Quantitative Assessment of HDL Function

HDL 功能的定量评估

• 批准号: 8989561
• 负责人: JAY W HEINECKE
• 金额: $ 43.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989561
• 关键词: ATP binding cassette transporter 1; Acute; Address; Affinity; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Apolipoprotein A-I; Apolipoproteins A; Arteries; Atherosclerosis; Behavior; Biochemical; Biological Assay; Biological Markers; Cardiovascular Diseases; Carotid Artery Diseases; Cause of Death; Cholesterol; Complement; Computing Methodologies; Enrollment; Genes; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Inflammation; Inflammatory; Isotopes; Lead; Lipids; Magnetic Resonance Imaging; Measures; Mediator of activation protein; Membrane; Pathway interactions; Peroxidases; Population; Post-Translational Protein Processing; Process; Property; Prospective Studies; Proteins; Proteome; Proteomics; Qualifying; Research; Resources; Serum; Shotguns; Societies; Sterols; Study Subject; Testing; Therapeutic; acute coronary syndrome; cardiovascular disorder risk; cholesterol control; citrate carrier; design; improved; in vivo; macrophage; mouse model; novel; novel diagnostics; novel therapeutic intervention; oxidation; oxidative damage; programs; prospective; response; reverse cholesterol transport

This application is submitted in response to PA-11-012-Toward an improved understanding of HDL- which states "The ultimate goal of this FOA is to develop reproducible and robust assays to measure HDL function and to identify novel genes and pathways related to HDL function." We believe we are well-qualified to address this need because our research program has focused on understanding the factors that contribute to the cardioprotective effects of HDL. Two key components of our approach have centered on (i) investigating the factors that control cholesterol efflux and HDL's ability to inhibit macrophage inflammation, and (ii) developing mass spectrometric approaches for quantifying oxidation products and proteins in HDL. Importantly, we have identified specific mechanism that may impair the cardioprotective effects of HDL. One involves oxidative damage of apoA-I (the major HDL protein) by myeloperoxidase (MPO). MPO impairs apoA-I's ability to remove cholesterol from macrophages by the ABCA1 pathway. Another potential mechanism involves alterations in the anti-inflammatory proteins that are carried by HDL. Using shotgun proteomics, we have demonstrated that HDL carries a unique cargo of proteins in cardiovascular disease (CVD) subjects and that those proteins might make previously unsuspected contributions to HDL's function. Moreover, we have shown that HDL of subjects with CVD or acute inflammation exhibts impaired ability to remove cholesterol from macrophages, the key first step in reverse cholesterol transport. Our studies will take advantage of three unique human populations. The first involves control subjects, subjects with acute coronary syndrome, and subjects with established CVD. The second involves control subjects and subjects with CVD enrolled in a prospective trial of statin therapy. The third population took part in a prospective study of subjects with carotid artery disease that was evaluated for atherosclerotic progression by MRI. The availability of these valuable resources will enable us to investigate specific mechanisms for generating dysfunctional HDL in subjects with CVD, the leading cause of death in industrialized societies.

本申请是为了响应 PA-11-012 - 提高对 HDL 的理解而提交的 - 其中指出“该 FOA 的最终目标是开发可重复且稳健的检测方法来测量 HDL 功能并识别与 HDL 功能相关的新基因和途径。”我们相信我们有资格 来满足这一需求，因为我们的研究计划侧重于了解影响因素 HDL 的心脏保护作用。我们方法的两个关键组成部分集中在（i）调查 控制胆固醇流出的因素和 HDL 抑制巨噬细胞炎症的能力，以及 (ii) 开发质谱方法来量化 HDL 中的氧化产物和蛋白质。 重要的是，我们已经确定了可能损害 HDL 心脏保护作用的特定机制。 其中之一涉及髓过氧化物酶 (MPO) 对 apoA-I（主要 HDL 蛋白）的氧化损伤。 MPO 损伤 apoA-I 通过 ABCA1 途径从巨噬细胞中清除胆固醇的能力。另一种潜力 机制涉及 HDL 携带的抗炎蛋白的改变。使用霰弹枪 蛋白质组学，我们已经证明 HDL 在心血管疾病中携带独特的蛋白质 (CVD) 受试者，这些蛋白质可能对 HDL 功能做出以前未曾怀疑的贡献。 此外，我们已经表明，患有 CVD 或急性炎症的受试者的 HDL 表现出受损的能力 从巨噬细胞中去除胆固醇，这是逆转胆固醇转运的关键第一步。 我们的研究将利用三个独特的人群。第一个涉及控制对象， 患有急性冠状动脉综合征的受试者，以及患有已确诊的CVD的受试者。第二个涉及控制 受试者和患有 CVD 的受试者参加了他汀类药物治疗的前瞻性试验。第三人口参加 在一项针对颈动脉疾病受试者的前瞻性研究中，评估了动脉粥样硬化的进展情况 通过核磁共振成像。这些宝贵资源的可用性将使我们能够研究具体机制 在患有心血管疾病的受试者中产生功能失调的高密度脂蛋白，这是工业化社会死亡的主要原因。

项目成果

High-density lipoproteins: a consensus statement from the National Lipid Association.

高密度脂蛋白：国家脂质协会的共识声明。

• 发表时间: 2013-09
• 作者: Toth, Peter P;Barter, Philip J;Rosenson, Robert S;Boden, William E;Chapman, M John;Cuchel, Marina;D'Agostino Sr, Ralph B;Davidson, Michael H;Davidson, W Sean;Heinecke, Jay W;Karas, Richard H;Kontush, Anatol;Krauss, Ronald M;Miller, Michael;R
• 通讯作者: R