Human peroxisome proliferator activated receptor gamma (PPARgamma) gene regulatory sequences and uses therefor

Abstract

This invention relates to the isolation and cloning of the promoter and other control regions of human PPARγ gene. It provides methods for identifying and screening for agents useful for the treatment of diseases and pathological conditions affected by the level of expression of the PPARγ gene. These agents interact directly or indirectly with the promoter or other control regions of the PPARγ gene.

1 . A method for modulating the expression level of a human PPARγ gene, comprising the step of administrating to a mammalian cell or a mammal a composition comprising an effective amount of a modulator of a control region of the human PPARγ gene.  
     
     
         2 . The method of  claim 1 , wherein the modulator increases the expression level of the human PPARγ gene.  
     
     
         3 . The method of  claim 1 , wherein the modulator lowers the expression level of the PPARγ gene.  
     
     
         4 . A method for treating a host suffering from a disease associated with abnormally high levels of a human PPARγ gene expression, comprising the step of administering to the host a composition containing a pharmaceutically effective amount of a down regulator of the PPARγ gene.  
     
     
         5 . A method for treating a host suffering from a disease associated with abnormally low levels of a human PPARγ gene expression, comprising the step of administering to the host a composition containing a pharmaceutically effective amount of an up regulator of the PPARγ gene.  
     
     
         6 . A method for identifying an agent that modulates or regulates the transcription of a PPARγ gene, comprising: 
 (a) providing an in vitro or in vivo system comprising an isolated, purified, or enriched nucleic acid molecule comprising a control region of a human peroxisome proliferator activated receptor gamma (PPARγ) gene, wherein the control region is operably or transcriptionally linked to a reporter sequence to initiate, terminate or regulate the transcription of the reporter sequence;    (b) contacting a candidate agent with the system; and    (c) comparing the level of transcription of the reporter sequence with the level of transcription in the absence of the agent, wherein a measurable difference in the level of transcription of the reporter sequence is an indication that the agent modulates the expression of the human PPARγ gene.    
     
     
         7 . The method of  claim 6 , wherein the control region of the nucleic acid molecule comprises nucleotides 1-125 of SEQ ID NO: 1.  
     
     
         8 . The method of  claim 6 , wherein the control region of the nucleic acid molecule comprises nucleotides 818-1320 of SEQ ID NO: 3.  
     
     
         9 . The method of  claim 6 , wherein the control region of the nucleic acid molecule comprises nucleotides 368-1144 of SEQ ID NO: 34.  
     
     
         10 . The method of  claim 6 , wherein an increase in the level of transcription of the reporter is an indicant that the candidate agent is an up regulator of transcription.  
     
     
         11 . The method of  claim 6 , wherein a decrease in the level of transcription of the reporter is an indicant that the candidate agent is down regulator of transcription.  
     
     
         12 . The method of  claim 6 , wherein the system is a cell, an animal or an in vitro transcription system.  
     
     
         13 . The method of  claim 12 , wherein the cell is a eukaryotic cell.  
     
     
         14 . The method of  claim 13 , wherein the cell is a yeast cell or a mammalian cell.  
     
     
         15 . The method of  claim 6 , wherein the reporter sequence encodes an enzyme that produces a detectable colorimetric or a fluorometric change.  
     
     
         16 . The method of  claim 15 , wherein the enzyme is selected from the group consisting of luciferase, a green fluorescent protein, chloramphenicol acetyl transferase, β-galactosidase, β-lactamase, secreted placental alkaline phosphatase, human growth hormone, an esterase, a phosphatase, tissue plasminogen activator and urokinase.