I am interested in mechanisms of vascular disturbances related to atherosclerosis, specifically in the contribution of the pro-inflammatory S100/ calgranulins proteins. S100 A12 was identified in human atheromatous vasculature as well as in the coronary plaque of diabetic patients with sudden coronary death suggesting a role in atherosclerosis and plaque destabilization. Increased serum S100A12 concentrations are present in patients with chronic inflammatory diseases including patients with vasculitis such as Kawasaki disease and in diabetic patients. One mechanism by which S100A12 promotes inflammation is by activation of the receptor for Advanced Glycation Endproducts (RAGE), a receptor strongly linked to vascular dysfunction and atherosclerosis. Specifically, I previously showed that RAGE is a central cell surface receptor for S100A12 leading to activation of endothelial cells and macrophages, cells critically involved in sustained inflammation and vascular dysfunction. I propose to test the hypothesis that S100A12 accelerates atherosclerosis by generating two transgenic mouse models with S100A12 expression targeted to the smooth muscle cells by using the SM22-a promoter and targeted to macrophages by using the CD11b promoter. Two models of vascular dysfunction will be studied: First, I will examine vascular response to a model of arterial injury as there is evidence that S100A12 modulates smooth muscle cell proliferation and migration. Second, I will bred the S100A12 transgenic mice with atherosclerosis prone ApoE null mice and assess at various time points. I expect that S100A12 will accelerate the development of atherosclerosis and I will examine if S100A12 mediates these effects in a RAGE-dependent and in RAGEindependent manner. To test this hypothesis, the S100A12 mice will be bred with the RAGE null and RAGE/ApoE double null mice. These experiments will shed light into the mechanism of pro-inflammatory and pro-thrombotic actions of S100A12 and will provide information on whether these proteins may serve as an important cellular target for the development of new drugs to treat atherosclerosis. ? ? ? ?
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