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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(申请人提供)：血脂异常和与之相关的氧化应激是导致动脉粥样硬化血栓形成的主要危险因素之一。血小板活化在动脉粥样硬化血栓形成和随后的由斑块破裂引发的急性冠脉综合征中起关键作用。许多与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强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，但关于高脂血症时体内导致血小板反应性增强的分子机制的了解才刚刚开始出现。近年来，血小板模式识别受体参与了血小板功能的研究。我们之前已经证明，血小板清道夫受体CD36是氧化应激的血小板感受器，并在血脂异常时促进血小板的高反应性。最近，我们和其他人证明了TLRs，另一个在血小板中作用未知的模式识别受体家族，可以调节血小板的功能。我们最近的数据表明，血小板TLR1/TLR2和TLR9单独或与CD36协同识别在氧化应激和血脂异常期间聚集在循环中的新的“改变的自我”配体。这些受体的连接激活了先天免疫系统共有的通路，并通过尚未建立的连接将该信号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，这些分子代表着血小板模式识别受体的“改变的自身”配体。我们以前已经发现了一个新的氧化胆碱甘油磷脂家族(OxPCCD36)，它们作为CD36的高亲和力配体，通过CD36在体内促进血小板的高反应性和血栓形成。我们最近的研究将这一观察扩展到一类新的产物，这些产物是通过PLA2降解oxPCCD36而形成的。我们发现，蛋白质的羧烷基吡咯加合物和磷脂酰乙醇胺是血小板TLRs的新型配体，是强大的血小板激动剂，并在体内聚集在血脂异常的情况下。然而，受体识别的确切分子机制、新型配体在体内血栓形成中的作用以及它们在血小板中诱导的信号通路尚不清楚。这项建议将解决这一假设，即血小板TLRs单独或与CD36协同促进血小板反应性和氧化应激过程中产生的内源性配体诱导的血栓前状态。