The central theme of this competitive renewal application for our PPG is based upon three hypotheses: (1) Apolipoprotein (apo) A-l-containing lipoproteins play a major role in atherogenesis;(2) apoB-containing lipoproteins play a major role in atherogenesis;and (3) the properties of the different apolipoprotein domains involved in the regulation of the functions of the apoA-l- and apoB-containing lipoproteins are determined to a major extent by the properties of the amphipathic motifs ubiquitous to apolipoproteins. From this we derive our central theme: Amphipathic motifs (the amphipathic a helix and the amphipathic (3 strand/sheet) are fundamental to a full understanding of the cause and reversal of atherosclerosis. Amphipathic motifs represent the fundamental paradigm guiding all proposed projects. The objectives in the next five years are to continue development of a comprehensive theory of the interaction of amphipathic motifs with lipid and to use this knowledge to: (a) determine the minimal structural features of apoA-l and HDL that are involved in both the assembly of apoA-l -containing lipoproteins and the structure, function and properties of HDL (b) determine the minimal structural features of apoB that are involved in both the biogenesis of apoB-containing lipoproteins and the structure, function and properties of LDL, and (c) apply this knowledge to understand mechanisms involved in prevention and reversal of atherosclerosis and potentially for the development of pharmacological agents. To accomplish these objectives, four projects are proposed: 1) Computational and experimental studies of structure/dynamics of HDL assemblies (Dr. Jere P. Segrest, Project Leader). 2) Molecular mechanisms of biogenesis of apolipoprotein B-containing lipoproteins (Dr. Nassrin Dashti, Project Leader). 3) Peptide modulators of HDL structure-function (Dr. G. M. Anantharamaiah, Project Leader). 4) Biology of apolipoprotein functional mimetics (Dr. David W. Garber, Project Leader). To support these projects, three core facilities are proposed: Core A: Administration and computation (Dr. Segrest), Core B: Peptide synthesis (Dr. Anantharamaiah), and Core C: Cell biology (Dr. Dashti). The proposed studies will contribute to the prevention and reversal of coronary heart disease through information leading to the development of better pharmaceutical agents.
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