ROLE OF CD 36 AS PRO-THROMBOTIC PLATELET SURFACE RECEPTOR

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。这一提议将检验CD36的假设 调节与全身疾病相关的血小板“高反应性”，从而促进动脉 血栓形成。CD36是一种“模式识别”或清道夫受体，识别氧化等配体 在病理条件下产生的低密度脂蛋白、糖化蛋白和凋亡细胞膜。它是 从而独一无二地定位于“感知”疾病。这一假说的推论是，血小板会被 CD36-配体相互作用可能对抗血小板治疗具有抵抗力，而血小板CD36水平 基因表达可能受基因多态的影响，可能与人类血栓形成风险有关。 提出了三个具体目标。第一个将利用人体血小板功能的体外检测来 描述CD36在血小板活化中的作用。CD36配体，包括氧化磷脂， 凋亡细胞、晚期糖基化终末产物和抗CD36自身抗体可使血小板对 低浓度其他激动剂的激活将被确定，CD36的机制也将被确定 启动血小板信号级联反应。第二个目标将描述CD36在血栓形成中的作用。 用小鼠模型进行活体实验。与载脂蛋白E零背景杂交的CD36缺失小鼠将被用作 动脉粥样硬化状态，CD36空白区呈现高血糖状态，将被用作糖尿病模型。其效果 对CD36的药理上调也将进行测试。第三个目标将决定 人类CD36基因多态性与动脉粥样硬化血栓形成的关系人血小板膜表面CD36水平的变化 个体之间的表达将与CD36基因相关，并与CD36基因相关 血栓形成风险和对阿司匹林和/或氯普利凝胶抵抗的血小板CD36的表达将是 下定决心。

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.