The central theme of this competitive renewal application for our PPG is based upon three hypotheses: (1) Apolipoprotein (apo) A-I-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-I- 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 amphip- athic P strand/sheet) are fundamentalto a full understandingof the cause and reversal of atherosclerosis. Amphipathic motifs represent the fundamental paradigm guiding all proposed projects. The objectives in the nextfive years are to continuedevelopment of a comprehensive theory of the interaction of amphipathic motifs with lipid and to use this knowledge to: (a) determine the ininirnal structural featuresof apoA-I and apoE that can prevent and/or reverse atherosclerosis, (b) determine the minimal structural features of apoB that are involved in both the biosynthesis 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 areproposed: 1)Structure-function ofopoA-I-contoining lipoproteins (Dr. Jere P. Segrest, Project Leader). 2) Structure and assembly of apoB-containing lipoproteins (Dr. Nassrin Dashti, Project Leader). 3) Antiatherogenic amphipathic peptides: Structure-function (Dr. G. M. Anantharamiah, Project Leader). 4)Apolipoproteins andfunctional mimics:in vivo studies (Dr. David W. Garber, Project Leader). Tosupport these projects, three core faculties areproposed: CoreA:Administra- tion, Computer and Instrumentation (Dr. Segrest), Core B: Peptide Synthesis and Protein Purification (Dr. Anantharamaiah), and Core C: MolecularBiology (Dr. Ling Li).
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