Atherogenesis is believed to consist of an intricate series of interrelated events in which blood-borne and cell-derived factors interact with arterial tissue to produce the characteristic pathologic alterations found in atherosclerosis. A central hypothesis that constitutes a major theme of this continuing program is that oxidative processes play a critical role in the changes in vascular cell function that occur during plaque development. The long-term objective of this Program is to elucidate the molecular mechanisms that lead to oxidative reactions in the vessel wall and to define the intracellular pathways and functions that are altered in endothelial cells (EC), smooth muscle cells (SMC), and monocyte/macrophages in response to changes in the cellular milieu, e.g., by oxidized lipids and lipoproteins and by pathophysiological proteins, such as ceruloplasmin and thrombin. Our objective will be approached through four highly focused, but well-integrated, projects. The first project focuses on the underlying mechanisms of both injury to, and proliferation of vascular cells in response to specific lipids of oxidized LDL. Antioxidant blockade of these phenomena will be studied in vitro and in vivo. The antioxidant theme will carry forward into in which the regulation of expression of selenoperoxidases, potent antioxidant enzymes, will be pursued on a molecular level. In a series of mechanistic in vitro and in vivo studied are proposed to address the role of ceruloplasmin in promoting the pro-oxidant state derived growth factor (PDGF) will be studied. The mechanism of induction of PDGF by both thrombin and lysophosphatidylcholine will be pursued. All of the proposed projects represent ongoing studied, and many of the proposed aims represent existing collaborative efforts among investigators of the program project which have developed during the first fourteen years of support. Two continuing scientific cores, Lipoprotein and Cell Culture are proposed to provide multi-project support, expertise and services in a cost-effective manner.
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