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(高密度脂蛋白)被认为是血浆中一组结构和功能上显著不同的颗粒。然而，在流行病学研究以及减少冠心病(CHD)的治疗方法的开发和测试中，高密度脂蛋白被视为一种均一脂蛋白类型。高密度脂蛋白-胆固醇或其主要蛋白载脂蛋白A-I的浓度是冠心病的一个强烈的反向危险因素。然而，一个共识是，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的含义以及如何利用高密度脂蛋白的信息来开发可以降低心血管疾病的治疗方法方面取得进展。高密度脂蛋白存在于由与冠心病风险有不同关系的蛋白质含量所定义的过多的亚群中。例如，具有apoC-III的高密度脂蛋白浓度预测心血管疾病的风险增加而不是降低，并且具有apoC-III的高密度脂蛋白缺乏总高密度脂蛋白和不具有载脂蛋白-III的高密度脂蛋白所具有的保护功能。某些高密度脂蛋白亚型功能异常和冠心病风险增加的一致性支持载脂蛋白改变高密度脂蛋白功能的关键概念，并且这种改变的功能参与了高密度脂蛋白类型对动脉粥样硬化和心血管疾病发生的影响。第一个特定的目标是测量高密度脂蛋白亚型的血浆浓度，这些亚型由含有或不含有通过蛋白质组学在高密度脂蛋白中发现的至少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，如对参与动脉粥样硬化的细胞的作用；胆固醇在细胞和高密度脂蛋白之间的传递；抑制氧化或炎症；止血；以及先天免疫。每种蛋白质将定义一对高密度脂蛋白亚型，它们要么有特定的蛋白质，要么没有特定的蛋白质，例如有载脂蛋白-III的高密度脂蛋白，没有载脂蛋白-III的高密度脂蛋白。我们将确定每一种新型高密度脂蛋白的浓度范围及其在代表性人群样本中随时间的稳定性。我们将通过脂肪和蛋白质含量以及大小来表征高密度脂蛋白的类型。我们预计，数据减少将产生一个由20对或更少的高密度脂蛋白类型组成的小组，用于第二个特定目标，以评估美国两个预期队列中的冠心病风险(护士健康研究II)和男性(健康专业人员跟踪研究)。在第三个具体目标中，我们将单独选择与风险有独立和强烈关系的高密度脂蛋白类型，这些类型增加了相对风险的大小，无论是不利的还是保护性的。我们将设计一个个性化的高密度脂蛋白风险指数，它结合了保护性、非保护性和不良类型的信息。我们还将研究根据已知的蛋白质主要功能分组的高密度脂蛋白亚型指数，例如胆固醇转移、止血、氧化等。这可能与一个人的冠心病的特定病因有关。我们将测试用新的高密度脂蛋白类型建立的指数在多大程度上增加了标准的冠心病风险预测模型。我们的最终目标是发现有助于预测CHD风险的指标；评估对饮食和药物治疗的反应；以及为预防CHD的药物开发发现新的特定高密度脂蛋白靶点。