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Pathophysiological Activities of Oxidized Phospholipids

氧化磷脂的病理生理活性

基本信息

批准号：
8432820
负责人：
EUGENE A PODREZ
金额：
$ 33.29万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2014-11-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432820
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

项目摘要

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性脉管炎病理生理学中的重要作用动脉血栓形成被广泛认识。然而，负责的机制在高脂血症过程中增强体内血小板反应性的方法知之甚少。我们最近分离并在结构上定义了一个新的氧化胆碱家族甘油磷脂（oxPCCD 36），其存在于体内的增强的氧化的位点，应力oxPC CD 36作为清道夫受体B类的高亲和力配体，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oxPCCD 36的降解而形成的一类产物， PLA 2（carboxyalkylpyrolle protein adducts）是一种新型的血小板激动剂，然而，介导其作用的受体尚不清楚。坦率地说，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，血小板TLR可能调节血栓形成时，他们的配体存在于循环中。该提案将解决血小板 TLR单独或与清道夫受体协同调节血小板反应性，氧化应激产生的内源性配体诱导的血栓前状态。这该提案还将继续研究羧烷基吡咯蛋白加合物的假设，作为血小板清除剂/Toll样受体的新型配体，并确定促血栓形成活性最后，我们将继续研究清道夫受体BI调节血小板功能和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：探讨oxPCCD 36对血小板活化和血栓形成的影响由血小板TLR单独或与清道夫受体B类共同介导。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。目的3：阐明其机制，并评估其生理和病理生理学变化羧烷基吡咯蛋白加合物（CAPs）之间相互作用的结果和血小板。