IDENTIFICATION OF PPAR GAMMA GENE REGULATORY COMPONENTS

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION Research over the past 3-4 years has established the ligand-activated transcription factor, peroxisome proliferator receptor (PPAR) gamma, as a dominant component of the adipogenic process. Toward the goal of understanding the molecular mechanisms involved in regulating expression of the PPARgamma gene during adipogenesis, the specific aims of the proposed research are: (1) To identify and characterize specific regulatory regions (cis-acting elements) within the promoter of the PPARgamma gene and (3) To determine how both adipogenic (dexamethasone) and anti-adipogenic (retinoic acid) stimuli modulate expression of the PPARgamma gene. The hypothesis to be tested is that during adipogenic (retinoic acid) stimuli modulate expression of the PPARgamma gene. The hypothesis to be tested is that during adipogenesis, transacting factors, which in response to adipogenic stimuli, bind to or dissociate from cis-acting elements within the promoter of the PPAR gamma gene ultimately resulting in transcriptional initiation. Cis-acting elements will be identified using ex vivo transfected reporter and DNaseI footprinting assays. Trans-acting factors will be identified using ex vivo transfected reporter and DNaseI footprinting assays. Trans-acting factors will be identified by analyzing sequence specific elements and/or protein purification using identified cis-acting element sequences. Finally, the influence of both adipogenic and anti-adipogenic stimuli on cis-acting elements will be examined using a pre-adipocyte implantation technique. Completion of the proposed research will contribute toward understanding the process of adipogenesis and may serve as a starting point for manipulation of the adipogenic process in the treatment of obesity and obesity-associated illnesses.