Molecular Mechanisms for Dysfunctional High Density Lipoprotein (HDL)

高密度脂蛋白 (HDL) 功能失调的分子机制

基本信息

批准号：
7883372
负责人：
JAY W HEINECKE
金额：
$ 38.01万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7883372
关键词：
3-chlorotyrosine ATP-Binding Cassette Transporters Address Affect Age Animal Model Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antioxidants Apolipoprotein A-I Apolipoproteins Apolipoproteins A Arteries Atherosclerosis Biology Blood specimen Cardiovascular Diseases Carotid Artery Diseases Cause of Death Cell membrane Cells Cholesterol Complement Goals High Density Lipoproteins Human Hypochlorous Acid In Vitro Inflammation Inflammatory Isotopes Lead Least-Squares Analysis Lipids Mass Spectrum Analysis Mediating Membrane Transport Proteins Methods Modification Molecular Mus Natural regeneration Nested Case-Control Study Oxidants Pathway interactions Patients Pattern Recognition Peptides Peroxidases Phagocytes Phospholipids Physiological Plasma Population Principal Component Analysis Process Property Prospective Studies Protease Inhibitor Proteins Proteomics Reaction Research Personnel Resources Risk Role Serine Serpins Shotguns Site Societies Study Subject System Testing Therapeutic Tyrosine Vitronectin aryldialkylphosphatase atherogenesis atheroprotective cardiovascular disorder risk chlorination complement C3 precursor genetic regulatory protein human disease in vivo lipid metabolism macrophage men multiple reaction monitoring novel diagnostics oxidation oxidative damage particle prevent programs prospective reverse cholesterol transport sex sulfated glycoprotein 2

项目摘要

DESCRIPTION (provided by applicant): It is widely believed that high density lipoprotein (HDL) protects against atherosclerosis by removing excess cholesterol from arterial cells. Recent studies indicate that HDL is also anti-inflammatory and inhibits lipid oxidation in vivo. These properties may contribute significantly to HDL's ability to inhibit atherosclerosis. Inflammation has been proposed to convert HDL to a dysfunctional form that loses these antiatherogenic effects. Understanding the role of dysfunctional HDL may lead to new diagnostic and therapeutic approaches to atherosclerosis and other inflammatory conditions. However, the underlying factors that render HDL dysfunctional remain poorly understood. One important pathway may involve oxidative damage to HDL by myeloperoxidase (MPO). We have shown that oxidation of apoA-l by MPO impairs the apolipoprotein's ability to remove cellular cholesterol by the ABCA1 pathway, and that HDL is targeted for damage by MPO in vivo. Furthermore, remarkably little is known regarding the identity of proteins that are carried in normal and dysfunctional HDL. We have used shotgun proteomics to test the hypothesis that HDL might carry proteins that make a previously unsuspected contribution to its cardioprotective activity. Our observations suggest that HDL carries a unique cargo of proteins in CVD subjects and that these proteins might make previously unsuspected contributions to the pro- and anti-inflammatory properties of HDL. We therefore propose to test the hypothesis that site-specific oxidation of apoA-l by MPO and deleterious alterations in the protein composition of HDL are molecular mechanisms for generating dysfunctional HDL in humans. Our specific aims are: i) Establish whether apolipoprotein A-l of HDL is targeted for oxidation in humans at risk for cardiovascular disease, ii) Determine whether site-specific oxidation of apoA-l in humans associates with loss of the apolipoprotein's ability to remove cellular cholesterol by the ABCA1 and ABCG1 pathways, iii) Determine whether pro- and anti-inflammatory proteins help generate dysfunctional HDL in humans.

描述（由申请人提供）：人们普遍认为，高密度脂蛋白（HDL）通过从动脉细胞中去除多余的胆固醇来预防动脉粥样硬化。最近的研究表明，HDL也具有抗炎，并抑制体内脂质氧化。这些特性可能对HDL抑制动脉粥样硬化的能力有显着贡献。已提出炎症将HDL转换为失去这些抗动脉粥样硬化作用的功能失调的形式。了解功能失调的HDL的作用可能会导致动脉粥样硬化和其他炎症状况的新诊断和治疗方法。但是，引起HDL功能失调的基本因素仍然吸收不足。一种重要的途径可能涉及髓过氧化物酶（MPO）对HDL的氧化损伤。我们已经表明，MPO对ApoA-L的氧化损害了载脂蛋白通过ABCA1途径去除细胞胆固醇的能力，而HDL的目标是由MPO在体内损害。此外，关于在正常和功能失调的HDL中携带的蛋白质的身份知之甚少。我们已经使用shot弹枪蛋白质组学来测试HDL可能携带蛋白质的假设，这些蛋白质可能对其心脏保护活性做出了先前不受欢迎的贡献。我们的观察结果表明，HDL在CVD受试者中具有独特的蛋白质货物，并且这些蛋白质可能对HDL的促疾病和抗炎特性做出了先前的贡献。因此，我们建议检验以下假设：HDL的蛋白质组成对ApoA-L的位点特异性氧化和有害的改变是人类中HDL功能障碍HDL的分子机制。我们的具体目的是：i）确定HDL的载脂蛋白A-L是否针对患有心血管疾病风险的人类的氧化，ii）ii）ii）ii）确定人类对apoA-L的位点特异性氧化是否是否与失去载脂蛋白的丧失能力与ABCA1和ABCG1 Patherty crete inii crete inii crete and abcg1 paths的能力相关，并确定abcg1 path的能力）人类功能失调的HDL。