Amphipathic Motifs, Lipoproteins and Atherosclerosis

描述（由申请人提供）： 我们的PPG的这种竞争性更新申请的中心主题基于三个假设：（1）含载脂蛋白（apo）A-I的脂蛋白在动脉粥样硬化形成中起主要作用;（2）含apoB的脂蛋白在动脉粥样硬化形成中起主要作用;和（3）参与apoA-1和apoB-2功能调节的不同载脂蛋白结构域的性质。含有脂蛋白的蛋白质在很大程度上由载脂蛋白普遍存在的两亲基序的性质决定。从这一点，我们得出我们的中心主题：两亲性基序（两亲性α螺旋和两亲性（3链/片）是根本的原因和动脉粥样硬化的逆转充分理解。两亲性基序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基序与脂质相互作用的综合理论，并利用这一知识：（a）确定apoA-I和HDL的最小结构特征，所述最小结构特征参与含apoA-I的脂蛋白的组装和结构，HDL（B）的功能和性质决定了apoB的最小结构特征，所述最小结构特征涉及含apoB的脂蛋白的生物发生和LDL的结构、功能和性质，和（c）应用这些知识来理解动脉粥样硬化的预防和逆转所涉及的机制，并潜在地用于开发药理学试剂。为了实现这些目标，提出了四个项目：1）HDL组件结构/动力学的计算和实验研究（项目负责人Jere P. Segrest博士）。2)含载脂蛋白B脂蛋白生物发生的分子机制（项目负责人Nassrin Dashti博士）。3)HDL结构-功能的肽调节剂（G. M. Anantharamaiah，项目负责人）。4)载脂蛋白功能模拟物的生物学（大卫W. Garber，项目负责人）。为了支持这些项目，提出了三个核心设施：核心A：管理和计算（Segrest博士），核心B：肽合成（Anantharamaiah博士）和核心C：细胞生物学（Dashti博士）。拟议的研究将有助于预防和逆转冠状动脉心脏病的信息，导致开发更好的药剂。

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.