HDL Proteins and Coronary Heart Disease

HDL 蛋白与冠心病

• 批准号: 8753171
• 负责人: FRANK M SACKS
• 金额: $ 81.89万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-25 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753171
• 关键词: Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Apolipoproteins C; Atherosclerosis; Biological; Biological Assay; Cells; Cholesterol; Consensus; Coronary heart disease; Development; Diet; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Etiology; Goals; Health Professional; Hemostatic function; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Incidence; Inflammation; Knowledge; Laboratory Research; Link; Lipids; Lipoproteins; Mass Spectrum Analysis; Measurement; Measures; Methodology; Methods; Modeling; Natural Immunity; Nurses' Health Study; Pathway interactions; Persons; Pharmaceutical Preparations; Plasma; Population; Process; Prospective Studies; Proteins; Proteomics; Relative Risks; Research; Risk; Risk Factors; Sampling; Scheme; Testing; Time; Tissues; Variant; Woman; Work; base; cohort; data reduction; diet and exercise; drug candidate; drug development; follow-up; functional group; heart disease risk; indexing; male health; novel; oxidation; particle; prevent; prospective; protein function; public health relevance; response

DESCRIPTION (provided by applicant): High density lipoproteins (HDL) are being recognized as a remarkably structurally and functionally heterogeneous group of particles in blood plasma. However, HDL is treated as a homogeneous lipoprotein type in epidemiological studies and in development and testing of treatments to reduce coronary heart disease (CHD). The concentration of HDL-cholesterol or its major protein apoA-I is a strong inverse risk factor for CHD. However, a consensus is developing that knowledge of the diversity of HDL in humans is needed to make progress on the meaning of a low or a high HDL level and how to use information on HDL to develop treatments that can lower CVD. HDL exists in a plethora of subpopulations defined by content of proteins that have diverse relations to risk of CHD. For example, the concentration of HDL that has apoC-III predicts increased rather than decreased risk of CVD, and HDL with apoC-III lacks protective functions possessed by the total HDL and HDL that does not have apoC-III. Concordance of abnormal function and increased CHD risk of certain HDL subtypes supports the key concept that apolipoproteins alter the function of HDL, and that this altered function is involved in effects of the HDL types on atherosclerosis and incidence of CVD. The first specific aim is to measure the plasma concentrations of HDL subtypes defined by their containing or not containing one or more of at least 60 proteins that have been found in HDL by proteomics. Each protein has a known function related to HDL or CHD such as effects on cells that participate in atherosclerosis; cholesterol transfer to and from cells and HDL; inhibiting oxidation or inflammation; hemostasis; and innate immunity. Each protein will define a pair of HDL subtypes, that either have or do not have a specific protein, e.g HDL with apoC-III, HDL without apoC-III. We will determine for each new type of HDL the range of its concentration and its stability over time in samples from representative populations. We will characterize the HDL types by lipid and protein contents and by size. We anticipate that data reduction will produce a panel of 20 or fewer pairs of HDL types for the second specific aim to evaluate for risk of CHD in two prospective US cohorts of women (Nurses' Health Study II) and men (Health Professionals Follow-up Study). In the third specific aim, we will select HDL types individually that have independent and strong relations to risk, and that add to the magnitude of relative risk, adverse or protective. We will devise a personalized risk index of HDL that combines the information on protective, nonprotective, and adverse types. We will also study indexes of HDL subtypes grouped according to the known major function of the protein, e.g. cholesterol transfer, hemostasis, oxidation, etc. This could be relevant to the particular etiology of a person's CHD. We will test how much the indexes built with novel HDL types together add to standard CHD risk prediction models. Our ultimate aim is to discover indexes that are useful in predicting CHD risk; evaluating response to diet and drug treatments; and discovering new specific HDL targets for development of drugs to prevent CHD.

描述（由申请人提供）：高密度脂蛋白（HDL）被认为是血浆中的结构和功能异质颗粒的明显异质群。然而，在流行病学研究以及降低冠心病（CHD）的处理和测试中，HDL被视为一种均质脂蛋白类型。 HDL-胆固醇或其主要蛋白ApoA-I的浓度是CHD的强大危险因素。但是，达成共识正在发展，需要对人类中HDL的多样性的了解来取得低或高HDL级别的含义以及如何使用HDL上的信息来开发可以降低CVD的治疗方法。 HDL存在于大量的亚种群中，这些亚群是由与冠心病风险不同的蛋白质含量定义的。例如，具有APOC-III的HDL浓度预测CVD风险的增加而不是降低CVD的风险，而使用APOC-III的HDL缺乏没有APOC-III的总HDL和HDL所具有的保护功能。异常功能的一致性和某些HDL亚型的CHD风险增加支持载脂蛋白改变HDL功能的关键概念，并且这种改变的功能与HDL类型对动脉粥样硬化和CVD发生率的影响有关。 第一个具体目的是测量由蛋白质组学在HDL中发现的至少60种蛋白质中的HDL亚型的血浆浓度。每种蛋白质具有与HDL或CHD有关的已知功能，例如对参与动脉粥样硬化的细胞的影响。胆固醇转移到细胞和HDL；抑制氧化或炎症；止血；和先天免疫。每种蛋白质都将定义一对HDL亚型，该亚型具有或没有特定蛋白质，例如，没有APOC-III的APOC-III，HDL HDL。我们将为每种新型的HDL确定其浓度范围及其稳定性，随着时间的流逝，来自代表性种群的样本中。我们将通过脂质和蛋白质含量以及大小来表征HDL类型。我们预计，减少数据将产生20个或更少的HDL类型的面板，以评估两名前瞻性美国妇女同伙（护士健康研究II）和男性（卫生专业人员随访研究）的第二个特定目的。在第三个特定目标中，我们将单独选择具有独立和牢固关系的HDL类型，这增加了相对风险，不利或保护性的幅度。我们将设计一个个性化的HDL风险指数，结合了有关保护性，非保护和不利类型的信息。我们还将研究根据已知的蛋白质主要功能分组的HDL亚型索引。胆固醇转移，止血，氧化等。这可能与一个人的冠心病的特定病因有关。我们将测试使用新型HDL类型构建的索引加在一起增加了标准CHD风险预测模型。我们的最终目的是发现有助于预测冠心病风险的索引；评估对饮食和药物治疗的反应；并发现新的特定HDL靶标，用于开发药物以防止CHD。