INTERACTIONS OF APO A-I WITH LIPIDS AND CELL SURFACES

APO A-I 与脂质和细胞表面的相互作用

• 批准号: 6296857
• 负责人: Michael C. Phillips
• 金额: $ 27.96万
• 依托单位: MCP HAHNEMANN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-11-11 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6296857
• 关键词: apolipoproteins; blood lipoprotein metabolism; high density lipoproteins; human tissue; hydropathy; intermolecular interaction; laboratory mouse; lipid transport; membrane activity; molecular polarity; molecular shape; molecular size; phospholipids; protein binding; protein engineering; protein structure function; protein transport; receptor; tissue /cell culture

The goal of this project is to elucidate the molecular mechanisms underlying the functions of apolipoprotein (apo) A-I in reverse cholesterol transport (RCT). Apo A-I is the major protein of plasma high density lipoprotein (HDL) and the functions of this molecule underlie the anti-atherogenic properties of this lipoprotein. Specific Aim 1 is to define the domains of apo A-I critical for the binding of phospholipid (PL) and the assembly of various types of HDL particles; this is significant because the ways in which apo A-I participates in RCT depend upon its state of lipidation. The structure-function relationships of apo A-I will be examined using protein molecules altered by mutagenesis. Specific Aim 2 is to define the molecular events involved in the "membrane micro-solubilization" process by which lipid-poor apo A-I (pre-beta-HDL) removes unesterified cholesterol and PL from the plasma membrane of cells. Specific Aim 3 is to elucidate the behavior of apo A-I as a ligand for the scavenger-receptor (SR)-B1 receptor and the molecular mechanism of the selective uptake into cells of cholesteryl ester mediated by the binding of HDL to this receptor. The lipid-binding capabilities of plasma apo A-I, engineered apo A-I and model peptides will be determined using a range of physical-biochemical techniques. The functional domains of apo A-I involved in mediating cholesterol and lipid transport at cell surfaces will be defined by using various engineered apo A-I molecules in cell culture systems. The results of this project will provide greater understanding of the mechanisms by which HDL protects against premature coronary artery disease.

该项目的目标是阐明分子机制 载脂蛋白 (apo) A-I 反向功能的基础 胆固醇转运（RCT）。 Apo A-I 是血浆高浓度的主要蛋白质 密度脂蛋白（HDL）和该分子的功能是 这种脂蛋白的抗动脉粥样硬化特性。具体目标 1 是 定义对磷脂结合至关重要的 apo A-I 结构域 (PL)以及各类HDL颗粒的组装；这是 意义重大，因为 apo A-I 参与 RCT 的方式取决于 根据其脂化状态。 apo的结构与功能关系 A-I 将使用通过诱变改变的蛋白质分子进行检查。 具体目标 2 是定义“膜”中涉及的分子事件。 贫脂载脂蛋白A-I（前β-HDL）的微溶解过程 去除细胞质膜上的未酯化胆固醇和 PL。 具体目标 3 是阐明 apo A-I 作为配体的行为 清道夫受体（SR）-B1受体及其分子机制 通过结合介导胆固醇酯选择性摄取到细胞中 HDL 与该受体的结合。血浆apo A-I的脂质结合能力， 工程化的 apo A-I 和模型肽将使用一系列 物理生化技术。 apo A-I 的功能域 参与介导细胞表面的胆固醇和脂质运输 将通过在细胞中使用各种工程apo A-I分子来定义 文化系统。该项目的成果将提供更大的 了解 HDL 预防早产的机制 冠状动脉疾病。