HIGH DENSITY LIPOPROTEIN STRUCTURE-FUNCTION CORRELATIONS

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The ultimate goal of this research is to elucidate the structure-function relationships in human high density lipoproteins (HDL), as they relate to the cholesterol transport role of this lipoprotein and to its protective effect against cardiovascular disease. The specific aims of this project are to prepare synthetic, chemically defined models of the various types of HDL (discoidal nascent HDL, and spherical HDL subclasses of different sizes) and to investigate in detail the structure and stability of the major apolipoprotein of HDL (apo A-I) in these reconstituted particles, as well as the physical properties of the surface and core lipid components. The structural information on these synthetic HDL particles will then be correlated with their activity as substrates for lecithin cholesterol acyltransferase and with their effectiveness as acceptors for cholesterol and phospholipids. The cholesterol acceptor role of HDL will be investigated further by examining the kinetics of transfer and equilibrium distribution of radiolabeled cholesterol between donor particles (very low, low density lipoproteins, and erythrocyte membranes) and various recombinant HDL, with defined chemical and physical properties. These studies will employ diverse biophysical and biochemical methods, including circular dichroism, fluorescence spectroscopy, electron microscopy, analytical ultracentrifugation, differential scanning calorimetry, gradient gel electrophoresis, chromatographic methods, and immunological techniques.