High density lipoprotein (HDL) plays a major role in cholesterol homeostasis and atherosclerosis. Yet our understanding of its structure, interactions with HDL-associated proteins, and alterations in funcfion during atherosclerosis, remain pooriy understood. We propose to use a mulfidisciplinary approach to better understand how distinct structural elements of HDL facilitate specific biological functions in reverse cholesterol transport (ROT) and may become "dysfunctional" through site-specific oxidative modificafion within human atherosclerotic plaque. We have developed novel tools for structurally, functionally and clinically characterizing dysfuncfional forms of HDL and their involvement in human disease. We will employ these to achieve our overall major goals of: (i) defining HDL funcfion and site-specific oxidafive modificafions within human atherosclerofic plaque that adversely impact upon normal lipoprotein function; and (ii) exploring the clinical utility of quantifying specific "dysfuncfional" HDL forms in human clinical studies. We will achieve this with the following specific aims:
Aim 1) To define important structural elements crifical for nascent HDL particle interaction with LOAT and maturation into a cholesterol-ester laden spheroidal form, and to test the hypothesis that site-specific oxidative modificafions of apoAl Tyri 66, a known functional residue in the LOAT interaction site modified within human atherosclerotic plaque, generates both a "dysfunctional" form of HDL and identifies individuals at increased risk for atherosclerotic heart disease.
Aim 2) To discover the structural modification induced by MPO-catalyzed oxidation on apoAl of HDL that converts the particle into a pro-inflammatory form and to test the hypothesis that MPO-specific oxidative modification of HDL identifies individuals at increased risk for atherosclerofic heart disease. Oollecfively, the proposed studies represent an innovafive and multidisciplinary approach designed to elaborate key structural elements of HDL that support specific atheroprotecfive funcfions and how site specific oxidafive modifications to specific residues in vivo adversely impacts upon normal lipoprotein funcfion and generate distinct "dysfuncfional" HDL forms of potenfial clinical prognostic utility.
The proposed studies will provide new insights into how specific structural features of high density lipoprotein (HDL) contribute to its normal biological functions in reverse cholesterol transport. They also explore the role of structurally distinct site-specific oxidative modifications to apoAl of HDL in altered athero-protective functions of the lipoprotein in humans. The studies will help identify new diagnostic tests for heart disease risk prediction, and potential therapeutic targets for treatment and prevention of heart disease.
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