Pathophysiological Activities of Oxidized Phospholipids

氧化磷脂的病理生理活性

• 批准号: 8235849
• 负责人: EUGENE A PODREZ
• 金额: $ 34.97万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235849
• 关键词: Address; Adhesions; Affinity; Agonist; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Assay; Blocking Antibodies; Blood Circulation; Blood Clot; Blood Platelets; Blood coagulation; CD36 gene; Cells; Cholesterol; Cytoplasmic Granules; Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Elements; Family; Functional disorder; Generations; Hyperlipidemia; In Vitro; Investigation; Lecithin; Ligands; Mediating; Metabolic syndrome; Molecular; Mus; Oxidative Stress; Pattern Recognition; Phase; Phospholipase A2; Phospholipids; Physiological; Platelet Activation; Play; Property; Proteins; Receptor Cell; Recombinants; Regulation; Risk; Risk Factors; Role; Rupture; SR-B proteins; SR-BI receptor; Signal Transduction; Site; Solid; Staging; Testing; Thrombosis; Toll-like receptors; Up-Regulation; acute coronary syndrome; adduct; in vivo; macrophage; novel; overexpression; oxidized lipid; receptor; receptor function; response; scavenger receptor; sensor

A significant role for increased platelet reactivity in the pathophysiology of occlusive arterial thrombosis is widely recognized. However, the mechanisms responsible for enhancing platelet reactivity in vivo during hyperlipidemia are poorly understood. We have recently isolated and structurally defined a novel family of oxidized choline glycerophospholipids (oxPCCD36) that are present in vivo at sites of enhanced oxidative stress. oxPCCD36 serve as high affinity ligands for scavenger receptors class B and modulate platelet reactivity and thrombosis in oxidative stress. Our preliminary studies demonstrated that a class of products formed as a result of degradation of oxPCCD36 by PLA2 (carboxyalkylpyrolle protein adducts) is a new and powerful platelet agonist, however, the receptors mediating its effect are not known. Platelets express a number of receptors with pattern recognition properties, including several toll like receptors (TLRs). A recent study suggested that platelet TLRs may modulate thrombosis when their ligands are present in circulation. This proposal will address the hypothesis that platelet TLRs alone, or in cooperation with scavenger receptors modulate platelet reactivity and prothrombotic state induced by endogenous ligands generated in oxidative stress. This proposal will also pursue the hypothesis that carboxyalkylpyrolle protein adducts serve as novel ligands for platelet scavenger /toll like receptors and identify the mechanisms of prothrombotic activity. Finally, we will continue the investigation of the molecular mechanism of scavenger receptor BI regulation of platelet function and thrombosis in dyslipidemia. Our preliminary data strongly support our hypothesis. The Specific Aims are: Aim1: To assess whether the platelet activating and prothrombotic activities of oxPCCD36 are mediated by platelet TLRs alone, or in cooperation with scavenger receptors class B. Aim2: To investigate the role of scavenger receptor-BI in platelet function in dyslipidemia and oxidative stress. Aim3: To elucidate the mechanism and assess the physiological and pathophysiological consequences of the interaction between carboxyalkylpyrolle protein adducts (CAPs) and platelets.

血小板反应性增加在闭塞的病理生理学中发挥重要作用 动脉血栓形成已被广泛认识。然而，负责的机制 在高脂血症期间增强体内血小板反应性尚不清楚。我们 最近分离并结构定义了一个新的氧化胆碱家族 甘油磷脂 (oxPCCD36) 存在于体内增强氧化位点 压力。 oxPCCD36 作为 B 类清道夫受体的高亲和力配体 调节氧化应激中的血小板反应性和血栓形成。我们的初步研究 证明了由于 oxPCCD36 降解而形成的一类产物 PLA2（羧烷基吡咯蛋白加合物）是一种新型强效血小板激动剂， 然而，介导其作用的受体尚不清楚。血小板表达多种 具有模式识别特性的受体，包括几种 Toll 样受体 (TLR)。 最近的一项研究表明，当血小板 TLR 发挥作用时，它们可能会调节血栓形成。 配体存在于循环中。该提案将解决血小板的假设 TLR 单独或与清道夫受体协同调节血小板反应性 由氧化应激中产生的内源性配体诱导的血栓前状态。这 该提案还将追求羧基烷基吡咯蛋白质加合物的假设 作为血小板清除剂/Toll 样受体的新型配体并确定其机制 促血栓活性。最后，我们将继续进行分子研究。 清道夫受体BI调节血小板功能及血栓形成的机制 血脂异常。我们的初步数据有力地支持了我们的假设。 具体目标是： 目的1：评估oxPCCD36是否具有血小板活化和促血栓形成活性 单独由血小板 TLR 介导，或与 B 类清道夫受体配合介导。 目的2：探讨清道夫受体-BI在血小板功能中的作用 血脂异常和氧化应激。 目标3：阐明机制并评估生理和病理生理学 羧烷基吡咯蛋白加合物 (CAP) 之间相互作用的后果 和血小板。