This application represents a continuation of a Program Project whose overall theme is the metabolism of lipids, cholesterol and lipoproteins as related to the development of atherosclerosis. The interactions of lipoproteins with cells and the subsequent metabolism of lipids within cells will be investigated. The basic information that will be gained is particularly relevant to understanding the protective action of high density lipoprotein (HDL) against premature coronary artery disease and the progression and regression of atherosclerotic plaque. This Program Project consists of three closely related projects: The first proposes to study the intracellular and extracellular mechanism by which cellular cholesterol homeostasis is maintained. Emphasis is placed on defining intracellular pools of cholesterol and the roles of plasma constituents in mediating cell cholesterol efflux. The second project involves a study of the functions of apolipoprotein A-I in mediating cholesterol transport at cell surfaces. The molecular mechanisms by which apo A-I removes and delivers cholesterol, cholesteryl ester and phospholipid from and to cell plasma membranes will be investigated. The last project focuses on the metabolism of cholesterol in model foam cells. Emphasis is placed on the structure of cholesteryl ester cytoplasmic droplets, characterization of the enzymes involved in their metabolism, and the consequences for macrophages of over-accumulation of unesterified cholesterol. The group of investigators comprising this Program Project share similar interests and goals in lipid and lipoprotein metabolism while providing broad scientific expertise. The scientific disciplines encompassed by these investigators include biochemistry, cell biology, molecular biology and physical biochemistry. The three scientific projects are supported by core laboratories: 1) Administrative/Central Service Core, 2) Tissue Culture Core and 3) Lipoprotein Core.
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