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（由申请人提供）：血脂异常及其相关的氧化应激是导致动脉粥样硬化的主要危险因素之一。血小板激活在动脉粥样硬化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大大增加有关。尽管广泛认识到血小板反应性增加在闭塞动脉血栓形成的病理生理学中的重要性，但对高脂血症期间体内血小板反应性增强的分子机制的了解才开始出现。最近已经对血小板模式识别受体参与血小板功能已得到理解。我们先前已经证明，血小板清道夫受体CD36充当血小板传感器的氧化应激，并促进血脂异常血小板过度反应性。最近，我们和其他人证明，TLR是另一个在血小板中具有以前未知作用的模式识别受体家族，可以调节血小板功能。我们最近的数据表明，单独或与CD36合作的血小板TLR1/TLR2和TLR9识别出在氧化应激和血脂异常期间循环中积累的新型“改变自身”配体。这些受体的连接激活了先天免疫系统常见的途径，并通过尚未建立的链接将此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结果。根据我们的研究，这些分子代表了血小板模式识别受体的“自我改变”配体。我们以前已经确定了一个新型的氧化胆碱甘油磷脂（OXPCCD36），该家族用作CD36的高亲和力配体，并通过CD36促进体内血小板过度反应性和血栓形成。我们最近的研究将这一观察结果扩展到了通过PLA2降解OXPCCD36形成的新型产品。我们表明，蛋白质和磷脂酰乙醇胺的羧基吡咯吡咯加合物是血小板TLR的新型配体，是功能强大的血小板激动剂，并且在血脂异常中在体内积聚。然而，尚不清楚受体识别的确切分子机制，新型配体体内血栓形成的贡献及其在血小板中诱导的信号传导途径的贡献尚不清楚。该建议将解决以下假设：单独或与CD36合作的血小板TLR促进血小板反应性和由氧化应激过程中产生的内源性配体引起的促血栓性状态。