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Pathophysiological Activities of of Oxidized Phospholipids

氧化磷脂的病理生理活性

基本信息

批准号：
9171370
负责人：
EUGENE A PODREZ
金额：
$ 35.66万
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 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9171370
关键词：
Address Affinity Agonist Amino Acids Atherosclerosis Biological Blood Circulation Blood Platelets CD36 gene Collaborations Complex Data Diabetes Mellitus Dyslipidemias Elements Family Functional disorder Generations Hyperlipidemia In Vitro Integrins Investigation Knowledge Lecithin Ligands Ligation Link Mediating Metabolic syndrome Modification Molecular Natural Immunity Oxidative Stress Oxides Pathway interactions Pattern recognition receptor Phosphatidylethanolamine Phospholipase A2 Phospholipids Platelet Activation Play Proteins Publishing Regulation Risk Factors Role Rupture Signal Pathway Signal Transduction Site System TLR1 gene TLR2 gene TLR6 gene TRAF6 gene Testing Thrombosis Toll-like receptors acute coronary syndrome adduct atherothrombosis in vivo monocyte neutrophil novel novel strategies oxidized lipid prevent public health relevance receptor response scavenger receptor sensor

项目摘要

DESCRIPTION (provided by applicant): Dyslipidemia and the oxidative stress associated with it are among the main risk factors leading to atherothrombosis. Platelet activation plays a key role in atherothrombosis and the subsequent acute coronary syndromes triggered by plaque rupture. Many dyslipidemia- related pathophysiological states are associated with a drastically increased response of platelets to agonists. While the significance of increased platelet reactivity in the pathophysiology of occlusive arterial thrombosis is widely recognized, knowledge of molecular mechanisms leading to enhanced platelet reactivity in vivo during hyperlipidemia has only started to emerge. Involvement of platelet pattern recognition receptors in platelet function has been recently appreciated. We have previously demonstrated that the platelet scavenger receptor CD36 serves as the platelet sensor for oxidative stress and promotes platelet hyperreactivity in dyslipidemia. Recently, we and others have demonstrated that TLRs, another family of pattern recognition receptors with previously unknown role in platelets, can regulate platelet function. Our recent data demonstrate that platelet TLR1/TLR2 and TLR9, alone or in collaboration with CD36, recognize novel "altered-self" ligands that accumulate in the circulation during oxidative stress and dyslipidemia. Ligation of these receptors activates pathways common to the innate immunity system, and connects this signaling to the integrin activation network in platelets via links that have not yet been established. Generation of biologically-active oxidized lipids and related products is a critical consequence of oxidative stress. According to our studies these molecules represent "altered self" ligands for platelet pattern recognition receptors. We have previously identified a novel family of oxidized choline glycerophospholipids (oxPCCD36) that serve as high affinity ligands for CD36 and promote platelet hyperreactivity and thrombosis in vivo via CD36. Our recent studies extended this observation to a novel class of products formed via degradation of oxPCCD36 by PLA2. We showed that carboxyalkylpyrrole adducts of proteins and phosphatidylethanolamine are novel ligands for platelet TLRs, are powerful platelet agonists and accumulate in vivo in dyslipidemia. However, the exact molecular mechanisms of receptor recognition, the contribution to thrombosis in vivo of novel ligands and the signaling pathways they induce in platelets are not known. This proposal will address the hypothesis that platelet TLRs, alone or in cooperation with CD36, promote platelet reactivity and the prothrombotic state induced by endogenous ligands generated during oxidative stress.

描述（由申请方提供）：血脂异常及其相关的氧化应激是导致动脉粥样硬化血栓形成的主要风险因素。血小板活化在动脉粥样硬化血栓形成和随后由斑块破裂引发的急性冠状动脉综合征中起关键作用。许多血脂异常相关的病理生理状态与血小板对激动剂的反应急剧增加有关。虽然血小板反应性增加在闭塞性动脉血栓形成的病理生理学中的重要性已被广泛认识，但导致高脂血症期间体内血小板反应性增强的分子机制的知识才刚刚开始出现。血小板模式识别受体参与血小板功能最近已得到重视。我们以前已经证明，血小板清道夫受体CD 36作为氧化应激的血小板传感器，并促进血脂异常的血小板高反应性。最近，我们和其他人已经证明，TLR，另一个家庭的模式识别受体与以前未知的作用，在血小板，可以调节血小板功能。我们最近的数据表明，血小板TLR 1/TLR 2和TLR 9，单独或与CD 36合作，识别新的“改变自我”的配体，在氧化应激和血脂异常期间在循环中积累。这些受体的连接激活先天免疫系统共有的途径，并通过尚未建立的链接将该信号传导连接到血小板中的整合素激活网络。生物活性氧化脂质和相关产物的产生是氧化应激的关键后果。根据我们的研究，这些分子代表血小板模式识别受体的“改变的自身”配体。我们以前已经确定了一个新的家庭的氧化胆碱甘油磷脂（oxPCCD 36），作为高亲和力的配体CD 36和促进血小板高反应性和血栓形成在体内通过CD 36。我们最近的研究将这一观察结果扩展到通过PLA 2降解oxPCCD 36形成的一类新产物。我们发现，羧烷基吡咯加合物的蛋白质和磷脂酰乙醇胺是新的血小板TLR的配体，是强大的血小板激动剂，并在血脂异常体内积累。然而，受体识别的确切分子机制、新型配体对体内血栓形成的贡献以及它们在血小板中诱导的信号传导途径尚不清楚。该提案将解决血小板TLR单独或与CD 36合作促进血小板反应性和氧化应激期间产生的内源性配体诱导的血栓前状态的假设。