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.
| White, C Roger; Giordano, Samantha; Anantharamaiah, G M (2016) High-density lipoprotein, mitochondrial dysfunction and cell survival mechanisms. Chem Phys Lipids 199:161-169 |
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| White, C Roger; Goldberg, Dennis I; Anantharamaiah, G M (2015) Recent developments in modulating atherogenic lipoproteins. Curr Opin Lipidol 26:369-75 |
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| Guo, Lilu; Chen, Zhongyi; Amarnath, Venkataraman et al. (2015) Isolevuglandin-type lipid aldehydes induce the inflammatory response of macrophages by modifying phosphatidylethanolamines and activating the receptor for advanced glycation endproducts. Antioxid Redox Signal 22:1633-45 |
| Segrest, Jere P; Jones, Martin K; Catte, Andrea et al. (2015) Surface Density-Induced Pleating of a Lipid Monolayer Drives Nascent High-Density Lipoprotein Assembly. Structure 23:1214-26 |
| Sharifov, Oleg F; Nayyar, Gaurav; Ternovoy, Vladimir V et al. (2014) Comparison of anti-endotoxin activity of apoE and apoA mimetic derivatives of a model amphipathic peptide 18A. Innate Immun 20:867-80 |
| Reddy, Srinivasa T; Navab, Mohamad; Anantharamaiah, Gattadahalli M et al. (2014) Apolipoprotein A-I mimetics. Curr Opin Lipidol 25:304-8 |
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