Metabolic Regulation of Platelet Reprogramming

犹他州大学血栓形成分子医学转化研究中心（U2 M2-TRCT）的总体目标是检验2型糖尿病（T2 DM）和代谢综合征（MS）中异常代谢环境导致血小板遗传和代谢重编程的假设。这种重编程直接导致血小板活化增加，这是血栓形成风险增加的受试者的特征。项目2的具体重点是阐明负责T2 DM和MS的人类和小鼠模型的血小板中发生的代谢重编程的机制，并确定血小板代谢的相关变化是否会直接导致血小板功能障碍。我们的初步研究表明，糖尿病改变了血小板的代谢谱， 与糖酵解和TCA（三羧酸）通量增加和脂质中间体积累一致的变化。此外，转录谱揭示了调节线粒体能量学、偶联效率（例如UCP 2）和线粒体动力学（例如Mfn 2）的基因表达的显著变化。 因此，我们假设T2 DM和MS的代谢环境增加血小板葡萄糖利用和线粒体代谢，诱导线粒体氧化应激，导致血小板活化。在目标1中，我们将检验T2 DM和MS导致线粒体功能障碍的假设，其特征在于线粒体解偶联、ROS过度产生和线粒体动力学受损。在目标2中，我们将确定T2 DM和MS改变线粒体功能的机制，并将检验操纵这些机制（即，血小板超氧化物歧化酶2、UCP 2和Mfn 2的KO）足以调节血小板活性。在目标3中，我们将确定T2 DM和MS患者血小板葡萄糖利用增加对血小板过度活化的贡献。 在血小板葡萄糖转运遗传减少或增加的糖尿病小鼠模型的研究中。 总的来说，这些研究将为肥胖和糖尿病患者改变血小板代谢和功能的机制提供新的见解。

The overall goal of the University of Utah Molecular Medicine Translational Research Center in Thrombosis (U2M2-TRCT) is to test the hypothesis that the abnormal metabolic milieu in type 2 diabetes (T2DM) and the metabolic syndrome (MS) leads to genetic and metabolic reprogramming of platelets. This reprogramming directly contributes to the increase in platelet activation that characterizes these subjects who are at increased risk for thrombosis. The specific focus of project 2 is to elucidate the mechanisms that are responsible for the metabolic reprograming that develops in platelets of humans and mouse models of T2DM and the MS, and to determine if the associated changes in platelet metabolism will directly contribute to platelet dysfunction. Our preliminary studies reveal that diabetes alters metabolome profiles of platelets with changes consistent with increased glycolysis and TCA (tricarboxylic acid) flux and accumulation of lipid intermediates. In addition, transcriptional profiling reveals significant changes in the expression of genes that regulate mitochondrial energetics, coupling efficiency (e.g. UCP2) and mitochondrial dynamics (e.g. Mfn2). Thus we hypothesize that the metabolic milieu of T2DM and the MS increases platelet glucose utilization and mitochondrial metabolism that induces mitochondrial oxidative stress, leading to platelet activation. In aim 1 we will test the hypothesis that T2DM and the MS leads to mitochondrial dysfunction, characterized by mitochondrial uncoupling, ROS overproduction and impaired mitochondrial dynamics. In aim 2 we will determine the mechanisms by which T2DM and the MS alter mitochondrial function and will test the hypothesis that manipulation of these mechanisms (i.e., KO of platelet superoxide dismutase 2, UCP2 and Mfn2) are sufficient to modulate platelet activity. In aim 3 we will determine the contribution of increased platelet glucose utilization to platelet hyperactivation in T2DM and the MS. This hypothesis will be addressed in studies of diabetic murine models with genetic reduction or augmentation in platelet glucose transport. Collectively these studies will shed new insight into mechanisms that alter platelet metabolism and function in obesity and diabetes.