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Pathophysiological Activities of Oxidized Phospholipids

氧化磷脂的病理生理活性

基本信息

批准号：
7886052
负责人：
EUGENE A PODREZ
金额：
$ 35.33万
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 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7886052
关键词：
Address Adhesions Affinity Agonist Arterial Fatty Streak Atherosclerosis Binding Biological Assay Blocking Antibodies Blood Circulation Blood Clot Blood Platelets Blood coagulation CD36 gene Cells Cholesterol Cytoplasmic Granules Data Development Diabetes Mellitus Disease Dyslipidemias Elements Family Functional disorder Generations Hyperlipidemia In Vitro Investigation Lecithin Ligands Mediating Metabolic syndrome Molecular Mus Oxidative Stress Pattern Recognition Phase Phospholipase A2 Phospholipids Physiological Platelet Activation Play Property Proteins Receptor Cell Recombinants Regulation Risk Risk Factors Role Rupture SR-B proteins SR-BI receptor Signal Transduction Site Solid Staging Testing Thrombosis Toll-like receptors Up-Regulation acute coronary syndrome adduct in vivo macrophage novel overexpression oxidized lipid public health relevance receptor receptor function response scavenger receptor sensor

项目摘要

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.

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学中的重要作用已被广泛认可。然而，在体内高脂血症期间负责增强血小板反应性的机制知之甚少。我们最近分离和结构定义了一个新的家庭的氧化胆碱甘油磷脂（oxPCCD 36），在体内的网站增强氧化应激。oxPCCD 36作为清除剂受体B类高亲和力配体，调节氧化应激中血小板反应性和血栓形成。我们的初步研究表明，PLA 2（羧烷基吡咯蛋白加合物）降解oxPCCD 36形成的一类产物是一种新型且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，血小板TLR可能调节血栓形成时，其配体存在于循环中。该提案将解决血小板TLR单独或与清道夫受体合作调节氧化应激中产生的内源性配体诱导的血小板反应性和血栓前状态的假设。该提案还将追求的假设，即羧烷基吡咯蛋白加合物作为新的血小板清道夫/收费样受体的配体，并确定促血栓活性的机制。最后，我们将继续研究清道夫受体BI调节血脂异常中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。具体目标是：目标1：评估oxPC CD 36的血小板活化和促血栓形成活性是否由血小板TLR单独介导，或与清道夫受体B类共同介导。目的2：探讨清道夫受体-BI在血脂异常和氧化应激状态下血小板功能中的作用。目标3：阐明羧烷基吡咯蛋白加合物（CAP）与血小板相互作用的机制，并评估其生理和病理生理后果。公共卫生相关性：动脉粥样硬化性疾病中血小板介导的凝血风险增加;然而，其机制知之甚少。我们最近证明，特定的氧化磷脂可以通过血小板受体控制血小板功能。本研究拟探讨血小板Toll样受体在动脉粥样硬化中对血小板功能和血栓形成的调节作用。