PPAR-gamma is a receptor involved in the activation of stellate cells in response to liver injury. The activity of this receptor is regulated by cofactors, which bind to PPAR-gamma and regulate gene transcription. The specificity of these cofactors for PPAR-gamma is determined in part by the binding of agonists or antagonists, which presumably alters the conformation of the receptor. This proposal seeks to identify novel protein cofactors to better understand the role of these cofactor/PPAR-gamma complexes in the progression of liver fibrosis. We propose three specific aims: 1) Identification of proteins expressed in liver that interact with PPAR-gamma-ligand complexes, 2) Investigation of the effects of identified PPAR-gamma-cofactors on biological function in liver, and 3) Engineering highly specific PPAR-gamma cofactors that clearly identify cofactor-specific activity. Cofactors will be identified by screening T7 libraries for proteins that interact with PPAR-gamma and the receptor specificity will be enhanced by phage display. The functional role of these cofactors will be determined through analysis of gene expression profiles using DNA arrays and over- and under-expression using adenoviral gene delivery and siRNA, respectively.
| Gaillard, Stephanie; Dwyer, Mary A; McDonnell, Donald P (2007) Definition of the molecular basis for estrogen receptor-related receptor-alpha-cofactor interactions. Mol Endocrinol 21:62-76 |
