Cardioprotective Mechanisms of HDL

HDL 的心脏保护机制

基本信息

批准号：
8644308
负责人：
JAY W HEINECKE
金额：
$ 42.63万
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/8644308
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 Event Gene Expression Genes Genetic Engineering 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

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.

描述（由申请人提供）：在动脉粥样硬化小鼠模型中，HDL 被认为具有动脉粥样硬化保护作用，因为它可以清除动脉壁巨噬细胞中多余的胆固醇并抑制炎症。我们已经证明 HDL 抑制巨噬细胞中的特定炎症途径（I 型干扰素反应途径），该途径受 TLR4-TRAM 信号传导调节。我们还证明，人类 HDL 中急性期反应蛋白 SAA1 和 SAA2 (SAA1/2) 水平升高与巨噬细胞甾醇流出受损有关。最近的研究表明，人血清 HDL 的甾醇流出能力与 CAD 状态密切相关，但与 HDL 胆固醇和蛋白质 (apoA-I) 水平无关。因此，血清 HDL 的胆固醇流出能力可能是动脉粥样硬化负荷的一个标志物，也可能是一个介质，它独立于 HDL-C 和 apoA-I。 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，我们将测试以下假设：(a) HDL 通过抑制 TLR4-TRAM 通路来防止巨噬细胞活化，以及 (b) 促炎蛋白和抗炎蛋白水平的改变导致小鼠和人类的 HDL 功能障碍。