Cardioprotective Mechanisms of HDL

HDL 的心脏保护机制

基本信息

批准号：
8323850
负责人：
JAY W HEINECKE
金额：
$ 43.19万
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：
2012-04-16 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8323850
关键词：
Acute-Phase Reaction Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Arteries Atherosclerosis CETP gene Cardiovascular Diseases Cause of Death Cells Cholesterol Clinical Research Complex Coronary Arteriosclerosis Development Dietary Intervention Employee Strikes Engineering Event Gene Expression Genes Genetic Variation Genetically Engineered Mouse Goals Heart Diseases High Density Lipoprotein Cholesterol High Density Lipoproteins Human Inflammation Inflammatory Interferon Type I Interferons Lead Link Macrophage Activation Mediator of activation protein Metabolism Metric Molecular Mus Natural Immunity Pathogenesis Pathway interactions Phenotype Plasma Play Population Property Proteins Proteome Proteomics Role Serum Signal Transduction Sterols TLR4 gene Testing Therapeutic Therapeutic Intervention Vascular Diseases Wild Type Mouse atheroprotective cardiovascular disorder risk diabetic cardiomyopathy disorder risk human disease in vivo inhibitor/antagonist interest macrophage mouse model novel therapeutic intervention prevent response septic therapy design translational study

Acute-Phase Reaction Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Arteries Atherosclerosis CETP gene Cardiovascular Diseases Cause of Death Cells Cholesterol Clinical Research Complex Coronary Arteriosclerosis Development Dietary Intervention Employee Strikes Engineering Event Gene Expression Genes Genetic Variation Genetically Engineered Mouse Goals Heart Diseases High Density Lipoprotein Cholesterol High Density Lipoproteins Human Inflammation Inflammatory Interferon Type I Interferons Lead Link Macrophage Activation Mediator of activation protein Metabolism Metric Molecular Mus Natural Immunity Pathogenesis Pathway interactions Phenotype Plasma Play Population Property Proteins Proteome Proteomics Role Serum Signal Transduction Sterols TLR4 gene Testing Therapeutic Therapeutic Intervention Vascular Diseases Wild Type Mouse atheroprotective cardiovascular disorder risk diabetic cardiomyopathy disorder risk human disease in vivo inhibitor/antagonist interest macrophage mouse model novel therapeutic intervention prevent response septic therapy design translational study

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项目摘要

DESCRIPTION (provided by applicant): In mouse models of atherosclerosis, HDL is thought to be atheroprotective because it removes excess cholesterol from macrophages of the artery wall and inhibits inflammation. We have shown that HDL inhibits a specific inflammatory pathway in macrophages - the type I interferon response pathway - that is regulated by TLR4-TRAM signaling. We also have demonstrated that elevated levels of the acute-phase response proteins SAA1 and SAA2 (SAA1/2) in human HDL associate with impaired sterol efflux from macrophages. Recent studies demonstrate that the sterol efflux capacity of human serum HDL strongly associates with CAD status but is independent of HDL-cholesterol and protein (apoA-I) levels. Thus, the cholesterol efflux capacity of serum HDL might be a marker-and perhaps mediator-of atherosclerotic burden that is independent of HDL- C and apoA-I. Changes in the HDL proteome could alter its ability to remove cellular cholesterol or inhibit macrophage inflammation. We therefore will test the hypotheses that (a) HDL prevents macrophage activation by inhibiting the TLR4-TRAM pathway and (b) altered levels of pro- and anti-inflammatory proteins render HDL dysfunctional in mice and humans. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CAD) is the leading cause of death in industrialized Western populations. Moreover, inflammation-a central theme of this proposal-is implicated in the pathogenesis of many other human diseases. The population at large might benefit from the proposed studies because we may identify ways to identify subjects at risk for CAD, which might lead to preventative treatment. In the long-term, it is possible that the studies outlined in this proposal might lead to the development of new therapeutic interventions designed to prevent or treat CAD.

描述（由申请人提供）：在动脉粥样硬化的小鼠模型中，HDL被认为是动脉保护性的，因为它从动脉壁的巨噬细胞中去除了多余的胆固醇并抑制炎症。我们已经表明，HDL抑制巨噬细胞中的特定炎症途径 - I型干扰素反应途径 - 受TLR4 -TRAM信号传导调节。我们还证明，在人HDL中，急性期反应蛋白SAA1和SAA2（SAA1/2）的水平升高，与巨噬细胞中的固醇流体受损相关。最近的研究表明，人血清HDL的固醇外排能力与CAD状态有很强的关联，但与HDL-胆固醇和蛋白质（APOA-I）水平无关。因此，血清HDL的胆固醇外排能力可能是动脉粥样硬化负担的标志物，也许是独立于HDL-C和APOA-I的介体。 HDL蛋白质组的变化可能会改变其去除细胞胆固醇或抑制巨噬细胞炎症的能力。因此，我们将测试（a）HDL通过抑制TLR4-TRAM途径来防止巨噬细胞激活的假设，并且（b）促促和抗炎蛋白的水平改变了小鼠和人类的HDL功能障碍。公共卫生相关性：心血管疾病（CAD）是工业化西方人口中死亡的主要原因。此外，炎症 - 该提案的中心主题与许多其他人类疾病的发病机理有关。总体人口可能会从拟议的研究中受益，因为我们可以确定识别有CAD风险的受试者的方法，这可能会导致预防治疗。从长远来看，该提案中概述的研究可能会导致旨在预防或治疗CAD的新治疗干预措施的发展。