Amphipathic Motifs, Lipoproteins and Atherosclerosis

描述(由申请人提供)： 我们PPG竞争更新申请的中心主题基于三个假设：(1)含载脂蛋白A-L的脂蛋白在动脉粥样硬化形成中发挥主要作用；(2)含载脂蛋白B的脂蛋白在动脉粥样硬化形成中起主要作用；(3)参与调控载脂蛋白A-L和含载脂蛋白B的不同载脂蛋白结构域的性质在很大程度上由载脂蛋白普遍存在的两亲性基序的性质决定。由此我们得出我们的中心主题：两亲性基序(两亲性a螺旋和两亲性(3链/片状)对于全面理解动脉粥样硬化的原因和逆转是基本的。两亲性主题代表了指导所有拟议项目的基本范式。未来五年的目标是继续发展两亲性基序与脂质相互作用的综合理论，并利用这方面的知识：(A)确定参与含载脂蛋白A-L的脂蛋白组装过程中的载脂蛋白A-L和高密度脂蛋白的最低结构特征以及高密度脂蛋白的结构、功能和性质；(B)确定参与含载脂蛋白B的脂蛋白的生物发生以及低密度脂蛋白的结构、功能和特性的载脂蛋白B的最低结构特征；以及(C)应用这些知识来了解参与预防和逆转动脉粥样硬化以及可能用于开发药物的机制。为了实现这些目标，提出了四个项目：1)高密度脂蛋白组件的结构/动力学的计算和实验研究(Jere P.Segrest博士，项目负责人)。2)含载脂蛋白B的脂蛋白生物发生的分子机制(Nassrin Dashti博士，项目负责人)。3)高密度脂蛋白结构-功能的多肽调节剂(G.M.Anantharamaiah博士，项目负责人)。4)载脂蛋白功能模拟生物学(David W.Garber博士，项目负责人)。为了支持这些项目，提议了三个核心设施：核心A：管理和计算(Segrest博士)，核心B：多肽合成(Anantharamaiah博士)，以及核心C：细胞生物学(Dashti博士)。拟议的研究将通过开发更好的药物制剂的信息，为预防和逆转冠心病做出贡献。

DESCRIPTION (provided by applicant): The central theme of this competitive renewal application for our PPG is based upon three hypotheses: (1) Apolipoprotein (apo) A-l-containing lipoproteins play a major role in atherogenesis; (2) apoB-containing lipoproteins play a major role in atherogenesis; and (3) the properties of the different apolipoprotein domains involved in the regulation of the functions of the apoA-l- and apoB-containing lipoproteins are determined to a major extent by the properties of the amphipathic motifs ubiquitous to apolipoproteins. From this we derive our central theme: Amphipathic motifs (the amphipathic a helix and the amphipathic (3 strand/sheet) are fundamental to a full understanding of the cause and reversal of atherosclerosis. Amphipathic motifs represent the fundamental paradigm guiding all proposed projects. The objectives in the next five years are to continue development of a comprehensive theory of the interaction of amphipathic motifs with lipid and to use this knowledge to: (a) determine the minimal structural features of apoA-l and HDL that are involved in both the assembly of apoA-l -containing lipoproteins and the structure, function and properties of HDL (b) determine the minimal structural features of apoB that are involved in both the biogenesis of apoB-containing lipoproteins and the structure, function and properties of LDL, and (c) apply this knowledge to understand mechanisms involved in prevention and reversal of atherosclerosis and potentially for the development of pharmacological agents. To accomplish these objectives, four projects are proposed: 1) Computational and experimental studies of structure/dynamics of HDL assemblies (Dr. Jere P. Segrest, Project Leader). 2) Molecular mechanisms of biogenesis of apolipoprotein B-containing lipoproteins (Dr. Nassrin Dashti, Project Leader). 3) Peptide modulators of HDL structure-function (Dr. G. M. Anantharamaiah, Project Leader). 4) Biology of apolipoprotein functional mimetics (Dr. David W. Garber, Project Leader). To support these projects, three core facilities are proposed: Core A: Administration and computation (Dr. Segrest), Core B: Peptide synthesis (Dr. Anantharamaiah), and Core C: Cell biology (Dr. Dashti). The proposed studies will contribute to the prevention and reversal of coronary heart disease through information leading to the development of better pharmaceutical agents.