Biology of Apolipoprotein Functional Mimetics

已有研究表明，载脂蛋白A的几种两亲性螺旋肽模拟物对L有抑制作用 增强动脉粥样硬化，改善血管功能，减少炎症过程。它还表明， 联合应用多肽和他汀类药物可使已经存在的动脉粥样硬化病变消退。我们假设 这些多肽修饰高密度脂蛋白或募集磷脂和载脂蛋白A-L形成载脂蛋白A-1-β。 含有依次招募抗动脉粥样硬化酶的颗粒，如对氧磷酶-1(PON-1)和/或 血小板活化因子乙酰水解酶(PAF-AH)。我们打算确定多肽是否具有抗动脉粥样硬化作用 在没有载脂蛋白A-L或PON-1的情况下的性质。我们假设模拟肽的作用方式是 招募载脂蛋白A-L为新的、更具生物活性的颗粒，或通过修改载脂蛋白A-L的结构使其更具生物活性 生物活性。这可能允许它招募和/或激活PON-1，导致导致动脉粥样硬化的氧化减少 脂类。我们将研究三个肽：4F，它具有很强的动脉粥样硬化保护作用；3F14，它还没有观察到 抗动脉粥样硬化特性；以及在体外抗动脉粥样硬化特性中居中的多肽2F。 这些多肽的不同之处仅在于疏水表面上的苯丙氨酸残基数量。以下是 提出了具体目标：具体目标1：载脂蛋白A-L在多肽功能中的作用。假设是 检测到载脂蛋白A-L是模拟多肽功能所必需的，a：我们将研究多肽对载脂蛋白A的影响 A-L的合成和分泌，b：我们将使用动脉粥样硬化易感小鼠，或者表达野生型载脂蛋白 A-L或ApoA-L为空。我们将研究载脂蛋白A-L对肽介导功能的需求。具体目标2： PON-1在多肽功能中的作用。要检验的假设是PON-1是模拟所必需的 肽功能，a：多肽介导的PON-1水平和活性的变化将被确定，b：使用 动脉粥样硬化易感小鼠表达PON-1或PON-1缺失，抗炎特性 将对多肽进行研究。 高密度脂蛋白被认为对动脉粥样硬化性心脏病具有保护作用。我们正在研究主要的蛋白质 在高密度脂蛋白中，载脂蛋白A-L使用称为多肽的小分子来模仿载脂蛋白A-L的性质。这些研究将 使用易患动脉粥样硬化的小鼠模型进行实验。目标是更好地理解 载脂蛋白A-L和高密度脂蛋白的保护作用，以及开发提高这些保护性能的方法。

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; 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.