The central theme of our PPG is that amphilpathic motifs (the amphipathic alpha helix and the amphipathic beta strand) are fundamental to an understanding of the cause and reversal of atherosclerosis. The major objective in the next five years is to develop a comprehensive theory of the interaction of amphipathic motifs with lipid and to use this knowledge: (a) to determine the minimal structural features of apolipoprotein A-I (HDL) that can reverse atherosclerosis, (b) to determine the minimal structural features of apolipoprotein B that are involved in the structure, function and biosynthesis of apo B-containing liporproteins. We have incorporated a multidisciplinary research strategy into our program that includes: 1) Design, synthesis and molecular biophysical studies of amphipathic peptide analogs, 2) computer modeling at both the molecular and the all atom level of the interactions of amphipathic motifs with lipids, 3) site-directed mutagenesis of apolipoproteins, expression in E. coli or in mammalian cells in culture and molecular biophysical and biological studies of the interactions of the mutated apolipoproteins with lipids and enzymes (collaboration between projects, and 4) expression of both mutated apolipoproteins and amphipathic alpha helical peptide analogs of apolipoproteins in transgenic mice models of atherosclerosis (including fat-sensitive mice and apo E knockout mice. Amphipathic motifs thus represent the fundamental paradigm guiding all four PPG projects. The four projects are: (Segresst), """"""""Rationally designed analogs of amphipathic alpha helixes"""""""", (Harvey), """"""""Molecular modeling of amphipathic motifs in lipids""""""""; (Dashti), """"""""Studies of amphipathic motifs in apolipoprotein B""""""""; (Anantharamaiah), """"""""Determinants of atherosclerosis prevention by apo A-I"""""""" core facilities are proposed to provide support for the four proposed projects. These are: an administrative core A, a peptide synthesis core B, an instrumentation and computer core C.
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