PPARg/TGF-b Cross-Talk in the Intestinal Epithelium

Mayo Clinic Jacksonville, Jacksonville FL

Investigators

Abstract

DESCRIPTION (provided by applicant): TGF-beta and PPAR-gamma are signaling molecules that activate genes required for the maintenance of normal intestinal epithelium. Aberrant TGF-a/PPAR-? signaling can lead to inflammation, pre-neoplastic lesions, and cancer. Our goal is to investigate the mechanisms by which TGF-a has differential effects on PPAR-gamma target gene expression. CD36 and ANGPTL4 are both primary transcriptional targets of PPAR-gamma and neither gene appears to be regulated by TGF-betaa alone. However, when RIE/PPAR-gamma cells are treated with both the synthetic PPAR-? ligand RS5444 and TGF-beta, the induction of CD36 is inhibited, whereas the induction of ANGPTL4 is not. We hypothesize that activated PPAR-gamma recruits a different set of cofactors to the CD36 and ANGPTL4 promoters and that TGF-beta interferes with complex formation at the CD36 promoter. In order to test this hypothesis, the rat CD36 and ANGPTL4 regulatory regions will be characterized by reporter gene assays and by EMSA. The cofactors present at each PPRE will be identified by ChIP and by EMSA. Genetic and pharmacological techniques will be used to test the contribution of each TGFbeta signaling pathway to the regulation of CD36 promoter activity.