PPARgamma is a transcription factor of the nuclear hormone receptor subfamily that has been postulated toparticipate in a diverse range of diseases. PPARgamma is highly expressed in the adipocyte and its role inmetabolism, 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 beappreciated. PPARgamma agonists lower blood pressure, reduce expression of pro-inflammatory molecules in thevessel wall, and improve endothelial function suggests that PPARgamma normally exhibits an important vascularprotective function. PPARgamma has also been implicated to play an important role in atherosclerosis. The centralhypothesis of this proposal is that PPARgamma plays an important role in the regulation of vascular function, bloodpressure 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, redoxsubstances, and inflammatory molecules. We will take advantage of a robust experimental platformconsisting of both bioinformatics and a series of novel genetic models to: 1) discover PPARgamma target genes inthe vasculature, and 2) examine the protective role of PPARgamma expression in vascular smooth muscle andendothelial cells in atherosclerosis. To accomplish these goals we proposed the following specific aims: 1) toidentify novel targets of PPARgamma in the vascular wall by using an integrated approach for prioritizing targetgene selection that combines gene expression analysis using oligonucleotide microarrays with bioinformaticsand computational analysis, and 2) to examine, the protective role of PPARgamma in endothelial and smoothmuscle cells during the progression of atherosclerosis using genetic models generated in our laboratorytargeting either wildtype or dominant negative mutants of PPARgamma to the vessel wall. Development ofatherosclerosis and vessel dysfunction will be assessed in ApoE-/- mice and in response to angiotensin-ll inApoE-/- mice. The establishment of these unique transgenic models will provide tools which will allow us forthe first time to not only examine the importance of the PPARgamma pathway in the blood vessel wall toatherosclerosis, but also separate the effects of PPARgamma in the endothelium and vascular smooth muscle.
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