APO A-1 STRUCTURAL MUTATION AND ATHEROSCLEROSIS

APO A-1 结构突变与动脉粥样硬化

• 批准号: 6527296
• 负责人: Mary G Sorci-Thomas
• 金额: $ 32.4万
• 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/6527296
• 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.

人类冠状动脉粥样硬化过早发生率 人口与血浆高浓度降低高度相关 密度脂蛋白 (HDL) 及其主要载脂蛋白，载脂蛋白 A-I (apo 人工智能）。转基因和基因敲除小鼠研究表明循环 HDL apo A-I 主要发挥“保护功能”，以应对高水平的 致动脉粥样硬化脂蛋白通过其接受、组织和运输的能力 胆固醇从动脉出来，被肝脏吸收并排泄到胆汁中。 这种“反向胆固醇转运途径”高度依赖于apo A-I 血浆中的酯转化。载脂蛋白 A-I 的能力被阻断或降低 执行此功能可导致胆固醇反向转运减少， 外周组织胆固醇的去除效率低下。数据来自申请人 实验室表明血浆载脂蛋白构象的结构改变 A-I 可以对 HDL apo A-I 的形成和成熟产生更深远的影响 不仅仅是天然 apo A-I 的缺失。他们的研究表明 LCAT 激活，因此，血浆胆固醇酯化被抑制 血浆中存在 apo A-I 突变体。突变体 apo A-I 通过以下方式做到这一点： 即使在含有天然成分的血浆中也能抑制血浆胆固醇酯化 或野生型apo A-I。因此，他们建议研究分子和 HDL 代谢严重破坏的细胞基础 突变型人 apo A-I 的肝脏表达，称为 6 apo A-I。这个突变体 apo A-I 缺少重复 6，单个脯氨酸间断 22 聚体，并且已被 显示与已知的人类 apo A-I 具有相似的血浆脂蛋白表型 突变，称为apo A-I。在新创建的转基因小鼠模型中，指定 Tg6 apo A-I 申请人建议进行膳食胆固醇喂养 确定突变型 apo A-I 是否可以预防小鼠动脉粥样硬化的研究 患有高胆固醇血症。他们还计划阐明分子和 6 apo A-I 破坏 HDL apo A-I 代谢的细胞基础。