Structural stability and functional remodeling of high-density lipoproteins

描述（由申请人提供）：高密度脂蛋白（HDL，或好胆固醇）是一种异质纳米颗粒，通过称为逆向胆固醇转运（RTC）的复杂过程去除细胞胆固醇。高密度脂蛋白可以预防心血管疾病、炎症、中风和其他主要疾病。在随机对照试验中，了解HDL亚类的不同功能特性及其重塑对提高HDL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重点。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质蛋白的能量-结构-功能关系，以更好地理解和控制脂质转运的分子机制。本项目主要研究血浆HDL及其主要蛋白apoA-I的结构稳定性和功能重塑。apoa - 1在HDL上形成结构支架，并通过激活血浆因子指导HDL代谢。apoa - 1失稳可引起淀粉样变性。在Aim 1中，我们将测试apoA-I适应胆固醇运输过程中HDL脂质负荷增加的新结构机制。我们将使用一种综合方法，将已建立的生物物理和生化方法与创新技术（如场循环核磁共振）相结合，以表征HDL表面动力学。这将由目标2补充：在随机对照试验的关键早期阶段，对细胞胆固醇向低脂apoA-I和新生HDL的外排进行功能研究。

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.