1559) 3' nested RACE primer: CTGCGGGCCGCCAGGCGCCGGGAATGTCCCCTGAATGCGCGCGGGCAGC CGCTACGTAACGGCATGACAGTG (SEQ ID NO: 1560) GGGCGACGCGCCCTTGCGCAGCCTGGAGCAAGCCAACCGCACCCGCTTT
US 2011/O 185439 A1 Jul. 28, 2011 60
- Continued - Continued TCTACCTCAGTTGATACAGTAACCCCATCTACACACACTCTTGTCTG TGTCTCTTTACCCAGAGTGGAAGATGCCATGTCTACTTCCATGTCGA CT CAAAACCTCCCCCTGACAACATTCCTCCTGCGTCCTCCACTCATG AAGAGACCTCCTCTAAGACCTTTTCTTTCTTAACATCCTTTTCATTT TGATCTCAACTACGTCTACACCAGAAGCAACT CAACCAATATCTCAA ACTGGGACTGAGAGTGTACAGACAGTTATTGATGCTGAAGCTACACG GTAGAGGAGACTTCTACCTATGCTCTCAGCTTCCCATATACTTTCAG TACAGCCTTAACTCCTGAAATCACACTTGCATCTACAGTGGCTGAAA TGGTGGTGGAGTTGTTGCCAGCTTGGCTACTGGCACCACAGAGACCT CTATGCTTTCCTCCACAATCACAGGACGAGTTTACACCCAGAATACA CTGTTGTTGATGAGACCACACCCTCACACATCTCTGCCAATAAGTTG CCTACAGCTGATGGACACTTGCTTACTTTGATGTCCACTAGATCAGC ACTACTTCAGTAAACAGTCACATTTCTTCATCTGCCACATATCGTGT TTCCACATCCAAGGCACCTGAGTCAGGTCCCACATCCACAACTGATG ACACACACCAGTGTCCATCCAGTTGGTGACTAGCAC CTCTGTCTTAT AAGCTGCCCATCTGTTCTCCAGCAATGAGACCATTTGGACTTCTAGG CTTCCGACAAAGACCAGATGACCATATCCCTGGGAAAAACCCCTAGA CCAGACCAGGCCCTGCTGGCATCTATGAACACAACCACCATACT CAC ACTATGGAGGTGACAGAAATGTCCCCATCAAAGAATTCTTTTATTTC ATTTGTGCCTAAGAAAATTTTACATCAGCATTTCATGAGAATACTAC ATACTCCCGGGGTACTCCATCTTTGGAAATGACAGATACAGGATTTC TTATACAGAATATTTATTCCGCAACTACCAATATCACCCCACTGAAA CTGAGACCACAAAAATTTCCAGTCACCAAACACATTCGCCTTCAGAG GCATCTCCAGAGGGCAAAGGTACCACTGCCAATGATGCTACTACAGC ATTCCACTTGGGACTCCCTCTGATGGAAATTTGGCTTCATCTCCCAC CAGATATACAACAGCTGTATCCAAATTGACATCACCATGGTTTGCTA TTCTGGAAGCACACAGATTACACCAACCTTGACCTCAAGTAACACAG ATTTCTCCATAGTTTCTGGAACCACATCCATAACCAATATGCCTGAA TAGGTGTTCACATTCCAGAAATGTCTACCAGTCTTGGGAAAACAGCT TTTAAACTTACCACTTTACTACTAAAAACAATAC CTATGTCTACAAA CTCCCCTCACAAGCTCTGACAATCACCACTTTTTTGTGTCCTGAAAA ACCTGCAAATGAACTTCCTTTGACACCAAGGGAGACTGTTGTTCCAT GGAAAGCACGAGTGCCCTTCCAGCATATACTCCCAGGACTGTGGAAA CAGTAGATATAATATCTACTCTTGCTTGCATTCAACCAAATTTTTCT TGATAGTAAACTCCACCTATGTGACT CACTCTGTCTCATATGGCCAG ACTGAGGAAAGTGCTTCTGAGACCACACAAACAGAAATAAATGGTGC GATACTTCATTTGTAGATACCACAACTTCCAGCTCAACAAGGATATC AATTGTATTTGGAGGTACAACGACCCCTGTACCAAAGTCAGCAACAA AAATCCTATGGACATCAATACAACTTTTTCACACTTGCATTCACTTA CACAAAGATTAAATGCCACTGTGACAAGAAAAGAAGCAACTTCCCAT GGACACAACCTGAGGTGACTTCAGTTGCCTCTTTCATTTCTGAAAGC TATCTTATGAGAAAATCAACTATAGCAGCAGTGGCTGAGGTTTCTCC ACACAGACTTTCCCTGAGTCCTTGTCTCTTTCCACAGCTGGACTATA ATTTTCAACAATGCTGGAAGTGACAGACGAATCAGCACAAAGGGTGA TAATGACGGTTTTACAGTTCTCTCCGACAGGATCACTACAGCCTTTT CAGCTTCTGTCACTGTTTCCTCTTTTCCTGATATAGAAAAGCTAAGT CTGTTCCAAATGTACCTACAATGCTTCCTAGAGAATCCTCTATGGCA ACCCCATTGGATAATAAAACTGCAACAACTGAGGTGAGAGAAAGTTG ACGTCCACTCCTATTTACCAGATGTCCTCATTGCCAGTTAATGTAAC GCTTTTGACAAAATTGGTGAAAACCACACCTAGGAGTTCATACAATG TGCCTTCACCTCCAAAAAAGTTTCTGACACTCCCCCAATAGTGATAA AAATGACAGAAATGTTTAATTTTAACCACACCTATGTAGCACATTGG CTAAATCTTCTAAAACAATGCATCCAGGTTGTTTGAAAAGTCCCTGT ACTTCAGAGACATCTGAGGGAATTTCAGCTGGATCTCCCACTTCTGG ACAGCCACTTCTGGGCCTATGTCTGAGATGTCCT CAATACCAGTTAA GAGCACACATATATTCGGTGAACCCCTGGGTGCTTCTACCACAAGGA TAACTCTGCTTTCACACCTGCAACAGTCTCTTCTGACACTTCCACA TATCAGAAACCAGTTTCTCCACTACCCCTACAGACAGGACAGCTACG AGAGTTGGGTTATTCTCTACTTTATTGTCTTCAGTTACCCCCAGGAT TCCTTGTCTGATGGTATCTTACCTCCACAGCCTACAGCTGCTCATTC CTACTATGACCATGCAAACATCTACATTGGATGTCACACCTGTGATA CTCAGCAACCCCTGTGCCTGTTACTCATATGTTCTCATTGCCAGTTA TATGCTGGGGCACTTCAAAAAACAAAATGGTTTCCTCTGCTTTCACT ATGGCAGTTCTGTGGTGGCTGAGGAGACTGAGGTTACCATGTCTGAG ACAGAAATGATAGAGGCACCTTCCAGGATCACACCTACGACCTTTCT CCTTCTACACTGGCCAGGGCTTTTTCTACATCTGTGCTCTCAGATGT CTCTCCAACAGAGCCAACTTTGCCCTTTGTAAAAACCGTTCCCACCA CTCAAATCTATCCTCAACTACAATGACCACAGCATTGGTACCACCTT CCATTATGGCTGGGATAGTGACTCCATTTGTAGGCACCACTGCCTTC TGGATCAGACTGCTTCCACAACCATTGTTATTGTGCCTACCCATGGA TCTCCACTCAGTTCTAAGAGCACTGGAGCTATTTCCTCCATTCCAAA GACTTGATTCGTACCACTTCAGAGGCCACGGTAATCTCTGTCAGGAA GACCACATTTTCACCATTTCTATCAGCAACT CAACAGTCATCACAAG GACATCCATGGCAGTTCCTTCTCTGACAGAAACACCATTTCATTCAC CAGATGAGGCTACAACTTTGGGCATATTATCTGGGATTACTAACAGG TGAGACTCTCCACTCCTGTGACAGCTAAGGCTGAGACCACCCTTTTC TCCCTATCTACTGTGAACAGTGGTACAGGGGTAGCTCTCACAGATAC US 2011/O 185439 A1 Jul. 28, 2011
- Continued - Continued GCCAGCTCTTCCTTAGCATCCTCTGAATTGATGAGAAAAATCAAAAG TTATTCCAGAATCACTGTTCCTGAAAATATGCTTTCACC TACTCATG TAAAATACATGGCAACTTCACACATGGAAACTTCACACAAGATCAAT CAGATAGTCTCCATACTTCCTTCAATATTCAGGTTTCCCCATCTCTG TGACGTTATTAGTAAACTGTGAACACGTTGCAGTGAAAAAACTAGAG ACTAGCTTTAAGAGTGCTTCTGGACCCACAAAAAATGTTAAAACAAC CCTGGAAATTGCAAAGCTGATGAAACAGCCTCTAAATACAAAGGGAC CACCAATTGCTTTTCTTCTAATACTAGAAAGATGACTTCCTTGTTAG CTATAAGTGGCTATTAACCAACCCTACGGAGACAGCCCAAACCAGAT AAAAGACTTCCTTAACAAACTATGCCACATCTTTGAATACCCCTGTT GCATAAAAAATGAGGATGGAAATGCCACAAGATTCT CAATCAGCATC TCATACCCTCCATGGACCCCATCCAGTGCAACTCTACCCTCTTTGAC AACACGGGCAAATCTCAGTGGGAAAAGCCAAAGTTTAAACAATGCAA ATCATTTGTTTATTCACCTCATAGTACTGAAGCTGAGATCTCTACTC ATTGCTTCAAGAACTTCCTGACAAGATTGTGGATCTTGCTAATATTA CAAAGACCTCTCCTCCTCCCACATCCCAAATGGTTGAATTTCCAGTT CCATAAGTGATGATTTTCCTAGGCAATGTCCCTGTGGGAGGGATTTT CTGGGAACAAGAATGACATCTAGTAATACCCAAC CTCTGCTTATGAC GGCTTCCATATATTTGCdTAAATCACTGACGGAGAGAATTCCTCTT TTCCTGGAACATACCCACAGCTGAAGGTTCTCAGTTTCCAATTTCCA AGCAACTTACAAACGATCTTGTTTAATTTCTTTGGCCAAACTTCA CCACTATTAATGTACCTACATCCAATGAGATGGAAACAGAGACTCTA CTCTTTAAGACCAAAAATGTCACTAAAGCATTAACCACCTATGTTGT CACCTTGTTCCTGGGCCTTTGTCAACATTCACAGCCTCTCAGACTGG GAGTGCCAGCATTTCAGATGATATGTTCATTCAAAACTTAGCTGACC TCTAGTATCTAAAGATGTCATGGCAATGTCATCAATTCCTATGTCAG CAGTGGTTATCACTCTGCAGCATATTGGAGGAAACCAGAATTATGGT GAATTCTTCCTAACCATGGGCTTTCTGAGAACCCTTCATTATCAACA CAAGTTCACTGTGCCTTTTGGGATTTTGAGAATAATGGGCTGGGTGG TCTTTAAGAGCTATCACTTCCACATTGGCTGACGTTAAGCACACATT ATGGAATTCGTCAGGCTGTAAAGTAAAGGAAACAAATGTAAATTACA TGAGAAAATGACCACATCTGTAACTCCTGGGACCACACTCCCATCAA CAATCTGTCAGTGTGACCACCT CACCCATTTTGGAGTCTTAATGGAA TTCTTTCTGGTGCCACTTCAGGATCTGTAATTTCAAAGTCACCCATT ACTTCGAAAAGATTATCCTGCCAAAATTCTGATCAACCTGTGCACAG CTGACATGGCTCTTATCTAGTCTCCCTTCTGGCTCCCCTCCGGCAAC CACTACTGATGCTAAACCTGGTATTTTTGATCAATTCTTGGTTGTCA TGTATCTAATGCCCCTCATGTTATGACTTCCTCTACAGTAGAGGTGT TCATTTCAGAAAGTGGGAGTTTGTATCACAGCTGCAGTGGCACTTCA CAAAATCAACATTTCTGACATCTGACATGATATCAGCGCACCCATTC TTACTTCCTGCTTGTTTCTTTTACTTGGATGGGCCTGGAGGCAGTCC ACTAACTTGACAACACTACCCTCTGCTACTATGAGCACCATACT CAC ACATGTATTTGGCTCTAGTCAAAGTCTTCAACATATACATTCCAAAT CCGAACCATTCCTACACC TACACTGGGTGGTATCACTACTGGCTTCC TATATCCTTAAATTTTGTCTAGTTGGTTGGGGAATCCCGGCTATCAT CAACTTCTCTCCCTATGTCTATAAATGTCACAGATGACATTGTGTAC GGTGGCAATCACAGTCA ATTTCCACACACCCTGAGGCATCCTCCAGAACCACAATAACTGCCAA PGR17 polypeptide sequence CCCCAGGACTGTGTCTCATCCTTCATCCTTCAGCAGAAAGACTATGT (SEQ ID NO: 29) MKEHIIYOKLYGLILMSSFIFLSDTLSLKGKKLDFFGRGDTYVSLIDT CACCTTCTACAACTGACCACACTCTATCTGTTGGTGCCATGCCTCTG IPELSRFTACIDLWFMDDNSRYWMAFSYITNNALLGREDIDLGLAGDH CCTAGCTCTACAATAACATCTTCATGGAACAGAATTCCAACTGCATC QOLILYRLGKTFSIRHHLASFQWHTICLIWDGVKGKLELFLNKERILE ATCACCCTCTACTTTAATTATTCCTAAGCCCACACTGGACTCCCTTC VTDOPHNLTPHGTLFLGHFLKNESSEVKSMMRSFPGSLYYFOLWDHIL TAAATATAATGACTACTACATCCACTGTTCCTGGAGCCTCATTTCCA ENEEFMKCLDGNIWSWEEDVWLVNKIIPTVDRTLRCVPENMTIOEKST CTCATATCCACTGGGGTGACATATCCTTTTACAGCAACTGTGTCTTC TVSOOIDMTTPSOITGVKPONTAHSSTLLSOSIPIFATDYTTISYSNT ACCAATATCGTCCTTTTTTGAAACAACTTGGCTGGACTCCACACCTT TSPPLETMTAOKILKTLVDETATFAWDVLSTSSAISLPTOSISIDNTT CCTTTCTATCTACGGAAGCATCGACTTCGCCTACTGCCACCAAGTCC NSMKKTKSPSSESTKTTKMVEAMATEIFQPPTPSNFLSTSRFTKNSWV ACAGTTTCCTTCTACAATGTTGAAATGAGCTTCTCTGTCTTTGTTGA STTSAIKSOSAVTKTTSLFSTIESTSMSTTPCLKOKSTNTGALPISTA AGAGCCAAGGATCCCTATTACCAGTGTTATAAATGAATTTACGGAAA GOEFIESTAAGTVPWFTWEKTSPASTHVGTASSFPPEPVLISTAAPVD ATTCGTTGAATTCTATATTTCAGAACAGTGAATTTTCTCTTGCTACT SVFPRNOTAFPLATTDMKIAFTVHSLTLPTRLIETTPAPRTAETELTS CTGGAAACCCAAATTAAAAGCAGGGACATTTCAGAGGAAGAGATGGT TNFODVSLPRVEDAMSTSMSKETSSKTFSFLTSFSFTGTESWOTVIDA CATGGATCGAGCTATTTTGGAACAGAGAGAAGGACAAGAAATGGCTA EATRTALTPEITLASTWAETMLSSTITGRVYTONTPTADGHLLTLMST CAATTTCCTATGTACCATACAGTTGTGTTTGTCAGGTCATCATAAAA RSASTSKAPESGPTSTTDEAAHLFSSNETIWTSRPDOALLASMNTTTI US 2011/O 185439 A1 Jul. 28, 2011 62
Human KIAA1828 - Continued 0562 Full length cDNA was isolated from human Pitu LTFWPNENFTSAFHENTTYTEYLSATTNITPLKASPEGKGTTANDAT itary by a combination of 5' and 3' Rapid Amplification of cDNA Ends (RACE) and internal RT-PCR experiments as ARYTTAWSKILTSPWFANFSIWSGTTSITNMPEFKLTTLLLKTIPMSTK described above. RACE pituitary was prepared using the PANELPLTPRETVWPSVDIISTLACIOPNFSTEESASETTOTEINGA Clontech SMART RACE Kit (Cat # K1811-1). Pituitary poly A RNA was obtained from Clontech (catio584-1). WFGGTTTPWPKSATTORLNATWTRKEATSHYLMRKSTIAAVAEWSPFS 0563. The following CLONTECH RACE primers were TMLEVTDESAORVTASVTVSSFPDIEKLSTPLDNKTATTEVRESWLLT used:
KLWKTTPRSSYNEMTEMFNFNHTYWAHWTSETSEGISAGSPTSGSTH 3'-RACE - CDS FGEPLGASTTRISETSFSTTPTDRTATSLSDGILPPOPTAAHSSATPV (SEQ ID NO: 1609) AAGCAGTGGTATCAACGCAGAGTACTTTTTTTTTTTTTTTTTTTT PWTHMFSLPWNGSSWWAEETEWTMSEPSTLARAFSTSWLSDWSNLSST TTTTTTTVN TMTTALVPPLDOTASTTIVIVPTHGDLIRTTSEATVISVRKTSMAVPS 5'-RACE - CDS LTETPFHSLRLSTPWTAKAETTLESTSWDTWTPSTHTLVCSKPPPDN (SEQ ID NO: 1610) TTTTTTTTTTTTTTTTTTTTTTTTVN PPASSTHVISTTSTPEATOPISOVEETSTYALSFPYTFSGGGVVASLA (WHERE N = A, C G T AND W = A, C, G) TGTTETSVVDETTPSHISANKLTTSVNSHISSSATYRVHTPVSIOLVT Smart IIA STSVLSSDKDOMTISLGKTPRTMEVTEMSPSKNSFISYSRGTPSLEMT (SEQ ID NO: 1611) AAGCAGTGGTATCAACGCAGAGTACGCGGG DTGFPETTKISSHOTHSPSEIPLGTPSDGNLASSPTSGSTOITPTLTS NUP SNTVGWHIPEMSTSLGKTALPSOALTITTFLCPEKESTSALPAYTPR' (SEQ ID NO: 1612) AAGCAGTGGTATCAACGCAGAGT VEMIVNSTYVTHSVSYGODTSFVDTTTSSSTRISNPMDINTTFSHLHS UPM-LONG LRTQPEVTSVASFISESTQTFPESLSLSTAGLYNDGFTVLSDRITTAF (SEO ID NO: 1613) CTAATACGACT CACTATAGGGCAAGCAGTGGTATCAACGCAGA SVPNVPTMLPRESSMATSTPIYOMSSLPVNVTAFTSKKVSDTPPIVIT GT
KSSKTMHPGCLKSPCTATSGPMSEMSSIPWNNSAFTPATWSSDTSTRW UPM-SHORT (SEQ ID NO: 1614) GLFSTLLSSWTPRTTMTMOTSTLDWTPWIYAGATSKNKMVSSAFTTEM CTAATACGACT CACTATAGGGC IEAPSRTPTTFLSPTEPTLPFWKTWPTTIMAGIWTPFWGTTAFSPLS 0564. The following cDNA primers were used: SKSTGAISSIPKTTFSPFLSATOOSSOADEATTLGILSGITNRSLSTV
NSGTGVALTDTYSRITVPENMLSPTHADSLHTSFNIOVSPSLTSFKSA J.-H-1828 - U1 (SEQ ID NO: 1672) SGPTKNWKTTTNCFSSNTRKMTSLLEKTSLTNYATSLNTPWSYPPWTP AGCCCCGCAATCTGTTGATAACT
SSATLPSLTSFWYSPHSTEAEISTPKTSPPPTSOMWEFPVLGTRMTSS J.-H-1828-L1 (SEO ID NO : 1673) NTOPLLMTSWNIPTAEGSOFPISTTINVPTSNEMETETLHLVPGPLST AAGCAGAAATTCAGGAGCGTGTG
FTASOTGLVSKDWMAMSSIPMSGILPNHGLSENPSLSTSLRAITSTLA J.-H-1828 - U2 (SEQ ID NO: 1674) DWKHTFEKMTTSWTPGTTLPSILSGATSGSWISKSPILTWLLSSLPSG TGGAGAAGGAGACGCATCTGC
SPPATWSNAPHWMTSSTWEWSKSTFLTSDMISAHPFTNLTTLPSATMS J.-H-1828 - L2 (SEO ID NO : 1675) TILTRTIPTPTLGGITTGFPTSLPMSINVTDDIWYISTHPEASSRTTI CTTGGT CACCTGCTTGTAGATGTT
TANPRTWSHPSSFSRKTMSPSTTDHTLSWGAMPLPSSTITSSWNRIPT J.-H-1828 -U3 (SEO ID NO : 1676) ASSPSTLIIPKPTLDSLLNIMTTTSTWPGASFPLISTGWTYPFTATWS CCTGACCTTTCCCAGTGTTCAATGT
SPISSFFETTWLDSTPSFLSTEASTSPTATKSTWSFYNWEMSFSWFWE J.-H-1828-L14 (SEO ID NO : 1677) EPRIPITSVINEFTENSLNSIFONSEFSLATLETOIKSRDISEEEMVM TTGTCCATGAGAATCTCCCGTCTG J.-H-1828 - Us DRAILEOREGOEMATISYWPYSCVCOVIIKASSSLASSELMRKIKSKI (SEO ID NO : 1678) GGACCCTGGAAAAACGAAACTACTG HGNFTHGNFTODOLTLLVNCEHVAVKKLEPGNCKADETASKYKGTYKW J.-H-1828 -L5 LLTNPTETAOTRCIKNEDGNATRFSISINTGKSOWEKPKFKOCKLLOE (SEO ID NO : 1679) TCCATGAGAATCTCCCGTCTGTC LPDKIVDLANITISDDFPROCPCGRDFGFHIFA