PPARgamma is a transcription factor of the nuclear hormone receptor subfamily that has been postulated to participate in a diverse range of diseases. PPARgamma is highly expressed in the adipocyte and its role in metabolism, particularly with regard to diabetes mellitus and insulin resistance has been extensively studied. However, an important role for PPARgamma in the blood vessel wall has only recently begun to emerge and be appreciated. PPARgamma agonists lower blood pressure, reduce expression of pro-inflammatory molecules in the vessel wall, and improve endothelial function suggests that PPARgamma normally exhibits an important vascular protective function. PPARgamma has also been implicated to play an important role in atherosclerosis. The central hypothesis of this proposal is that PPARgamma plays an important role in the regulation of vascular function, blood pressure and atherosclerosis through the activation and repression of target genes in the blood vessel wall. These target genes include, but are not restricted to genes encoding vasoactive substances, redox substances, and inflammatory molecules. We will take advantage of a robust experimental platform consisting of both bioinformatics and a series of novel genetic models to: 1) discover PPARgamma target genes in the vasculature, and 2) examine the protective role of PPARgamma expression in vascular smooth muscle and endothelial cells in atherosclerosis. To accomplish these goals we proposed the following specific aims: 1) to identify novel targets of PPARgamma in the vascular wall by using an integrated approach for prioritizing target gene selection that combines gene expression analysis using oligonucleotide microarrays with bioinformatics and computational analysis, and 2) to examine, the protective role of PPARgamma in endothelial and smooth muscle cells during the progression of atherosclerosis using genetic models generated in our laboratory targeting either wildtype or dominant negative mutants of PPARgamma to the vessel wall. Development of atherosclerosis and vessel dysfunction will be assessed in ApoE-/- mice and in response to angiotensin-ll in ApoE-/- mice. The establishment of these unique transgenic models will provide tools which will allow us for the first time to not only examine the importance of the PPARgamma pathway in the blood vessel wall to atherosclerosis, but also separate the effects of PPARgamma in the endothelium and vascular smooth muscle.
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