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

基本信息

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
项目类别：
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

项目摘要

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（HDL或好胆固醇）是异质的纳米颗粒，通过称为反向胆固醇转运（RTC）的复杂过程去除细胞胆固醇。 HDL预防心血管疾病，炎症，中风和其他主要疾病。了解HDL亚类的不同功能性能及其在RCT期间的重塑对于提高HDL质量是必要的，并且是寻找新型诊断工具和疗法以补充他汀类药物，纤维纤维和其他降脂药物的推力。我们的工作将为这项工作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结构功能关系，以更好地理解和控制脂质转运的分子机制。该项目的重点是血浆HDL的结构稳定性和功能重塑及其主要蛋白ApoA-I。 APOA-I在HDL上形成一个结构支架，并通过激活血浆因子来指导HDL代谢。 Apoa-I不稳定会导致淀粉样变性。在AIM 1中，我们将测试新的基于结构的APOA-I适应在胆固醇传输过程中HDL脂质负荷增加的机制。我们将使用一种集成方法，将已建立的生物物理和生化方法与创新技术（例如野外循环NMR）结合在一起来表征HDL表面动力学。 AIM 2：细胞胆固醇外排对脂质贫困APOA-I和在RCT的关键早期步骤中的新生HDL的功能研究将得到补充。 AIM 3将测试全身性淀粉样变性中ApoA-I不稳定和错误折叠的新的基于结构的机制。我们的研究将提供一个结构性和动态框架，以理解超过60种HDL相关蛋白质在健康和疾病中的功能，并指导对HDL的搜索，并具有改进的特性，以将来用作诊断标记和基于HDL的心血管疾病的个性化疗法，并有助于确定Apoa-I Amyyboissis的治疗方法，并有助于识别出dissymyboistation dissymysisis的治疗方法。