Biology of Apolipoprotein Functional Mimetics

载脂蛋白功能模拟物的生物学

基本信息

批准号：
8242748
负责人：
DAVID W GARBER
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/8242748
关键词：
Acyltransferase Animal Model Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Apolipoprotein E Apolipoproteins Apolipoproteins A Arterial Fatty Streak Atherosclerosis Binding Biological Biology Blood Vessels Cells Cholesterol Cholesterol Esters Clear Cell Coculture Techniques Coronary heart disease Diet Disease Endothelial Cells Enzymes Excretory function Exhibits Face Heart Diseases Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Human In Vitro Infiltration Inflammatory Integral Membrane Protein Knockout Mice Lecithin Lesion Lipid Peroxides Lipids Lipoproteins Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Methods Modeling Monkeys Mus Paraoxonase 1 Patients Peptides Peripheral Phenylalanine Phosphatidylcholine-Sterol O-Acyltransferase Phospholipids Plasma Platelet Activating Factor Process Production Property Proteins Recruitment Activity Role SR-BI receptor Smooth Muscle Structure Testing Thick Transgenic Mice Transport Process Vesicle activator 1 protein atherogenesis atheroprotective high density lipoprotein-3 improved inhibitor/antagonist low density lipoprotein inhibitor mimetics monocyte mouse model oxidized lipid particle peptide analog physical property prevent protective effect reverse cholesterol transport small molecule

项目摘要

It has been shown that several amphipathic helical peptide mimetics of apolipoprotein (apo) A-l inhibit atherosclerosis, improve vascular function, and reduce inflammatory processes. It has also been shown that co-administration of peptide with statin regresses already-existing atherosclerotic lesions. We hypothesize that these peptides modify high density lipoprotein (HDL) or recruit phospholipids and apo A-l to form apo Al- containing particles which in turn recruit antiatherogenic enzymes such as paraoxonase-1 (PON-1) and/or platelet activating-factor acetylhydrolase (PAF-AH). We intend to determine if peptides have antiatherosclerotic properties in the absence of apo A-l or PON-1. We hypothesize that mimetic peptides act by recruiting apo A-l into new, more bioactive particles, or by modifying the structure of apo A-l so that it is more bioactive. This may allow it to recruit and/or activate PON-1, resulting in a reduction of atherogenic oxidized lipids. We will study three peptides: 4F, which is strongly atheroprotective; 3F[14], which has no observed atheroprotective properties; and peptide 2F, which is intermediate in its in vitro atheroprotective properties. These peptides differ only in the number of phenylalanine residues on the hydrophobic face. The following specific aims are proposed: Specific Aim 1: The role of apo A-l in peptide function. The hypothesis to be tested is that apo A-l is required for mimetic peptide function, a: We will study the effect of peptides on apo A-l synthesis and secretion, b: We will use atherosclerosis-susceptible mice, either expressing wild-type apo A-l or apo A-l null. We will study the requirement of apo A-l for peptide-mediated functions. Specific Aim 2: The role of PON-1 in peptide function. The hypothesis to be tested is that PON-1 is required for mimetic peptide function, a: Peptide-mediated changes in PON-1 levels and activity will be determined, b: Using atherosclerosis-susceptible mice expressing PON-1 or PON-1 null, anti-inflammatory properties of the peptides will be studied. HDL is considered to be protective against atherosclerotic heart disease. We are studying the major protein of HDL, apo A-l, using small molecules called peptides to mimic the properties of apo A-l. These studies will be done using mouse models that are susceptible to atherosclerosis. The objective is to better understand how apo A-l and HDL are protective, and to develop methods to improve those protective properties.

已经表明，载脂蛋白（apo）A-1的几种两亲性螺旋肽模拟物可抑制动脉粥样硬化、改善血管功能并减少炎症过程。研究还表明，肽与他汀类药物联合给药可以消退已经存在的动脉粥样硬化病变。我们假设这些肽修饰高密度脂蛋白 (HDL) 或募集磷脂和 apo A-1 以形成含 apo A1 的颗粒，这些颗粒反过来又募集抗动脉粥样硬化酶，如对氧磷酶-1 (PON-1) 和/或血小板活化因子乙酰水解酶。 PAF-AH）。我们打算确定在缺乏 apo A-1 或 PON-1 的情况下肽是否具有抗动脉粥样硬化特性。我们假设模拟肽通过将apo A-1募集到新的、更具生物活性的颗粒中，或者通过修改apo A-1的结构以使其更具生物活性来发挥作用。这可能使其募集和/或激活 PON-1，从而减少导致动脉粥样硬化的氧化脂质。我们将研究三种肽：4F，具有很强的动脉粥样硬化保护作用； 3F[14]，没有观察到动脉粥样硬化特性；肽2F，其体外动脉粥样硬化保护特性处于中等水平。这些肽的区别仅在于疏水面上苯丙氨酸残基的数量。提出以下具体目标：具体目标 1：apo A-1 在肽功能中的作用。要测试的假设是apo A-l是模拟肽功能所必需的，a：我们将研究肽对apo A-l合成和分泌的影响，b：我们将使用动脉粥样硬化易感小鼠，表达野生型apo A-l或apo A-l 无效。我们将研究 apo A-1 对肽介导功能的需求。具体目标 2：PON-1 在肽功能中的作用。要测试的假设是模拟肽功能需要 PON-1，a：将确定肽介导的 PON-1 水平和活性变化，b：使用将研究表达PON-1或PON-1无效的动脉粥样硬化易感小鼠，肽的抗炎特性。高密度脂蛋白被认为可以预防动脉粥样硬化性心脏病。我们正在研究 HDL 的主要蛋白质 apo A-l，使用称为肽的小分子来模拟 apo A-l 的特性。这些研究将使用易患动脉粥样硬化的小鼠模型进行。目的是更好地了解 apo A-1 和 HDL 如何发挥保护作用，并开发改善这些保护特性的方法。