ROLE OF CD 36 AS PRO-THROMBOTIC PLATELET SURFACE RECEPTOR

CD 36 作为促血栓形成血小板表面受体的作用

• 批准号: 7226375
• 负责人: Roy L Silverstein
• 金额: $ 36.06万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-24 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226375
• 关键词: CD antigens; apoptosis; aspirin; atherosclerosis; autoantibody; biological signal transduction; clopidogrel; cysteine endopeptidases; diabetes mellitus; disease /disorder model; disease /disorder proneness /risk; flow cytometry; genetic polymorphism; genotype; glycation; human genetic material tag; human subject; inflammation; laboratory mouse; oxidation; pathogenic diet; phospholipids; platelet activation; platelets; stimulant /agonist; thrombosis

Arterial thrombosis is a common complication of many systemic diseases, including atherosclerosis, diabetes, cancer, and chronic inflammatory conditions. This proposal will test the hypothesis that CD36 mediates platelet "hyper-reactivity" associated with systemic diseases, and thus contributes to arterial thrombosis. CD36 is a "pattern recognition" or scavenger receptor that recognizes ligands such as oxidized LDL, glycated proteins, and apoptotic cell membranes that are generated during pathological conditions. It is thus uniquely positioned to "sense" disease. Corollaries to the hypothesis are that platelets sensitized by CD36-ligand interactions may be resistant to anti-platelet therapies, and that levels of platelet CD36 expression, perhaps under the influence of genetic polymorphisms, may contribute to human thrombotic risk. Three specific aims are proposed. The first will utilize in vitro assays of human platelet function to characterize the role of CD36 in platelet activation. Whether CD36 ligands, including oxidized phospholipids, apoptotic cells, advanced glycation end products, and anti-CD36 autoantibodies can sensitize platelets to activation by low concentrations of other agonists will be determined, as will mechanisms by which CD36 initiates platelet signaling cascades. The second aim will characterize the pro-thrombotic role of CD36 in vivo using murine models. CD36 null mice crossed to an apoE null background will be used as a model of an atherogenic state, and CD36 nulls rendered hyperglycemic will be used as a model of diabetes. The effect of pharmacologic upregulation of CD36 will also be tested. The third aim will determine the potential role of human CD36 polymorphisms in athero-thrombosis. Variance in levels of human platelet surface CD36 expression among individuals will be correlated with CD36 genotype, and associations of CD36 genotype and platelet CD36 expression with thrombotic risk and platelet resistance to aspirin and/or clopridogel will be determined.

动脉血栓形成是许多系统性疾病的常见并发症，包括动脉粥样硬化， 糖尿病、癌症和慢性炎症。这项提议将检验CD 36 介导与全身性疾病相关的血小板“高反应性”，因此有助于动脉粥样硬化。 血栓形成CD 36是一种“模式识别”或清道夫受体，其识别配体如氧化的 LDL、糖化蛋白和凋亡细胞膜在病理条件下产生。是 因此被独特地定位以“感知”疾病。该假说的推论是， CD 36-配体相互作用可能对抗血小板治疗有抵抗力，并且血小板CD 36的水平 可能在遗传多态性的影响下，表达可能有助于人类血栓形成的风险。 提出了三个具体目标。第一个实验将利用人体血小板功能的体外测定， 表征CD 36在血小板活化中的作用。无论CD 36配体，包括氧化磷脂， 凋亡细胞、晚期糖基化终末产物和抗CD 36自身抗体可使血小板敏感， 将确定低浓度其他激动剂的激活，以及CD 36 启动血小板信号级联。第二个目的是描述CD 36在血栓形成中的促血栓作用。 体内使用鼠模型。与apoE空白背景杂交的CD 36空白小鼠将用作免疫缺陷的模型。 致动脉粥样硬化状态，并且CD 36无效导致高血糖将被用作糖尿病模型。效果 还将测试CD 36的药理学上调。第三个目标将决定 人CD 36多态性与动脉粥样硬化血栓形成人血小板表面CD 36水平的变化 个体之间的表达将与CD 36基因型相关，并且CD 36基因型的关联 血小板CD 36表达与血栓形成风险和血小板对阿司匹林和/或氯吡多凝胶的耐药性将是 测定