In this Project, we will investigate molecular mechanisms by which PPARs counter-regulate innate immune responses and influence the ability of macrophages to contribute to atherosclerotic vascular disease. There is now extensive evidence that PPARa, PPARy and PPARd ligands inhibit inflammatory processes in macrophages and other cells within the artery wall that are linked to the progression of atherosclerosis and its clinical complications, but the mechanisms that are responsible for these effects remain poorly understood. We recently identified an NCoR/SUMOylation-dependent pathway by which PPARy ligands inhibit specific subsets of toll-like receptor (TLR) 4-responsive genes. This mechanism involves ligand-dependent sumoylation of PPARy, which targets it to NCoR corepressor complexes on the promoters of inflammatory response genes. This in turn prevents the signal-dependent removal of NCoR complexes that is normally a prerequisite for transcriptional activation.
Three Specific Aims are proposed to explore the significance of these findings with respect to the control of inflammatory programs of gene expression that underlie innate immune responses and the development of atherosclerosis.:
Specific Aim 1 will utilize a combination of molecular, cellular and genomics approaches to test the hypothesis that NCoR, and the highly related corepressor SMRT, are differentially required to maintain inflammatory response genes silent under quiescent conditions. In collaboration with Project 3, we will test the hypothesis that NCoR and SMRT are actively removed from these promoters upon stimulation of macrophages and B1 cells by modified LDL and specific TLR2 and TLR4 agonists. We will test the hypothesis that the NCoR/SMRT repression checkpoint is inappropriately relieved in macrophage foam cells in vivo, resulting in a partially activated phenotype.
Specific Aim 2 will test the hypothesis that the NCoR/SMRT/SUMOylation dependent pathway is a quantitatively important mechanism mediating anti-inflammatory actions of PPARy and PPARd agonists in macrophages. In collaboration with Project 2, we will define the genome-wide profiles of PPARy and PPARS repression of genes activated by the TLR2 agonist Pam3 in NCoR[-/-] and SMRT[-/-] macrophages. We will determine the ability of PPARy and PPARd-specific agonists to exert anti-inflammatory effects in macrophages lacking the SUMO E3 ligase PIAS1.
Specific Aim 3 will test the hypothesis that the NCoR/SMRT/SUMOylation-dependent pathway plays a quantitatively important role in mediating antiatherogenic effects of PPARy agonists in vivo. In collaboration with Project 4, we will use a combination of selective PPARy modulators and PPARy mutants to define the relative importance of ligand-dependent activation and ligand-dependent repression in inhibiting the development of atherosclerosis in LDL receptordeficient (LDLR[-/-]) mice. The results of these studies are likely to contribute to an improved understanding of the inflammatory component of atherosclerosis and the anti-atherogenic actions of PPARy agonists.
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