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：
7466188
负责人：
DAVID W GARBER
金额：
$ 27.86万
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/7466188
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 Ester Transfer Proteins Cholesterol Esters Class Clear Cell Coculture Techniques Coronary heart disease Diet Disease Disease regression Endothelial Cells Enzymes Excretory function Exhibits Face Heart Diseases Helix (Snails)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 Numbers 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 ear helix high density lipoprotein-3 human CETP protein 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; 3F14, 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-L抑制的几种两性两亲性螺旋肽模拟物动脉粥样硬化，改善血管功能并减少炎症过程。也已经表明肽与他汀类药物的共同给药会回归已经存在的动脉粥样硬化病变。我们假设这些肽会改变高密度脂蛋白（HDL）或募集磷脂和Apo A-L以形成Apo al- 含有颗粒，这些颗粒反过血小板激活因子乙酰水合酶（PAF-AH）。我们打算确定肽是否患有抗脉管硬化在没有APO A-L或PON-1的情况下的性质。我们假设模拟肽通过将APO A-L招募到新的，更多的生物活性颗粒中，或通过修改APO A-L的结构，以使其更多生物活性。这可以使其募集和/或激活PON-1，从而降低动脉粥样硬化的氧化。脂质。我们将研究三种肽：4F，这是强烈的动脉保护性； 3f14，没有观察到动脉保护特性；和肽2F，其体外动脉保护特性中间。这些肽仅在疏水面上的苯丙氨酸残基数量上有所不同。下列提出了具体目的：具体目标1：APO A-L在肽功能中的作用。假设是测试是APO A-L是模拟肽功能所必需的，A：我们将研究肽对APO的影响 A-L合成和分泌，B：我们将使用动脉粥样硬化敏感的小鼠，要么表达野生型Apo A-L或APO A-L NULL。我们将研究APO A-L对肽介导的功能的需求。具体目标2： PON-1在肽功能中的作用。要检验的假设是模拟物需要PON-1 肽功能，A：将确定肽介导的PON-1水平和活性的变化，B：使用表达PON-1或PON-1 NULL的动脉粥样硬化小鼠，抗炎特性将研究肽。 HDL被认为是针对动脉粥样硬化心脏病的保护性。我们正在研究主要蛋白质使用称为肽的小分子模仿Apo A-L的特性。这些研究会使用易受动脉粥样硬化的小鼠模型完成。目的是更好地理解 APO A-L和HDL如何保护性，并开发改善这些保护性能的方法。