Pathophysiological Activities of Oxidized Phospholipids

描述（由申请人提供）：血小板反应性增加在闭塞性动脉血栓形成的病理生理中起着重要作用，这一点已得到广泛认可。然而，在体内高脂血症期间增强血小板反应性的机制尚不清楚。我们最近分离并从结构上定义了一个新的氧化胆碱甘油磷脂家族（oxPCCD36），它存在于体内氧化应激增强的部位。oxPCCD36作为B类清道夫受体的高亲和力配体，在氧化应激中调节血小板反应性和血栓形成。我们的初步研究表明，由PLA2（羧烷基软鹿素蛋白加合物）降解oxPCCD36形成的一类产物是一种新的强大的血小板激动剂，然而，介导其作用的受体尚不清楚。血小板表达许多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的配体存在于循环中时，它们可能会调节血栓形成。该提案将解决血小板TLRs单独或与清除率受体合作调节氧化应激产生的内源性配体诱导的血小板反应性和血栓形成前状态的假设。本研究还将探讨羧基烷基鹿蹄素蛋白加合物作为血小板清除剂/toll样受体的新型配体的假设，并确定血栓形成前活性的机制。最后，我们将继续研究清道夫受体BI调节血脂异常患者血小板功能和血栓形成的分子机制。我们的初步数据有力地支持了我们的假设。具体目的是：目的1：评估oxPCCD36的血小板活化和血栓前活性是单独由血小板TLRs介导，还是与b类清除率受体共同介导。目的2：探讨清除率受体bi在血脂异常和氧化应激时血小板功能中的作用。目的：阐明羧烷基鹿蹄草蛋白加合物（CAPs）与血小板相互作用的机制，并评估其生理和病理生理后果。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Risk for platelet-mediated blood clotting is increased in atherosclerotic disease; however, the mechanisms are poorly understood. We have recently demonstrated that specific oxidized phospholipids can control platelet function via platelet receptors. In this proposal we will study how platelet toll like receptors regulate platelet function and thrombosis in atherosclerosis.