Multidisciplinary Approaches to HDL Structure, Assembly and Function

HDL 结构、组装和功能的多学科方法

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：该程序项目授予的中心假设“用于HDL结构，组装和功能的多学科方法”，是平台蛋白Apoa-I是一种构象动态的脚手架，可促进其他HDL蛋白质和其他脂质重质重质因素，从而对其进行潜在的生物效应。根据最近的计算和实验观察结果，我们建议APOA-I中的特定区域为对接关键的拟议抗动脉粥样硬化蛋白（例如LCAT，PON1，PON1，CETP，PLTP，PLTP，ABCA1和ABCG1）提供了重要且可测试的机制。在临床，流行病学，动物和遗传研究中，HDL-C与心血管疾病风险有牢固的逆关联。这些观察结果引发了对HDL进行干预的强烈兴趣。但是，最近的研究提出了质疑HDL-C是否与人类中的CVD状态相关还是升高HDL-C是必要的疗法。我们在该提案中的目标是使用多学科团队的方法来理解APOA-I平台功能的分子机制，包括使Apoa-I能够作为平台发挥作用的分子机制。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及其伴侣蛋白及其伴侣蛋白的化学交联和定位的诱变，III），III）结构结构探查，以质谱和细胞的范围探索群体和细胞的测试方法，以探索临床的临床效果，并将其构成临床效果，并探索HD的临床作用。来自HDL-C。我们拟议的研究计划集中在三个主题上：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。 Sean Davidson，项目负责人（U. Cincinnati）；项目3：LCAT缺乏人类的HDL结构/功能 - 项目负责人Jay Heinecke（美国华盛顿）。这三个主题涉及三位具有独特（和互补）专业知识领域的世界一流科学家之间的动态互动，所有研究HDL都是一个独特的合作，在任何单个机构中都不太可能存在，并且在科学和HDL领域中很少见。每个项目都提出了在没有PPG的情况下无法进行的几项合作研究。所有项目都将广泛使用四个核心，它们是PPG的关键组成部分：核心A：管理 - 杰里斯特·塞格斯特（Jere Segrest），核心负责人（UAB）；核心B：计算生物学 - 马丁·琼斯（Martin Jones），核心负责人（UAB）；核心C：HDL定量 - 托马斯·韦萨尔（Tomas Vaisar），核心负责人（美国华盛顿）；核心D：蛋白质产生和相互作用 - W。核心负责人Sean Davidson（U. Cincinnati）。总而言之，我们认为，要解决HDL在血管生物学中的作用，将模型系统研究与计算和功能方法结合并在翻译研究中测试所产生的思想至关重要。重要的是，我们认为我们的调查人员团队具有表现出的专业知识和协同作用，以采用这种确切的方法。