Modulators of HDL Structure-Function

HDL 结构-功能调节剂

基本信息

批准号：
7466153
负责人：
G M ANANTHARAMAIAH
金额：
$ 43.36万
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：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7466153
关键词：
Address Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antioxidants Apolipoproteins Apolipoproteins A Area Arterial Fatty Streak Arylesterase Atherosclerosis Biological Blood Circulation Cell Adhesion Molecules Cells Chemicals Cholesterol Cholesterol Esters Class Complex Cultured Cells Development Disease regression 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 high density lipoprotein-3 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 prep-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 preJBHDL 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 pre(3-HDL particles; and 2) enhanced receptor (SRB-1) interaction of a-HDL particles to clear cholesteryl ester, thus regenerating active pre(3-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定了高密度的动脉粥样硬化保护特性脂蛋白（HDL）。除了从外周血中提取胆固醇的主要抗动脉粥样硬化特性外， HDL 还具有抗炎和抗氧化特性。 HDL 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-模拟物肽可显着减少动脉粥样硬化敏感患者的动脉粥样硬化病变形成尽管胆固醇水平没有变化，但小鼠模型。我们假设这是通过形成 prep-HDL 样颗粒具有增强的 paroxonase-1 (PON1) 活性，能够破坏脂质氢过氧化物 (LOOH) 并增强胆固醇逆向转运，这是其主要的抗动脉粥样硬化特性载脂蛋白A-L。因此，抗动脉粥样硬化肽调节 HDL 的特性，使得促动脉粥样硬化 HDL 转化为抗动脉粥样硬化的高密度脂蛋白 (HDL)。我们提出了两种抗动脉粥样硬化形成的机制 a 和 preJBHDL 在抗动脉粥样硬化肽存在下：1) 增强与 ABCA1 的相互作用，形成只含有 apo A-l 的颗粒水平增加，前 (3-HDL) PON1 水平增加颗粒； 2) 增强α-HDL颗粒的受体(SRB-1)相互作用以清除胆固醇酯，从而再生活性前（3-HDL 颗粒）。我们假设抗动脉粥样硬化特性受以下因素控制肽（肽-脂质复合物）招募 apoA-l、LOOH 和 PON1 等酶的能力存在于HDL中。例如，如果 PON1 对这些颗粒没有活性，那么这种 HDL 就会产生炎症，因为它拥有LOOH。为了检验我们的假设，我们提出以下具体目标： 1a．肽的影响 HDL的组成结构。 1b.肽缔合的结构方面； 2a.抗动脉粥样硬化每个肽的潜力。 2b.测试选定肽的抗动脉粥样硬化特性动脉粥样硬化敏感小鼠模型。我们将使用物理、物理化学、体外细胞培养和动脉粥样硬化动物模型的体内研究，以表征肽介导的结构和功能 HDL 变化与抗动脉粥样硬化特性相关。这些研究将首次使我们能够了解肽调节的抗动脉粥样硬化 HDL 的详细结构以及 apoA-l-模拟肽的抗动脉粥样硬化和抗炎作用机制。此外，这些研究将导致设计具有增强抗动脉粥样硬化和抗炎作用的简单分子效力并可能导致改善动脉粥样硬化的新方法。