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 alpha helix and the amphipathic beta 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-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 are proposed: 1) Structure-function of apoA-Icontaining lipoproteins (Dr. Jere P. Segrest, Project Leader). 2) Structure and assembly of apoBcontaining lipoproteins (Dr. Nassrin Dashti, Project Leader). 3) Antiatherogenic amphipathic peptides: Structure-function (Dr. G. M. Anantharamiah, Project Leader). 4) Apolipoproteins and functional mimics: in vivo studies (Dr. David W. Garber, Project Leader). To support these projects, three core facilities are proposed: Core A: Administration, Computer and Instrumentation (Dr. Segrest), Core B: Peptide Synthesis and Protein Purification (Dr. Anantharamaiah), and Core C: Molecular Biology (Dr. Ling Li).
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