Modulators of HDL structure-function

HDL结构-功能调节剂

基本信息

批准号：
7298870
负责人：
G M ANANTHARAMAIAH
金额：
$ 36.25万
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：
2007
资助国家：
美国
起止时间：
2007-08-07 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7298870
关键词：
Address Adhesions Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antioxidants Apolipoproteins Apolipoproteins A Apolipoproteins B 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 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

DESCRIPTION (provided by applicant): 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. This occurs via the formation of preD-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 D and preDHDL 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 preD-HDL particles; and 2) enhanced receptor (SRB-1) interaction of D-HDL particles to clear cholesteryl ester, thus regenerating active preD-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 chemical, in vitro cell culture and in vivo studies in animal models of atherosclerosis to characterize the structure and function of peptide-mediated 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.

描述（由申请人提供）：许多种群和动物研究已经建立了高密度脂蛋白（HDL）的动脉保护特性。除了其从外围细胞中提取胆固醇并将其转移到肝脏以进行排泄（反向胆固醇转运，RCT）外，HDL还具有抗炎和抗氧化剂的特性。 HDL治疗领域的新兴区域是载脂蛋白模拟肽的发展。我们已经表明，尽管胆固醇水平没有变化，但口服施用的ApoA-L-Mimimity肽在动脉粥样硬化敏感的小鼠模型中导致动脉粥样硬化病变的形成显着降低。这是通过形成pED-HDL样颗粒的形成，具有增加的甲氧基酶-1（PON1）活性，能够破坏脂质氢过氧化物（LOOH）并增强反向胆固醇转运，这是ApoA-L的主要抗动脉粥样硬化特性。因此，抗皮质肽调节了HDL的特性，使促动脉植物HDL转化为抗动脉粥样硬化HDL。我们提出了两种在存在抗皮疗法肽的情况下形成抗皮疗形成D和PERDHDL的两种机制：1）增强与ABCA1的相互作用以形成增加的APO A-L水平，仅含有颗粒的POR1 pON1水平增加，而PON1 pON1的PERD-HDL颗粒水平增加； 2）D-HDL颗粒增强的受体（SRB-1）相互作用以清除胆固醇酯，从而再生活性的PERD-HDL颗粒。我们假设抗动力性特性受肽（肽脂复合物）募集ApoA-L，LooH和酶（例如HDL中存在的PON1）的能力。例如，如果PON1在这些颗粒上不活跃，则该HDL具有炎症性，因为它具有Looh。为了检验我们的假设，我们提出了以下特定目的：1a肽结构对HDL的组成的影响。 1b肽关联的结构方面； 2a。每种肽的抗透明剂潜能。 2b在动脉粥样硬化敏感小鼠模型中对选定肽的抗透明剂特性进行了测试。我们将在动脉粥样硬化的动物模型中使用物理化学，体外细胞培养和体内研究，以表征与抗染色性特性相关的肽介导的HDL变化的结构和功能。这些研究将首次使我们能够理解肽调节的抗动脉粥样硬化HDL的详细结构方面，以及ApoA-L-Mimity肽的抗皮疗法和抗炎作用的机制。此外，这些研究将导致抗动脉粥样硬化和抗炎效力增加的简单分子的设计，并有可能导致新型的方式改善动脉粥样硬化。