DETERMINANTS OF ATHEROSCLEROSIS PROTECTION

University Of Alabama At Birmingham, Birmingham AL

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Linked publications & trials

Abstract

Recent developments provide strong support for the role of plasma lipoproteins in atherosclerotic plaque formation. The aim of this proposal is to study the minimal structural features of human apo A-I (HuA-I) that inhibit and/or reverse atherosclerosis. Using as a working hypothesis that the amphipathic helical motif is the predominant structural and functional domain in apo A-I, we have begun animal experiments using model amphipathic helical peptide analogs to define those minimal structural features. We have obtained exciting preliminary data indicating that peptide mimics of human apo A-I (HuA-I) inhibit diet-induced foam cell formation in mice, and spontaneous lesion formation that is known to take place in mice lacking the apo E gene. The present proposal will test this hypothesis further in peptide or mutant apo A-I transgenic and in apo E knockout mice via the following specific aims: 1. Studies of atherosclerosis protection by model amphipathic helical peptides. a. Intraperitoneal injection or transgenic expression in diet-sensitive mice that form lipid-rich foam cell lesions. b. Peptide intraperitoneal administration or expression of peptide transgenes in mice lacking the apo E gene will be done to study the ability of peptide to inhibit fibrous lesions. 2. Studies of site- directed mutants of human apolipoprotein A-I. a. Design and study of apo A-I mutants. b. Expression of well-characterized apo A-I mutants in transgenic mouse models.