Biology of Apolipoprotein Functional Mimetics

研究表明，几种载脂蛋白（apo） A-l的两亲性螺旋肽模拟物可抑制动脉粥样硬化，改善血管功能，减少炎症过程。也有研究表明，肽与他汀类药物联合使用可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）或招募磷脂和载脂蛋白a -1形成含载脂蛋白a -1的颗粒，这些颗粒反过来招募抗动脉粥样硬化酶，如对氧磷酶-1 （PON-1）和/或血小板活化因子乙酰水解酶（PAF-AH）。我们打算确定在没有载脂蛋白a -1或PON-1的情况下，肽是否具有抗动脉粥样硬化特性。我们假设模拟肽的作用是通过将载脂蛋白a - 1招募到新的，更具生物活性的颗粒中，或者通过修改载脂蛋白a - 1的结构使其更具生物活性。这可能允许它招募和/或激活PON-1，导致致动脉粥样硬化氧化脂质的减少。我们将研究三种肽：4F，它具有强烈的动脉粥样硬化保护作用；3f[14]，没有观察到的动脉粥样硬化保护特性；和肽2F，这是其体外动脉粥样硬化保护特性的中间产物。这些肽的不同之处在于疏水性表面上苯丙氨酸残基的数量。提出以下具体目标：具体目标1：载脂蛋白a - 1在肽功能中的作用。要验证的假设是载脂蛋白a - 1是模拟肽功能所必需的，a：我们将研究肽对载脂蛋白a - 1合成和分泌的影响，b：我们将使用表达野生型载脂蛋白a - 1或载脂蛋白a - 1缺失的动脉粥样硬化易感小鼠。我们将研究载脂蛋白a - 1对肽介导功能的需求。特异性目的2:PON-1在肽功能中的作用。要检验的假设是PON-1是模拟肽功能所必需的，a：肽介导的PON-1水平和活性的变化将被确定，b：使用

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.