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（apo）A-I和apo E-3具有不同的抗动脉粥样硬化性质。 天然存在的apo A-I突变体在代谢方面不同。载脂蛋白A-I突变体 旨在阐明磷脂复合物中载脂蛋白A-I的结构，我们将 确定这些突变体的代谢及其对动脉粥样硬化形成的影响。肽模拟物 载脂蛋白A-I在体外具有抗动脉粥样硬化的特性。我们已经证明，A类 两亲性螺旋肽类似物注射C57 BL/6 J小鼠后抑制动脉粥样硬化 喂食致动脉粥样硬化饮食，并口服给予全D-残基肽类似物， 图1显示了在西方饮食的LDL受体缺陷（LDL-R缺失）小鼠中的动脉粥样硬化。该项目将 研究具有特异性的两亲性螺旋肽类似物的体内作用， 体外测定的抗动脉粥样硬化性质。我们将确定哪些特定属性（例如 因为需要LCAT活化、胆固醇流出或保护免受氧化作用） 用于抑制动脉粥样硬化易感小鼠的动脉粥样硬化。肽类似物具有 与载脂蛋白E类似的阳离子结构域能够迅速降低 vivo.我们有证据表明，这些肽类似物清除致动脉粥样硬化脂蛋白， 蛋白聚糖介导的肽-脂蛋白复合物的快速摄取。我们将测试 假设将带正电荷的残基结合到致动脉粥样硬化脂蛋白上， 导致血脂异常小鼠中致动脉粥样硬化脂蛋白的快速肝脏清除， 抑制动脉粥样硬化。我们目前的工作假设是，在体内， 动脉粥样硬化保护机制，减少动脉粥样硬化而不改变水平 致动脉粥样硬化的脂蛋白，以及致动脉粥样硬化脂蛋白和动脉粥样硬化本身的减少， 可以通过改变致动脉粥样硬化脂蛋白的表面性质来实现。研究这个 概念，我们提出了一个双臂的方法证明：1：在体内的决定因素， A类两亲肽或载脂蛋白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的水平;和2：施用阳离子脂质体的体内效应。 降低致动脉粥样硬化脂蛋白血浆水平的两亲性螺旋肽。