Biology of Apolipoprotein Functional Mimetics

已经显示，载脂蛋白（apo）A-I的几种两亲性螺旋肽模拟物抑制动脉粥样硬化，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施用使已经存在的动脉粥样硬化病变消退。我们假设这些肽修饰高密度脂蛋白（HDL）或募集磷脂和载脂蛋白A-I以形成含载脂蛋白A1的颗粒，所述颗粒继而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）。我们打算确定在不存在载脂蛋白A-1或PON-1的情况下肽是否具有抗动脉粥样硬化性质。我们假设模拟肽通过将载脂蛋白A-1募集到新的、更具生物活性的颗粒中，或者通过修饰载脂蛋白A-1的结构使其更具生物活性来起作用。这可能允许它募集和/或激活PON-1，导致致动脉粥样硬化的氧化脂质减少。我们将研究三种肽：4F，其具有强烈的动脉粥样硬化保护作用; 3F[14]，其没有观察到的动脉粥样硬化保护特性;和肽2F，其在体外动脉粥样硬化保护特性中是中间的。 这些肽的不同之处仅在于疏水表面上的苯丙氨酸残基的数量。具体目标1：apo A-I在肽功能中的作用。要检验的假设是apo A-1是模拟肽功能所必需的。a：我们将研究肽对apo A-1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-1或apo A-1无效。我们将研究apo A-I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。待检验的假设是PON-1是模拟肽功能所必需的。a：将测定PON-1水平和活性的肽介导的变化，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的肽的抗炎性质。 HDL被认为是预防动脉粥样硬化性心脏病的保护性物质。我们正在研究高密度脂蛋白的主要蛋白，载脂蛋白A-1，使用称为肽的小分子来模拟载脂蛋白A-1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。目的是更好地了解载脂蛋白A-I和HDL是如何保护的，并开发改善这些保护特性的方法。

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.