Compositions and methods of using apoptosis signaling kinase related kinase (ASKRK)

Abstract

The invention provides apoptosis signaling kinase related kinase (ASKRK) nucleic acid and polypeptide sequences and methods of using such sequences to identify modulators of ASKRK. Such modulators can be used for the treatment of diabetes or for delaying the onset of diabetes. The invention also provides methods of diagnosing diabetes or pre-diabetes and methods of making a prognosis based on the detection of ASKRK nucleic acids and proteins.

1 . An isolated polypeptide comprising SEQ ID NO:2 or SEQ ID NO:4. 
     
     
         2 . A method for identifying an agent for treating a diabetic or pre-diabetic individual, the method comprising the steps of:
 (i) contacting a candidate agent with a pancreatic or kidney cell that expresses a nucleic acid encoding a polypeptide having kinase activity that comprises at least 50 contiguous amino acids of SEQ ID NO:2;   (ii) determining the activity of the polypeptide; and   (ii) selecting an agent that inhibits the activity of the polypeptide, thereby identifying an agent for treating a diabetic or pre-diabetic individual.   
     
     
         3 . The method of  claim 2 , wherein the polypeptide comprises SEQ ID NO:2 or SEQ ID NO:4. 
     
     
         4 . The method of  claim 2 , wherein the polypeptide is overexpressed relative to normal. 
     
     
         5 . The method of  claim 2 , wherein the cell is a pancreatic cell. 
     
     
         6 . The method of  claim 2 , wherein the pancreatic cell is from a diabetic animal. 
     
     
         7 . The method of  claim 2 , wherein the step of determining the activity of activity of the polypeptide comprises determining the ability of the polypeptide to phosphorylate a substrate. 
     
     
         8 . The method of  claim 2 , wherein the step of determining the activity of activity of the polypeptide comprises determining the level of apoptosis. 
     
     
         9 . The method of  claim 2 , wherein the step of determining the activity of the polypeptide comprises determining the amount of protein present using an immunoassay. 
     
     
         10 . The method of  claim 2 , wherein the agent is an siRNA. 
     
     
         11 . The method of  claim 2 , wherein the agent is an antisense RNA. 
     
     
         12 . The method of  claim 2 , further comprising:
 administering the agent to a pancreatic beta cell population;   determining the level of apoptosis in the population; and   selecting a candidate agent that decreases the level of apoptosis   
     
     
         13 . A method for identifying an agent for treating a diabetic or pre-diabetic individual, the method comprising the steps of:
 (i) contacting a candidate agent with a kidney or pancreatic cell that expresses a nucleic acid encoding a polypeptide having phosphorylating activity that comprises at least 50 contiguous amino acids of SEQ ID NO:2;   (ii) determining the level of an RNA that encodes the polypeptide; and   (ii) selecting an agent that inhibits the level of the RNA relative to normal, thereby identifying an agent for treating a diabetic or pre-diabetic individual.   
     
     
         14 . The method of  claim 13 , wherein the polypeptide comprises SEQ ID NO:2 or SEQ ID NO:4. 
     
     
         15 . The method of  claim 13 , wherein the cell is a pancreatic cell. 
     
     
         16 . The method of  claim 13  wherein the pancreatic cell is from a diabetic animal. 
     
     
         17 . The method of  claim 13 , wherein the step of determining the level of an RNA that encodes the polypeptide comprises an amplification reaction. 
     
     
         18 . The method of  claim 13 , wherein the cell is a pancreatic islet cell. 
     
     
         19 . The method of  claim 13 , wherein the agent is an siRNA. 
     
     
         20 . The method of  claim 13 , wherein the agent is an antisense RNA. 
     
     
         21 . The method of  claim 13 , further comprising:
 administering the agent to a pancreatic beta cell population;   determining the level of apoptosis in the population; and   selecting a candidate agent that decreases the level of apoptosis.   
     
     
         22 . A method of introducing an expression cassette into a pancreatic cell, the method comprising,
 introducing into the cell an expression vector comprising a nucleic acid that, when expressed, inhibits the expression of a nucleic acid encoding a polypeptide having phosphorylating activity that comprises at least 50 contiguous amino acids of SEQ ID NO:2.   
     
     
         23 . The method of  claim 22 , wherein the polypeptide comprises SEQ ID NO:2. 
     
     
         24 . The method of  claim 22 , further comprising introducing the cell into a diabetic animal. 
     
     
         25 . The method of  claim 24 , wherein the cell is from the human.