Atherogenesis is 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. The central hypothesis of this continuing program is that oxidative and inflammatory processes play a critical role in altering vascular cell function during plaque development. The long-term objectives of this program are to: a) elucidate the molecular mechanisms that lead to oxidative reactions in the vessel wall; b) understand the transcriptional and translational mechanisms that regulate gene expression in vascular cells; and c) define the intracellular pathways and functions that are altered in vascular cells in response to changes in the cellular milieu, e.g., oxidized lipids and lipoproteins, and to pathophysiological proteins, such as ceruloplasmin, interferon, and thrombin. Our objectives will be approached through four highly focused, but well-integrated, projects. The first project focuses on the mechanism of cell death in vascular cells exposed to oxysterols, and how cell death affects arterial lesion progression. Project 1 will also define the role of the selenoenzyme phospholipid hydroperoxide glutathione peroxidase in protecting vascular cells from apoptosis. Project 1 is thematically linked to Project 2, which will investigate the mechanism and regulation of selenoenzyme synthesis. The goal of Project 2 is to understand how selenocysteine, the 21st amino acid, is inserted into selenoenzymes during translation. Translational control is also a focus of Project 3, which proposes to elucidate the regulation of macrophage-derived ceruloplasmin by the inflammatory cytokine, interferon-gamma. The role of ceruloplasmin in arterial lesion progression will be defined. The theme of inflammation continues in Project 4, which will identify and characterize the pathways that regulate thrombin-induced expression of platelet-derived growth factor by the endothelium. All of the proposed projects are ongoing studies, and many of the proposed aims represent existing collaborative efforts among investigators of the program project, which developed during the first 19 years of support. Two scientific cores (Cell Culture and Lipoprotein/Atherosclerosis) and an Administrative Core will provide multiproject support, expertise and service in a cost-effective manner, which significantly strengthens each investigator's research effort.
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