This application represents a continuation of a Program Project whose overall goal is to elucidate the contributions of the cholesterol transport functions of high density lipoprotein (HDL) to the prevention of the development of atherosclerosis. The mechanisms by which HDL mediates reverse cholesterol transport (RCT), the process whereby cholesterol is removed from peripheral cells and transported to the liver for clearance from the body, will be investigated. Experiments will be conducted in a coordinated fashion at the molecular, cellular, whole animal and human levels. This Program Project consists of three closely related and interactive projects. Project 1 proposes to investigate using novel assays the effects of HDL quantity and quality on the net flux of cholesterol by different pathways between cells and serum, and the impact on cholesterol flux of the hydrolysis of cholesteryl est droplets in macrophage foam cells. Project 2 aims to understand human apolipoprotein (apo) A-l structure-function and the molecular mechanisms by which this protein binds lipids and creates HDL particles by interaction with the ATP-binding cassette transporter Al. Project 3 involves the use of in vivo methods to understand the molecular regulation of RCT. The mechanisms responsible for the effects of apoA-l mutations and plasma factors (lecithin-cholesterol acyltransferase, cholesteryl ester transfer protein, phospholipid transfer protein) on HDL metabolism and macrophage RCT will be evaluated in mice. New methods for the assessment of RCT in human will be used to examine the influence of HDL quantity and quality in this setting. 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, protein chemistry, animal physiology and medicine. The program is supported by three core laboratories: 1) Administrative/Central Service Core, 2) Tissue Culture Core and 3) Lipoprotein Core. The incidence of premature coronary artery disease is reduced in human populations with elevated levels of plasma HDL cholesterol. The reasons for this protective effect are not understood fully and this project seeks to uncover the molecular mechanisms underlying the beneficial properties of HDL.
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