STRUCTURAL BASIS OF THE ANTI-ATHEROGENIC PROPERTIES OF APO A-1

项目2：载脂蛋白A抗动脉粥样硬化性能的结构基础--L 这个项目的目标是阐明潜在的功能的分子机制。 载脂蛋白A-L与胆固醇逆向转运载脂蛋白A-L是血浆高密度脂蛋白的主要成分 脂蛋白(HDL)和这个分子的功能是其抗动脉粥样硬化特性的基础 脂蛋白。具体目的1是定义载脂蛋白A-L的两个三级结构域的关键性质 分子，并更好地确定无脂的人载脂蛋白A-L结构在生理稀溶液中 浓度。载脂蛋白A-L结构域性质对亲和力和亲和力的影响 此外，还将探讨脂质结合的机制。这些目标将通过使用 工程载脂蛋白A-L分子和一系列物理-生化方法。具体目标2是建立 异质新生高密度脂蛋白颗粒通过三磷酸腺苷结合生物发生的机制基础 磁带转运体A1(ABCA1)介导的细胞脂质外流至载脂蛋白A-L。载脂蛋白A-L结构与功能的关系 细胞类型的影响将通过测量磷脂和胆固醇分子的外流来确定 从培养中生长的巨噬细胞、成纤维细胞和肝细胞到改造的载脂蛋白A-L分子。特定的 目标3确定载脂蛋白A-L的三级结构域的性质对蛋白质 用腺相关病毒诱导表达的自然人胆固醇转运功能 载脂蛋白A-L在小鼠中的变异，以评估对随机对照试验和动脉粥样硬化的影响(与项目3合作)。 含载脂蛋白A-L突变的小鼠高密度脂蛋白颗粒调节胆固醇的功能 进出牢房的运输将与项目1合作确定。 早发冠状动脉疾病的发病率在升高的人群中降低 血浆高密度脂蛋白、胆固醇和载脂蛋白A水平-L。这种保护作用的原因尚不完全清楚。 该项目旨在揭示载脂蛋白A-L有益特性的分子机制。

PROJECT 2: STRUCTURAL BASIS OF THE ANTI-ATHEROGENIC PROPERTIES OF APO A-l The goal of this project is to elucidate the molecular mechanisms underlying the functions of apolipoprotein (apo) A-l in reverse cholesterol transport (RCT). ApoA-l is the major protein of plasma highdensity lipoprotein (HDL) and the functions of this molecule underlie the anti-atherogenic properties of the lipoprotein. Specific Aim 1 is to define the key properties of the two tertiary structure domains of the apoA-l molecule, and to better define lipid-free human apoA-l structure in dilute solution at physiological concentrations. The influence of the properties of the two apoA-l structural domains on the affinity and mechanism of lipid binding will also be investigated. These objectives will be accomplished by using engineered apoA-l molecules and a range of physical-biochemical methods. Specific Aim 2 is to establish the mechanistic basis for the biogenesis of heterogeneous nascent HDL particles via the ATP-binding cassette transporter Al (ABCA1 )-mediated efflux of cellular lipids to apoA-l. The role of apoA-l structure and influence of cell type will be determined by measuring the efflux of phospholipid and cholesterol molecules from macrophages, fibroblasts and liver cells growing in culture to engineered apoA-l molecules. Specific Aim 3 is to define the effects of the properties of the tertiary structural domains of apoA-l on the protein's functionality in cholesterol transport using adeno-associated virus-induced expression of natural human apoA-l variants in mice to assess the effects on RCT and atherosclerosis (in collaboration with Project 3). The functionalities of the mouse HDL particles containing the apoA-l mutations in mediating cholesterol transport into and out of cells will be determined in collaboration with Project 1. The incidence of premature coronary artery disease is reduced in human populations with elevated levels of plasma HDL cholesterol and apoA-l. The reasons for this protective effect are not understood fully and this project seeks to uncover the molecular mechanisms underlying the beneficial properties of apoA-l.