Apolipoproteins and functional mimics: in vivo studies

载脂蛋白和功能模拟物：体内研究

• 批准号: 6630718
• 负责人: DAVID W GARBER
• 金额: $ 27万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630718
• 关键词: amphiphilicity; antiatherogenic agent; apolipoproteins; atherosclerosis; blood lipoprotein metabolism; chemoprevention; clearance rate; genetically modified animals; human tissue; laboratory mouse; lipid transport; liver metabolism; peptide analog; protein structure function; site directed mutagenesis

DESCRIPTION (provided by applicant): Human apolipoprotein (apo) A-I and apo E-3 possess different anti-atherogenic properties. Naturally-occurring mutants of apo A-I differ in their metabolism. Apo A-I mutants have been designed to elucidate the structure of apo A-I in phospholipid complexes, and we will determine the metabolism of these mutants and their effects on atherogenesis. Peptide mimics of apo A-I possess anti-atherogenic properties in vitro. We have shown that class A amphipathic helical peptide analogs inhibit atherosclerosis when injected into C57BL/6J mice fed an atherogenic diet, and orally administered all-D-residue peptide analogs inhibit atherosclerosis in LDL-receptor deficient (LDL-R null) mice on a Western diet. This project will investigate the in vivo effects of amphipathic helical peptide analogs possessing specific in vitro-determined anti-atherogenic properties. We will determine which specific properties (such as LCAT activation, cholesterol efflux, or protection from the effects of oxidation) are required for atherosclerosis inhibition in atherosclerosis-susceptible mice. Peptide analogs possessing a cationic domain analogous to those of apo E are able to lower plasma cholesterol rapidly in vivo. We have evidence that these peptide analogs clear atherogenic lipoproteins by a proteoglycan-mediated rapid uptake of peptide-lipoprotein complexes. We will test the hypothesis that incorporation of positively charged residues onto atherogenic lipoproteins will result in a rapid hepatic clearance of atherogenic lipoproteins in dyslipidemic mice, resulting in inhibition of atherosclerosis. Our current working hypothesis is that in vivo, two general mechanisms for atherosclerosis protection, reduction in atherosclerosis without changing levels of atherogenic lipoproteins, and reduction in atherogenic lipoproteins and atherosclerosis itself, can be achieved by altering surface properties of atherogenic lipoproteins. To study this concept, we propose a two-arm approach demonstrating: 1: the in vivo determinants of atherosclerosis protection by class A amphipathic peptides or apo A-I mutants that do not alter levels of atherogenic lipoproteins; and 2: the in vivo effects of administration of cationic amphipathic helical peptides that reduce plasma levels of atherogenic lipoproteins.

描述(由申请人提供)： 人载脂蛋白A-I和载脂蛋白E-3具有不同的抗动脉粥样硬化作用。 自然产生的载脂蛋白A-I突变体的新陈代谢不同。载脂蛋白A-I突变体 旨在阐明磷脂复合体中载脂蛋白A-I的结构，我们将 确定这些突变体的新陈代谢及其对动脉粥样硬化形成的影响。多肽模拟物 载脂蛋白A-I在体外具有抗动脉粥样硬化的作用。我们已经证明了A类 C57BL/6J小鼠注射两亲性螺旋肽类似物抑制动脉粥样硬化 喂食致动脉粥样硬化饮食，口服全D-残基多肽类似物抑制 西方饮食中低密度脂蛋白受体缺陷(低密度脂蛋白受体缺失)小鼠的动脉硬化。这个项目将 研究具有特异性In的两亲性螺旋肽类似物的体内效应 体外测定的抗动脉粥样硬化特性。我们将确定哪些特定属性(如 如LCAT激活、胆固醇外流或保护免受氧化影响)是必需的 用于抑制动脉粥样硬化易感小鼠的动脉粥样硬化。具有A的多肽类似物 与载脂蛋白E类似的阳离子结构域能够迅速降低血浆胆固醇 活着。我们有证据表明，这些多肽类似物通过一种 蛋白多糖介导的多肽-脂蛋白复合体的快速摄取。我们将测试 假设将正电荷残基掺入致动脉粥样硬化的脂蛋白上将 导致血脂异常小鼠肝脏快速清除致动脉粥样硬化的脂蛋白，从而导致 抑制动脉粥样硬化。我们目前的工作假设是，在活体内，两个一般 保护动脉粥样硬化的机制，在不改变水平的情况下减少动脉粥样硬化 导致动脉粥样硬化的脂蛋白，以及导致动脉粥样硬化的脂蛋白和动脉硬化本身的减少， 可以通过改变致动脉粥样硬化脂蛋白的表面性质来实现。研究这一点 概念，我们提出了一种双臂方法来演示：1：体内决定因素 A类两亲性多肽或载脂蛋白A-I突变体对动脉粥样硬化的保护作用 致动脉粥样硬化脂蛋白水平；和2：阳离子给药的体内效应 降低血浆致动脉粥样硬化脂蛋白水平的两亲性螺旋多肽。