Mammalian relaxin receptors

Abstract

High affinity relaxin receptors, polypeptide compositions related thereto, as well as nucleotide compositions encoding the same, are provided. These proteins, herein termed LGR7 and LGR8, are orphan leucine-repeat-containing, G protein-coupled receptors. These receptors have a wide and a unique tissue expression pattern. The receptors, particularly soluble fragments thereof, are useful as therapeutic agents capable of inhibiting the action of relaxin and InsL3. The receptors and fragments thereof also find use in the screening and design of relaxin agonists and antagonists. Conditions treatable with relaxin agonists or antagonists include prevention or induction of labor, treatment of endometriosis, treatment of skin conditions such as scleroderma that require collagen or extracellular matrix remodelling. Additionally, relaxin has been implicated in the dilation of blood vessels' smooth muscle cells directly and through release of nitric oxide and atrial natriuretic peptide. Relaxin has also been used in the treatment of severe chronic pain, particularly pain arising from stretching, swelling, or dislocation of tissues.

What is claimed is:  
     
         1 . A composition comprising an LGR8 polypeptide, comprising at least 18 contiguous amino acids of the sequence set forth in SEQ ID NO:2.  
     
     
         2 . A composition according to  claim 1 , wherein said LGR8 polypeptide is a soluble fragment of LGR8.  
     
     
         3 . A composition according to  claim 1 , wherein said LGR8 polypeptide comprises a mutation that confers a gain of function.  
     
     
         4 . A composition comprising an LGR7 polypeptide, wherein said polypeptide is a soluble fragment of LGR7.  
     
     
         5 . The composition according to  claim 2 , wherein said composition further comprises a pharmaceutically acceptable carrier.  
     
     
         6 . The composition according to  claim 4 , wherein said composition further comprises a pharmaceutically acceptable carrier.  
     
     
         7 . A method of inhibiting premature labor, the method comprising administering a patient suffering from premature labor the composition according to  claim 2 .  
     
     
         8 . A method of inhibiting premature labor, the method comprising administering a patient suffering from premature labor the composition according to  claim 5 .  
     
     
         9 . An isolated nucleic acid molecule comprising a cDNA sequence encoding a mammalian LGR8 polypeptide that will hybridize under stringent conditions of 50° C. or higher in the presence of 0.1×SSC to the sequence set forth in SEQ ID NO:1, or encodes the peptide of SEQ ID NO:2.  
     
     
         10 . An antibody that specifically recognizes a relaxin receptor.  
     
     
         11 . A non-human transgenic animal model for relaxin receptor gene function wherein said transgenic animal comprises an introduced alteration in a LGR7 or LGR8 gene.  
     
     
         12 . A method of screening for biologically active agents that modulate relaxin function, the method comprising: 
 combining a candidate biologically active agent with any one of: 
 (a) an LGR7 or LGR8 polypeptide;  
 (b) a cell comprising a nucleic acid encoding an LGR7 or LGR8 polypeptide; or  
 (c) a non-human transgenic animal model for relaxin receptor gene function comprising one of: (i) a knockout of an LGR7 or LGR8 gene; (ii) an exogenous and stably transmitted LGR7 or LGR8 gene; and  
   determining the effect of said agent on relaxin function.    
     
     
         13 . A method of screening for biologically active agents that modulate InsL3 function, the method comprising: 
 combining a candidate biologically active agent with any one of: 
 (a) an LGR8 polypeptide;  
 (b) a cell comprising a nucleic acid encoding an LGR8 polypeptide; or  
 (c) a non-human transgenic animal model for relaxin receptor gene function comprising one of: (i) a knockout of an LGR8 gene; (ii) an exogenous and stably transmitted LGR8 gene; and  
   determining the effect of said agent on LGR8 function.    
     
     
         14 . A method of designing biologically active agents that modulate LGR7 or LGR8 function, the method comprising: 
 determining the binding sites between LGR8 or LGR7 and a cognate ligand;    designing a pharmacomimetic molecule that mimics the binding site of either said LGR8 or LGR7; or the binding site of said cognate ligand.    
     
     
         15 . The method according to  claim 13 , wherein said cognate ligand is relaxin or InsL3.  
     
     
         16 . A method for the treatment of cryptorchidism, the method comprising: 
 administering to an individual suffering from said cryptorchidism an agonist of LGR8 in a pharmaceutically effective dose.    
     
     
         17 . A method for the treatment of scleroderma, the method comprising: 
 administering to an individual suffering from said scleroderma an agonist of LGR7 or LGR8 in a pharmaceutically effective dose.    
     
     
         18 . A method for the induction of labor, the method comprising: 
 administering to an individual for which induction of labor is desired, an agonist of LGR7 or LGR8 in a pharmaceutically effective dose.    
     
     
         19 . A method for the diagnosis of a genetic condition associated LGR8 or LGR7, the method comprising: 
 analyzing a sample of a patient suspected of said genetic condition for expression or sequence of LGR7 or LGR8, wherein an alteration in expression or sequence as compared to a normal sample is indicative of said genetic condition.    
     
     
         20 . The method according to  claim 19 , wherein said condition is cryptorchidism.