| Human g protein-coupled receptor and modulators thereof for the treatment of ischemic heart disease and congestive heart failure -> Monitor Keywords |
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Human g protein-coupled receptor and modulators thereof for the treatment of ischemic heart disease and congestive heart failureRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, In Vivo Diagnosis Or In Vivo Testing, Testing Efficacy Or Toxicity Of A Compound Or Composition (e.g., Drug, Vaccine, Etc.)Human g protein-coupled receptor and modulators thereof for the treatment of ischemic heart disease and congestive heart failure description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070224127, Human g protein-coupled receptor and modulators thereof for the treatment of ischemic heart disease and congestive heart failure. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This patent application claims the benefit of priority from the following provisional application, filed via U.S. Express mail with the United States Patent and Trademark Office on the indicated date: U.S. Provisional No. 60/400,774, filed Aug. 1, 2002. The foregoing application is incorporated by reference herein in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to methods of identifying whether a candidate compound is a modulator of an orphan G protein-coupled receptor (GPCR). Preferably the GPCR is human. In some embodiments, the GPCR is expressed endogenously by cardiomyocytes. In some embodiments, the GPCR is coupled to Gi and lowers the level of intracellular cAMP. In some embodiments, overexpression of the GPCR promotes survival of cardiomyocytes. In some embodiments, overexpression of the GPCR rescues cardiomyocytes from hypoxia/reoxygenation induced apoptosis. In some embodiments, the GPCR is down-regulated in individuals with congestive heart failure. Agonists of the invention are envisioned to be useful as therapeutic agents for the treatment of ischemic heart disease, including myocardial infarction, post-myocardial infarction remodeling, and congestive heart failure. BACKGROUND OF THE INVENTION [0003] A. Ischemic Heart Disease and Congestive Heart Failure Congestive heart failure (CHF) affects nearly 5 million Americans with over 500,000 new cases diagnosed annually. By definition, CHF is a clinical syndrome in which heart disease reduces cardiac output, increases venous pressures, and is accompanied by molecular abnormalities that cause progressive deterioration of the failing heart and premature myocardial cell (myocyte) death (From; Heart Failure: Pathophysiology, Molecular Biology, and Clinical Management, Katz, A M, Lippincott Williams and Wilkins, 2000). In the adult heart, myocyte (cardiomyocyte) death is a critical element of the natural history of heart failure because the cells that are lost cannot be replaced. Because the 5-year survival rate, once heart failure becomes symptomatic, is less that 50%, any definition of heart failure that does not consider the molecular processes that accelerate myocardial death overlooks a major clinical feature of this syndrome. To this end, current research from many groups has focused on the molecular mechanisms and signaling pathways that regulate myocyte death and survival. Cell culture and small animal studies have clearly demonstrated that G-protein coupled receptors on cardiac myocytes are highly important regulators of cardiac contractile function and are also involved in the regulation of myocyte death and survival [for review, see Adams and Brown, Oncogene (2001) 20:1626-1634]. However, there are no drugs currently available in the clinic designed to inhibit cardiac myocyte death or directly activate survival pathways. Recently published evidence in mice and rats demonstrate that activation of survival pathways [Lee et al., Endocrinology (1999) 140:4831-40] or inhibitors of cardiac myocyte death pathways [Laugwitz et al., Hum Gene Ther (2001) 12:2051-63] significantly improves cardiac function and animal survival. Thus it is clear that similar therapeutic strategies for the treatment of human heart failure hold great promise. [0004] B. G Protein-Coupled Receptors [0005] Although a number of receptor classes exist in humans, by far the most abundant and therapeutically relevant is represented by the G protein-coupled receptor (GPCR) class. It is estimated that there are some 30,000-40,000 genes within the human genome, and of these, approximately 2% are estimated to code for GPCRs. Receptors, including GPCRs, for which the endogenous ligand has been identified, are referred to as "known" receptors, while receptors for which the endogenous ligand has not been identified are referred to as "orphan" receptors. [0006] GPCRs represent an important area for the development of pharmaceutical products: from approximately 20 of the 100 known GPCRs, approximately 60% of all prescription pharmaceuticals have been developed. For example, in 1999, of the top 100 brand name prescription drugs, the following drugs interact with GPCRs (the primary diseases and/or disorders treated related to the drug is indicated in parentheses): TABLE-US-00001 Claritin .RTM. (allergies) Paxil .RTM. (depression) Cozaar .RTM. (hypertension) Propulsid .RTM. (reflux disease) Pepcid .RTM. (reflux) Effexor .RTM. (depression) Allegra .RTM. (allergies) Diprivan .RTM. (anesthesia) Hytrin .RTM. (hypertension) Plavix .RTM. (MI/stroke) Xalatan .RTM. (glaucoma) Harnal .RTM. (prostatic hyperplasia) Prozac .RTM. (depression) Zoloft .RTM. (depression) Iimitrex .RTM. (migraine) Risperdal .RTM. (schizophrenia) Gaster .RTM. (ulcers) Depakote .RTM. (epilepsy) Lupron .RTM. (prostate cancer) BuSpar .RTM. (anxiety) Wellbutrin .RTM. (depression) Toprol-XL .RTM. (hypertension) Singulair .RTM. (asthma) Vasotec .RTM. (hypertension) Zyprexa .RTM. (psychotic disorder) Zantac .RTM. (reflux) Serevent .RTM. (asthma) Atrovent .RTM. (bronchospasm) Cardura .RTM. (prostatic ypertrophy) Zoladex .RTM. (prostate cancer) Ventolin .RTM. (bronchospasm) Zyrtec .RTM. (rhinitis) Tenormin .RTM. (angina) Diovan .RTM. (hypertension) (Med Ad News 1999 Data). [0007] GPCRs share a common structural motif, having seven sequences of between 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane (each span is identified by number, i.e., transmembrane-1 (IM-1), transmembrane-2 (TM-2), etc.). The transmembrane helices are joined by strands of amino acids between transmembrane-2 and transmembrane-3, transmembrane-4 and transmembrane-5, and transmembrane6 and transmembrane-7 on the exterior, or "extracellular" side, of the cell membrane (these are referred to as "extracellular" regions 1, 2 and 3 (EC-1, EC-2 and EC-3), respectively). The transmembrane helices are also joined by strands of amino acids between transmembrane-1 and transmembrane-2, transmembrane-3 and transmembrane-4, and transmembrane-5 and membrane-6 on the interior, or "intracellular" side, of the cell membrane (these are referred to as "intracellular" regions 1, 2 and 3 (IC-1, IC-2 and IC-3), respectively). The "carboxy" ("C") terminus of the receptor lies in the intracellular space within the cell, and the "amino" ("N") terminus of the receptor lies in the extracellular space outside of the cell. [0008] Generally, when a ligand binds with the receptor (often referred to as "activation" of the receptor), there is a change in the conformation of the receptor that facilitates coupling between the intracellular region and an intracellular "G-protein." It has been reported that GPCRs are "promiscuous" with respect to G proteins, i.e., that a GPCR can interact with more than one G protein. See, Kenakin, T., 43 Life Sciences 1095 (1988). Although other G proteins exist, currently, Gq, Gs, Gi, Gz and Go are G proteins that have been identified. Ligand-activated GPCR coupling with the G-protein initiates a signaling cascade process (referred to as "signal transduction"). Under normal conditions, signal transduction ultimately results in cellular activation or cellular inhibition. Although not wishing to be bound to theory, it is thought that the IC-3 loop as well as the carboxy terminus of the receptor interact with the G protein. [0009] Under physiological conditions, GPCRs exist in the cell membrane in equilibrium between two different conformations: an "inactive" state and an "active" state. A receptor in an inactive state is unable to link to the intracellular signaling transduction pathway to initiate signal transduction leading to a biological response. Changing the receptor conformation to the active state allows linkage to the transduction pathway (via the G-protein) and produces a biological response. [0010] A receptor may be stabilized in an active state by a ligand or a compound such as a drug. Recent discoveries, including but not exclusively limited to modifications to the amino acid sequence of the receptor, provide means other than ligands or drugs to promote and stabilize the receptor in the active state conformation. These means effectively stabilize the receptor in an active state by simulating the effect of a ligand binding to the receptor. Stabilization by such ligand-independent means is termed "constitutive receptor activation." SUMMARY OF THE INVENTION [0011] The present invention relates to an orphan GPCR designated herein as RUP41. RUP41 is related to GPR22 (GenBank.RTM. Accession No. U66581). [0012] RUP41 is expressed endogenously by cardiac myocytes (cardiomyocytes). The expression profile of human RUP41 was determined by Affymetrix gene chip and verified by multi-tissue dot blot and Northern blot Partial coding sequence for rat ortholog of RUP41, amplified from genomic DNA, has been identified and is disclosed. This fragment of the rat RUP41 polynucleotide sequence is 97% identical to the published mouse RUP41 polynucleotide sequence (XM.sub.--137998). RUP41 is disclosed herein to be coupled to Gi, resulting in inhibition of adenylyl cyclase and suppression of cAMP production. It is further disclosed that expression of endogenous RUP41 levels in experimental models of ischemic and hypertrophic hearts is decreased. It is further disclosed that over-expression of RUP41 promotes survival of cardiomyocytes. The disclosed properties of RUP41 indicate that an agonist of RUP41 is likely to be useful for the treatment of heart diseases associated with cardiomyocyte apoptosis. [0013] In part the present invention is directed to methods of identifying whether a candidate compound is a modulator of RUP41. In other some embodiments, the present invention is directed to methods of modulating the activity of RUP41, comprising the step of contacting RUP41 with a modulator of RUP41. In some embodiments, said modulator lowers the intracellular level of cAMP. In some embodiments, the modulator is an agonist. [0014] In some embodiments, said contacting occurs in vitro. In some embodiments, RUP41 modulator is introduced into cell culture models of cardiomyocyte apoptosis in a method of determining whether said modulator is effective in inhibiting cardiomyocyte apoptosis. In some embodiments, said modulator lowers the intracellular level of cAMP. In some embodiments, the modulator is an agonist. [0015] In some embodiments, said contacting occurs in vivo. In some embodiments, RUP41 modulator is administered to mice and rats undergoing surgical models of ischemic heart disease and heart failure in a method of determining whether said modulator is effective in reducing the pathology associated said ischemic heart disease and heart failure. In yet other some embodiments, RUP41 modulator is administered to animals subjected to experimental myocardial infarction in a method of determining whether said modulator has benefit for cardiac remodeling and function. In some embodiments, said modulator lowers the intracellular level of cAMP. In some embodiments, the modulator is an agonist. [0016] Modulators of RUP41 are envisioned to be useful as therapeutic agents for the treatment of ischemic heart disease, including myocardial infarction, post-myocardial infarction remodeling, and congestive heart failure. In some embodiments, said modulator lowers the intracellular level of cAMP. In some embodiments, the modulator is an agonist. [0017] Polynucleotide sequence and the encoded polypeptide sequence for a first allele of human RUP41 are provided in the Sequence Listing as SEQ ID NO:1 and SEQ ID NO:2, respectively (the coding region for the polypeptide of SEQ ID NO:2 corresponds to nucleotides 237-1,538 of SEQ ID NO:1). Amino acid sequence for a second allele of human RUP41 polypeptide (GenBank.RTM. Accession No. AAB63815), comprising a single substitution of cysteine for lysine at amino acid position 425 of SEQ ID NO:2, is provided as SEQ ID NO:3 (the corresponding coding sequence is provided as nucleotides 79,559-80,860 of GenBank.RTM. Accession No. AC002381). Polynucleotide sequence and the encoded polypeptide sequence of mouse RUP41 are provided as SEQ ID NO:4 and SEQ ID NO:5, respectively. Polynucleotide sequence comprising partial coding sequence for rat RUP41 is disclosed as SEQ ID NO:6. [0018] In a first aspect, the invention features a method of identifying whether a candidate compound is a modulator of a RUP41 GPCR, said receptor comprising a polypeptide selected from the group consisting of: [0019] (a) the polypeptide of SEQ ID NO:2; [0020] (b) the polypeptide of SEQ ID NO:3; and [0021] (c) the polypeptide of SEQ ID NO:5; Continue reading about Human g protein-coupled receptor and modulators thereof for the treatment of ischemic heart disease and congestive heart failure... 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