Quantitative Assessment of HDL Function

HDL 功能的定量评估

基本信息

批准号：
8258563
负责人：
JAY W HEINECKE
金额：
$ 43.13万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8258563
关键词：
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 Exhibits Genes Goals High Density Lipoprotein Cholesterol High Density Lipoproteins Human Inflammation Inflammatory Isotopes Lead Lipids Magnetic Resonance Imaging Measures Mediator of activation protein Membrane Metric 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

项目摘要

DESCRIPTION (provided by applicant): 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 exhibits 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. PUBLIC HEALTH RELEVANCE: Identifying proteins that alter HDL's function and are selectively enriched or depleted in subjects at risk for CVD would support the hypothesis that inflammation converts human HDL to a dysfunctional form. Our long-term goal is to understand the factors that impair HDL's ability to remove cholesterol and inhibit macrophage inflammation, which may have important implications for HDL therapeutics.

描述（由申请人提供）：本申请是为了响应 PA-11-012-为了提高对 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测定法来测量 HDL 功能并识别与 HDL 功能相关的新基因和途径。”我们相信我们完全有资格满足这一需求，因为我们的研究项目专注于了解有助于 HDL 心脏保护作用的因素。我们方法的两个关键组成部分集中在（i）研究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）开发用于量化HDL中的氧化产物和蛋白质的质谱方法。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 损害 apoA-I 通过 ABCA1 途径清除巨噬细胞中胆固醇的能力。另一个潜在的机制涉及高密度脂蛋白携带的抗炎蛋白的改变。使用鸟枪法蛋白质组学，我们已经证明 HDL 在心血管疾病 (CVD) 受试者中携带独特的蛋白质，并且这些蛋白质可能对 HDL 的功能做出以前未曾怀疑的贡献。此外，我们还发现，患有心血管疾病或急性炎症的受试者的高密度脂蛋白（HDL）从巨噬细胞中清除胆固醇的能力受损，而巨噬细胞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。第一个涉及对照受试者、患有急性冠状动脉综合征的受试者和患有已确诊的CVD的受试者。第二个涉及对照受试者和参加他汀类药物治疗前瞻性试验的患有 CVD 的受试者。第三组人群参加了一项针对颈动脉疾病受试者的前瞻性研究，通过 MRI 评估动脉粥样硬化进展情况。这些宝贵资源的可用性将使我们能够研究在 CVD 受试者中产生功能失调的 HDL 的具体机制，CVD 是工业化社会死亡的主要原因。公共健康相关性：识别改变 HDL 功能并在有 CVD 风险的受试者中选择性富集或耗尽的蛋白质将支持炎症将人类 HDL 转化为功能障碍形式的假设。我们的长期目标是了解损害 HDL 清除胆固醇和抑制巨噬细胞炎症能力的因素，这可能对 HDL 治疗具有重要意义。