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.
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