Pathophysiological Activities of Oxidized Phospholipids

血小板反应性增高在闭塞症病理生理中的重要作用 动脉血栓形成是公认的疾病。然而，负责 高脂血症时体内增强血小板反应性的机制还知之甚少。我们 最近分离并在结构上定义了一个新的氧化胆碱家族 体内存在于氧化增强部位的甘油磷脂(OxPCCD36) 压力。OxPCCD36作为清道夫受体B和B类的高亲和力配体 在氧化应激状态下调节血小板的反应性和血栓形成。我们的初步研究 证明了由于oxPCCD36的降解而形成的一类产物 PLA2是一种新型、高效的血小板激动剂， 然而，介导其作用的受体尚不清楚。血小板表达大量的 具有模式识别特性的受体，包括几个Toll样受体(TLRs)。 最近的一项研究表明，血小板TLRs可能调节血栓形成，当它们的 配基存在于循环中。这项提议将解决这样一个假设，即血小板 TLRs单独或与清道夫受体协同调节血小板反应性和 氧化应激产生的内源性配体引起的血栓前状态。这 提案还将继续提出假设，即羧烷基醇解物蛋白加合物可以 作为血小板清除剂/Toll样受体的新配体，并鉴定其作用机制 血栓前活性。最后，我们将继续对分子的研究 清道夫受体BI对大鼠血小板功能和血栓形成的调节机制 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：探讨oxPCCD36对血小板活化和血栓形成活性的影响。 由血小板TLRs单独或与清道夫B类受体协同介导。 目的：探讨清道夫受体BI在高血压病患者血小板功能中的作用。 血脂异常和氧化应激。 目的：阐明血管紧张素转换酶的作用机制，评价其生理和病理生理学改变。 羧烷基醇解物蛋白加合物(CAPS)相互作用的后果 还有血小板。

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.