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Modulators of HDL Structure-Function

HDL 结构-功能调节剂

基本信息

批准号：
8242747
负责人：
G M ANANTHARAMAIAH
金额：
$ 23.96万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242747
关键词：
Address Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antioxidants Apolipoprotein A-I Apolipoproteins Apolipoproteins A Apolipoproteins B Area Arterial Fatty Streak Arylesterase Atherosclerosis Biological Blood Circulation Cell Adhesion Molecules Cell Culture Techniques Cells Chemicals Cholesterol Cholesterol Esters Complex Development Endothelial Cells Enzymes Excision Excretory function Face High Density Lipoprotein therapy High Density Lipoproteins Human Hydrolase In Vitro Inflammatory Infusion procedures Lead Lesion Lipid Peroxides Lipids Lipoproteins Liver Low-Density Lipoproteins Magic Mediating Membrane Methods Modality Molecular Molecular Weight Natural regeneration Peptides Peripheral Phosphatidylcholine-Sterol O-Acyltransferase Plasma Platelet Activating Factor Population Positioning Attribute Production Property Recruitment Activity Resolution Sampling Solutions Structure Testing Time Umbilical vein animal population study atheroprotective base cytokine design in vivo macrophage membrane model mimetics monocyte mouse model novel oxidized lipid particle peptide analog peptide structure receptor reconstitution research study reverse cholesterol transport

项目摘要

Numerous population and animal studies have established the atheroprotective properties of high density lipoproteins (HDL). In addition to its main antiatherogenic property of extracting cholesterol from peripheral cells and transferring it to the liver for excretion (reverse cholesterol transport, RCT), HDL also possesses anti-inflammatory and antioxidant properties. An emerging area in the field of HDL therapy is the development of apolipoprotein mimetic peptides. We have shown that orally administered apoA-l-mimetic peptides result in a dramatic reduction in the atherosclerotic lesion formation in atherosclerosis-sensitive mouse models despite no change in cholesterol levels. We hypothesize that this occurs via the formation of preB-HDL-like particles that possess increased paroxonase-1 (PON1) activity which are able to destroy lipid hydroperoxides (LOOH) and enhance reverse cholesterol transport, the major antiatherogenic properties of apoA-l. Thus antiatherogenic peptides modulate the properties of HDL such that proatherogenic HDL is converted into antiatherogenic HDL. We propose two mechanisms for the formation of both antiatherogenic a and preBHDL in the presence of antiatherogenic peptides: 1) enhanced interaction with ABCA1 to form increased levels of apo A-l-only containing particle with increased amounts of PON1 levels of preB-HDL particles; and 2) enhanced receptor (SRB-1) interaction of a-HDL particles to clear cholesteryl ester, thus regenerating active preB-HDL particles. We hypothesize that the antiatherogenic properties are governed by the ability of the peptide (peptide-lipid complexes) to recruit apoA-l, LOOH, and enzymes such as PON1 present in HDL. If, for example, PON1 is not active on these particles, this HDL is inflammatory since it possesses LOOH. To test our hypothesis we propose the following specific aims: 1a. Influence of peptide structure on the composition of HDL. 1b. Structural aspects of peptide association; 2a. Antiatherogenic potential of each peptide. 2b. Testing of selected peptides for their antiatherogenic properties in atherosclerosis sensitive mouse models. We will use physical, physico-chemical, in vitro cell culture and in vivo studies in animal models of atherosclerosis to characterize the structure and function of peptidemediated HDL changes that are related to antiatherogenic properties. These studies will for the first time enable us to understand the detailed structural aspects of peptide-modulated antiatherogenic HDL and the mechanism of antiatherogenic and anti-inflammatory actions of apoA-l-mimetic peptides. Furthermore, these studies will lead to the design of simple molecules with increased antiatherogenic and anti-inflammatory potencies and potentially lead to novel modalities to ameliorate atherosclerosis.

大量的人群和动物研究已经确立了高密度脂蛋白（HDL）的动脉粥样硬化保护特性。除了其主要的抗动脉粥样硬化特性，即从外周细胞中提取胆固醇并将其转移到肝脏排泄（逆向胆固醇转运，RCT）外，HDL还具有抗炎和抗氧化特性。高密度脂蛋白治疗领域的一个新兴领域是载脂蛋白模拟肽的开发。我们已经证明口服apoa -l模拟物