NATIONAL RESEARCH AND DEMONSTRATION CTR. - ARTERIOSCLERO

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The program proposed in this application for a Specialized Center of Research in Atherosclerosis represents a multi-faceted approach to the study of lipoprotein structure and metabolism. The overall objective of this program is to elucidate on a molecular level how lipids are secreted as lipoproteins, how the lipid and apoprotein components of these lipoproteins are organized within the particle, how this organization is altered both passively and actively during metabolism, how lipoproteins interact with cells and regulate their function, and how lipids ultimately accumulate in these cells producing blood vessel disease. In this comprehensive program, specific projects will be directed toward the elucidation of the amino acid sequence of apolipoprotein E and of the nucleic acid sequence of its messenger RNA, determination of the structural features of apolipoproteins which confer lipid-binding properties and enhance the activity of lecithin:cholesterol acyltransferase, understanding the kinetics and thermodynamics of lipid and apolipoprotein exchange and transfer, elucidating the structural alterations which attend metabolic maturation of nascent to mature high density lipoproteins, determination of the metabolic interrelationships existing among the different high density lipoprotein populations, measuring the rate of cellular uptake of lipids in low density lipoproteins, and elucidating the underlying cause of the abnormal cellular metabolism of hypertriglyceridemic very low density lipoproteins. Execution of the proposed studies will require a wide range of physical (e.g. magnetic resonance, light and electron microscopy, fluorescence, circular dichroism, calorimetry, zonal ultracentrifugation), chemical (protein sequencing, peptide synthesis, lipid synthesis), and biological (cell culture) techniques. These research activities will be integrated by an Administrative Core and will be supported by a Data Processing and Instrument Development Core, a Lipoprotein Isolation and analytical Services Core, and an Apoprotein Isolation and Quantitation Core. The proposed program is expected to provide new and significant basic information that will lead to a clearer understanding of the structure and metabolism of plasma lipoproteins and their role in the pathogenesis of atherosclerosis.