Multidisciplinary Approaches to HDL Structure, Assembly and Function

HDL 结构、组装和功能的多学科方法

• 批准号: 9073915
• 负责人: Jere P Segrest
• 金额: $ 251.71万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9073915
• 关键词: ATP binding cassette transporter 1; Address; Advisory Committees; Animal Genetics; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Apolipoprotein A-I; Apolipoproteins; Area; Arteries; Bioinformatics; Biological; Biological Assay; Biological Models; Biology; Blood Vessels; CETP gene; Cardiovascular Diseases; Cells; Chemicals; Cholesterol; Clinical; Clinical Research; Collaborations; Collection; Complex; Computational Biology; Computer Simulation; Computers; Data; Data Set; Development; Docking; Environment; Epidemiologic Studies; Epidemiology; Future; Genetic Engineering; Genetic study; Heart Diseases; Heterogeneity; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Homology Modeling; Human; In Vitro; Institution; Intervention; Lipids; Lipoproteins; Maps; Measures; Metabolism; Methods; Molecular; Molecular Models; Mus; Myocardial Infarction; Pharmaceutical Preparations; Phenotype; Phosphatidylcholine-Sterol O-Acyltransferase; Plasma; Production; Program Research Project Grants; Proteins; Recombinant Proteins; Research; Research Personnel; Role; Route; Science; Scientist; Services; Site; Site-Directed Mutagenesis; Structure; Test Result; Testing; Therapeutic; Time; Tube; Ursidae Family; Visit; Washington; aqueous; base; cardiovascular disorder risk; crosslink; drug development; in vivo; innovation; interdisciplinary approach; interest; lipid transport; meetings; molecular modeling; multidisciplinary; mutant; nanoscale; particle; prevent; programs; reconstitution; scaffold; simulation; symposium; translational study

DESCRIPTION (Provided by applicant): The central hypothesis of this Program Project Grant, "Multidisciplinary Approaches to HDL Structure, Assembly and Function", is that the platform protein, apoA-I, is a conformationally dynamic scaffold that facilitates interactions among other HDL proteins and lipid remodeling factors that exert potent biological effects on the artery wall. On the basis of recent computational and experimental observations, we propose that specific regions in apoA-I provide an important and testable mechanism for docking of key proposed anti-atherosclerotic proteins, such as LCAT, PON1, CETP, PLTP, ABCA1 and ABCG1. There is a robust, inverse association of HDL-C with cardiovascular disease risk in clinical, epidemiological, animal and genetic studies. These observations have triggered intense interest in targeting HDL for intervention. However, recent studies call into question whether HDL-C relates to CVD status in humans or elevating HDL-C is necessarily therapeutic. Our objective in this proposal is to use a multidisciplinary team approach to understand, in unprecedented detail, the molecular mechanisms for the platform functions of apoA-I, including the molecular mechanisms that enable apoA-I to function as a platform. Through the PPG mechanism, we propose to achieve our objective by use of three integrated innovative methods: i) computational simulation and molecular modeling, ii) chemical crosslinking and site-directed mutagenesis of apoA-I and its partner proteins, iii) structure-function probing with mass spectrometric and cell-based assays that will explore the clinical impact of HDL composition and test new ways of assessing HDL functionality that are distinct from that of HDL-C. Our proposed research program centers on three topics: Project 1: Structural basis of HDL assembly―Jere Segrest, Project Leader (UAB); Project 2: Structural basis of HDL maturation―W. Sean Davidson, Project Leader (U. Cincinnati); Project 3: HDL structure/function in LCAT deficient humans―Jay Heinecke, Project Leader (U. Washington). These three topics involve dynamic interactions among three world class scientists with unique (and complementary) areas of expertise all studying HDL, a unique collaboration unlikely to exist at any single institution and rare in science and in the HDL field. Each project has proposed several collaborative studies among projects that would not be possible in the absence of a PPG. All projects will make extensive use of four Cores, which are key components of the PPG: CORE A: Administration―Jere Segrest, Core Leader (UAB); CORE B: Computational biology―Martin Jones, Core Leader (UAB); CORE C: HDL quantitation―Tomas Vaisar, Core Leader (U. Washington); CORE D: Protein production and interaction―W. Sean Davidson, Core Leader (U. Cincinnati). In summary, we believe that to address HDL's role in vascular biology it will be critical to combine model system studies with computational and functional approaches and to test the resulting ideas in translational studies. Importantly, we believe that our team of investigators has the demonstrated expertise and synergy to pursue this exact approach.

描述（由申请人提供）：该项目资助的中心假设，“HDL结构，组装和功能的多学科方法”，是平台蛋白apoA-I是一种构象动态支架，有助于其他HDL蛋白和脂质重塑因子之间的相互作用，对动脉壁产生有效的生物学效应。基于最近的计算和实验观察，我们提出apoA-I中的特定区域提供了一个重要的和可测试的机制，用于对接关键的抗动脉粥样硬化蛋白，如LCAT，PON 1，CETP，PLTP，ABCA 1和ABCG 1。在临床、流行病学、动物和遗传学研究中，HDL-C与心血管疾病风险存在稳健的负相关性。这些观察结果引发了人们对针对HDL进行干预的强烈兴趣。然而，最近的研究质疑HDL-C是否与人类的CVD状态有关，或者升高HDL-C是否一定具有治疗作用。我们在这个提案中的目标是使用一个多学科的团队的方法来理解，在前所未有的细节，apoA-I的平台功能的分子机制，包括使apoA-I作为一个平台的分子机制。通过PPG机制，我们建议通过使用三种综合创新方法来实现我们的目标：i）计算模拟和分子建模，ii）apoA-I及其配偶体蛋白的化学交联和定点诱变，iii）用质谱和细胞-质谱进行结构-功能探测，基于分析，将探索HDL组成的临床影响，并测试评估HDL功能的新方法，这些方法与HDL-C不同。 我们提出的研究计划集中在三个主题：项目1：HDL组装的结构基础-Jere Segrest，项目负责人（UAB）;项目2：HDL成熟的结构基础-W。肖恩戴维森，项目负责人（美国）。辛辛那提）;项目3：LCAT缺乏的人类HDL结构/功能-杰伊海内克，项目负责人（美国）。华盛顿）。这三个主题涉及三位世界级科学家之间的动态互动，他们都具有独特的（和互补的）专业领域，都在研究HDL，这种独特的合作不太可能存在于任何单一的机构，在科学和HDL领域也很少见。每个项目都提出了在没有项目编制小组的情况下不可能进行的若干项目间合作研究。所有项目都将广泛使用PPG的四个核心：核心A：管理-核心负责人（UAB）Jere Segrest;核心B：计算生物学-核心负责人（UAB）Martin Jones;核心C：HDL定量-核心负责人（UAB）Tomas Vaisar。华盛顿）;核心D：蛋白质的产生和相互作用-W。肖恩戴维森，核心领导人（美国）。辛辛那提）。总之，我们认为，为了解决HDL在血管生物学中的作用，将联合收割机模型系统研究与计算和功能方法相结合，并在转化研究中测试由此产生的想法是至关重要的。重要的是，我们相信，我们的调查人员团队拥有经过证明的专业知识和协同作用，可以采用这种方法。