Structural stability and functional remodeling of high-density lipoproteins

高密度脂蛋白的结构稳定性和功能重塑

• 批准号: 8725177
• 负责人: Olga Gursky
• 金额: $ 37.81万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725177
• 关键词: Affect; Amyloidosis; Apolipoprotein A-I; Apolipoprotein A-II; Atherosclerosis; Biochemical; Cardiovascular Diseases; Cardiovascular system; Cells; Chemicals; Cholesterol; Complement; Complex; DBL Oncoprotein; Diabetes Mellitus; Diagnostic; Disease; Dissociation; Enzymes; Equilibrium; Excision; Fibrates; Future; Goals; Head; Health; High Density Lipoproteins; Immune response; In Vitro; Inflammation; Kinetics; Ligands; Lipids; Lipoprotein (a); Lipoproteins; Location; Measures; Metabolism; Methods; Mining; Molecular; Molecular Conformation; Motion; Mutation; N-terminal; Outcome; Outcome Study; Pathway interactions; Pharmaceutical Preparations; Plasma; Point Mutation; Process; Progress Reports; Property; Protein Conformation; Proteins; Publications; Recombinants; Registries; Research; Role; Shapes; Solutions; Stroke; Structure; Structure-Activity Relationship; Surface; Techniques; Testing; Work; base; cardiovascular disorder therapy; design; dimer; flexibility; high density lipoprotein receptor; human disease; improved; improved functioning; in vivo; innovation; insight; lipid transport; mutant; nanoparticle; novel; novel diagnostics; overexpression; particle; protein misfolding; public health relevance; reverse cholesterol transport; scaffold; therapeutic target; tool

DESCRIPTION (provided by applicant): High-density lipoproteins (HDL, or Good Cholesterol) are heterogeneous nanoparticles that remove cell cholesterol via a complex process termed reverse cholesterol transport (RTC). HDL protect against cardiovascular disease, inflammation, stroke and other major diseases. Understanding distinct functional properties of HDL subclasses and their remodeling during RCT is necessary to improve HDL quality, and is the current thrust in search for novel diagnostic tools and therapies to complement statins, fibrates and other lipid-lowering drugs. Our work will provide the molecular basis necessary for this effort. Our long-term goal is to elucidate the energetics-structure-function relationship in lipopo- teins to better understand and control the molecular mechanisms of lipid transport. This project is focused on the structural stability and functional remodeling of plasma HDL and their main protein, apoA-I. ApoA-I forms a structural scaffold on HDL and directs HDL metabolism by activating plasma factors. ApoA-I destabilization can cause amyloidosis. In Aim 1, we will test the new structure-based mechanism of apoA-I adaptation to the increasing lipid load in HDL during cholesterol transport. We will use an integrated approach combining established biophysical and biochemical methods with innovative techniques such as field-cycling NMR to characterize HDL surface dynamics. This will be complemented by Aim 2: functional studies of cell cholesterol efflux to lipid-poor apoA-I and to nascent HDL at the critical early steps of RCT. Aim 3 will test the new structure- based mechanism of apoA-I destabilization and misfolding in systemic amyloidosis. Our studies will provide a structural and dynamic framework necessary for understanding functions of over 60 HDL-associated proteins in health and disease, guide the search for HDL with improved properties for future use as diagnostic markers and personalized HDL-based therapies for cardiovascular disease, and help identify therapeutic targets for apoA-I amyloidosis, a devastating disease for which there is no treatment.

描述(由申请人提供)：高密度脂蛋白(高密度脂蛋白，或好胆固醇)是一种异质纳米颗粒，通过称为反向胆固醇转运(RTC)的复杂过程来去除细胞胆固醇。高密度脂蛋白可预防心血管疾病、炎症、中风和其他重大疾病。了解高密度脂蛋白亚类的不同功能特性及其在RCT过程中的重塑对于提高高密度脂蛋白质量是必要的，也是目前寻找新的诊断工具和治疗方法来补充他汀类药物、贝特类药物和其他降脂药物的主要方向。我们的工作将为这一努力提供必要的分子基础。我们的长期目标是阐明脂蛋白中的能量学-结构-功能关系，以更好地理解和控制脂质运输的分子机制。本课题主要研究血浆高密度脂蛋白及其主要蛋白apoA-I的结构稳定性和功能重塑。载脂蛋白A-I在高密度脂蛋白上形成一个结构支架，通过激活血浆因子来指导高密度脂蛋白的代谢。载脂蛋白A-I不稳定可导致淀粉样变性。在目标1中，我们将测试apoA-I适应胆固醇运输过程中高密度脂蛋白中不断增加的脂质负荷的新的基于结构的机制。我们将使用一种综合的方法，结合现有的生物物理和生化方法与创新的技术，如场循环核磁共振，以表征高密度脂蛋白的表面动力学。这将得到目标2的补充：在随机对照试验的关键早期步骤，对细胞胆固醇流出到脂质贫乏的apoA-I和新生的高密度脂蛋白的功能研究。 目标3将测试系统性淀粉样变中apoA-I失稳和错误折叠的新的基于结构的机制。我们的研究将为理解60多种高密度脂蛋白相关蛋白在健康和疾病中的功能提供必要的结构和动态框架，指导寻找具有更好性能的高密度脂蛋白，以便将来用作心血管疾病的诊断标记物和基于高密度脂蛋白的个性化治疗，并帮助确定载脂蛋白A-I淀粉样变性的治疗靶点，这是一种毁灭性的疾病，目前尚无治疗方法。