APO A-1 STRUCTURAL MUTATION AND ATHEROSCLEROSIS

APO A-1 结构突变与动脉粥样硬化

• 批准号: 6192276
• 负责人: Mary G Sorci-Thomas
• 金额: $ 32.62万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6192276
• 关键词: apolipoproteins; atherosclerosis; conformation; electron microscopy; enzyme inhibitors; gene mutation; genetically modified animals; high density lipoproteins; hypercholesterolemia; immunoprecipitation; laboratory mouse; phosphatidylcholine sterol acyltransferase; protein structure; structural biology; transfection

The incidence of premature coronary atherosclerosis in the human population is highly correlated to decreased concentrations of plasma high density lipoproteins (HDL) and its major apoprotein, apolipoprotein A-I (apo A-I). Transgenic and knockout mouse studies have shown that circulating HDL apo A-I primarily plays a "protective function" in response to high levels of atherogenic lipoproteins through its ability to accept, organize and transport cholesterol out of the artery to the liver for uptake and excretion into bile. This "reverse cholesterol transport pathway" is highly dependent upon apo A-I's ester conversion in the plasma. Blockage or reduction in apo A-I's ability to carry out this function can lead to reduced reverse cholesterol transport and inefficient removal of peripheral tissue cholesterol. Data from the applicants' laboratory show that structural alterations in the conformation of plasma apo A-I can have a more profound effect on HDL apo A-I formation and maturation than merely the absence of native apo A-I alone. Their studies show that LCAT activation and thus, plasma cholesterol esterification is inhibited by the presence of a mutant form of apo A-I in plasma. The mutant apo A-I does this by inhibiting plasma cholesterol esterification even in plasma containing native or wild type apo A-I. Thus, they propose to investigate the molecular and cellular basis for the severe disruption in HDL metabolism resulting from the hepatic expression of the mutant human apo A-I, termed 6 apo A-I. This mutant of apo A-I lacks repeat 6, a single proline punctuated 22-mer and has been shown to have a similar plasma lipoprotein phenotype to a known human apo A-I mutation, called apo A-I. In a newly created transgenic mouse model, designated Tg6 apo A-I the applicants propose to conduct dietary-cholesterol feeding studies to determine if mutant apo A-I protects against atherosclerosis in mice with hypercholesterolemia. They also plan to elucidate the molecular and cellular basis for 6 apo A-I's disruption of HDL apo A-I metabolism.

早期冠状动脉粥样硬化在人类中的发生率 人口与血浆HIGH浓度的降低高度相关 密度脂蛋白及其主要载脂蛋白载脂蛋白A-I A-I)。转基因和基因敲除小鼠的研究表明，循环中的高密度脂蛋白载脂蛋白 A-I主要起到保护作用，以应对高水平的 脂蛋白通过其接受、组织和运输的能力而致动脉粥样硬化 胆固醇从动脉到肝脏的摄取和排泄到胆汁中。 这种“反向胆固醇运输途径”高度依赖于载脂蛋白A-I的 酯在血浆中的转化。阻断或降低载脂蛋白A-I的能力 执行这一功能可以减少胆固醇的反向转运和 对外周组织胆固醇的清除效率低下。申请者的数据 实验室研究表明，血浆载脂蛋白构象的结构变化 A-I对高密度脂蛋白载脂蛋白A-I的形成和成熟有更深远的影响 而不仅仅是缺少本地的载脂蛋白A-I。他们的研究表明，LCAT 激活，从而抑制血浆胆固醇的酯化 血浆中存在突变形式的载脂蛋白A-I。突变的载脂蛋白A-I通过 即使在含有天然胆固醇的血浆中也能抑制血浆胆固醇的酯化 或野生型载脂蛋白A-I。因此，他们建议研究分子和 高密度脂蛋白代谢严重紊乱的细胞学基础 突变的人载脂蛋白A-I在肝脏中的表达，命名为6-载脂蛋白A-I。这个突变体 载脂蛋白A-I缺少重复6，一个由22个聚体组成的单一脯氨酸，一直是 与已知的人类载脂蛋白A-I具有相似的血浆脂蛋白表型 突变，称为载脂蛋白A-I。在一种新创建的转基因小鼠模型中，被命名为 TG6载脂蛋白A-I申请人建议进行膳食胆固醇喂养 确定突变载脂蛋白A-I是否对小鼠动脉粥样硬化有保护作用的研究 患有高胆固醇血症。他们还计划阐明分子和 6-载脂蛋白A-I干扰高密度脂蛋白A-I代谢的细胞基础