HDL Proteins and Coronary Heart Disease

HDL 蛋白与冠心病

• 批准号: 8916827
• 负责人: FRANK M SACKS
• 金额: $ 77.74万
• 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/8916827
• 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; 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; 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; predictive modeling; prevent; prospective; protein function; 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）被认为是血浆中具有显著结构和功能异质性的一组颗粒。然而，在流行病学研究和减少冠心病（CHD）治疗的开发和测试中，HDL被视为一种均质脂蛋白类型。高密度脂蛋白胆固醇或其主要蛋白apoa - 1的浓度是冠心病的一个强烈的反向危险因素。然而，一个共识正在形成，即需要了解人类高密度脂蛋白的多样性，才能在低或高高密度脂蛋白水平的意义上取得进展，以及如何利用高密度脂蛋白的信息来开发降低心血管疾病的治疗方法。高密度脂蛋白存在于由蛋白质含量定义的大量亚群中，这些蛋白质与冠心病的风险有不同的关系。例如，含有apoC-III的HDL的浓度预示着CVD风险的增加而不是降低，并且含有apoC-III的HDL缺乏总HDL和不含apoC-III的HDL所具有的保护功能。某些HDL亚型的功能异常和冠心病风险增加的一致性支持了载脂蛋白改变HDL功能的关键概念，并且这种功能的改变与HDL类型对动脉粥样硬化和心血管疾病发病率的影响有关。第一个具体目标是测量HDL亚型的血浆浓度，这些亚型由它们含有或不含有蛋白质组学在HDL中发现的至少60种蛋白质中的一种或多种来定义。每种蛋白质都有与高密度脂蛋白或冠心病相关的已知功能，例如对参与动脉粥样硬化的细胞的影响；细胞和高密度脂蛋白之间的胆固醇转移；抑制氧化或炎症的；止血;先天免疫。每种蛋白质都会定义一对HDL亚型，这些亚型要么具有特定的蛋白质，要么不具有特定的蛋白质，例如HDL具有apoC-III， HDL不具有apoC-III。我们将确定每种新型HDL的浓度范围及其随时间在代表性人群样本中的稳定性。我们将通过脂质和蛋白质含量以及大小来描述HDL类型。我们预计，数据减少将产生一个20对或更少的HDL类型的小组，用于第二个特定目的，即评估两个前瞻性美国队列中女性（护士健康研究II）和男性（卫生专业人员随访研究）的冠心病风险。在第三个具体目标中，我们将单独选择HDL类型，这些类型与风险有独立且强的关系，并且增加了相对风险，不利或保护的大小。我们将设计一个个性化的HDL风险指数，结合保护性、非保护性和不良类型的信息。我们还将研究HDL亚型的指标，根据已知的蛋白质的主要功能分组，如胆固醇转移，止血，氧化等。这可能与一个人冠心病的特定病因有关。我们将测试与新型HDL类型一起建立的指数对标准冠心病风险预测模型的贡献。我们的最终目标是发现对预测冠心病风险有用的指标；评估对饮食和药物治疗的反应；发现新的高密度脂蛋白特异性靶点，用于开发预防冠心病的药物。