INTERACTIONS OF APO A-I WITH LIPIDS AND CELL SURFACES

这个项目的目标是阐明分子机制。 反向研究载脂蛋白A-I的功能 胆固醇转运(RCT)。载脂蛋白A-I是血浆HIGH的主要蛋白质 密度脂蛋白(HDL)和这个分子的功能是 这种脂蛋白的抗动脉粥样硬化特性。具体目标1是 确定对磷脂结合至关重要的载脂蛋白A-I结构域 (PL)和各种类型的高密度脂蛋白颗粒的组装；这是 重要的是载脂蛋白A-I参与随机对照试验的方式取决于 在它的唇化状态下。载脂蛋白的结构-功能关系 将使用突变改变的蛋白质分子对A-I进行检测。 具体目标2是定义与膜有关的分子事件 低脂载脂蛋白A-I(前β-高密度脂蛋白)的“微增溶”过程 从细胞质膜上去除未酯化的胆固醇和磷脂。 具体目标3是阐明载脂蛋白A-I作为配体的行为 清道夫受体(SR)-B1受体及其作用的分子机制 结合介导的胆固醇酯对细胞的选择性摄取 高密度脂蛋白结合到这个受体上。血浆载脂蛋白A-I的脂质结合能力， 工程的载脂蛋白A-I和模型多肽将使用一系列 物理-生化技术。载脂蛋白A-I的功能域 参与调节细胞表面胆固醇和脂质的运输 将通过在细胞中使用各种工程的载脂蛋白A-I分子来定义 文化体系。该项目的成果将提供更大的 了解高密度脂蛋白预防早产的机制 冠状动脉疾病。

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.