Metabolic Regulation of Platelet Reprogramming

犹他大学分子医学血栓转译研究中心(U2M2-TRCT)的总体目标是检验这一假说，即2型糖尿病(T2 DM)和代谢综合征(MS)的代谢环境异常会导致血小板的遗传和代谢重新编程。这种重新编程直接导致了血小板活化的增加，这是血栓形成风险增加的这些受试者的特征。项目2的具体重点是阐明在T2 DM和MS的人和小鼠模型中，负责代谢重编程的机制，并确定相关的血小板代谢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，糖尿病通过以下方式改变血小板的代谢组谱 变化与糖酵解和TCA(三羧酸)通量的增加和脂质中间体的积累相一致。此外，转录图谱显示，调控线粒体能量学、偶联效率(例如UCP2)和线粒体动力学(例如Mfn2)的基因的表达发生了显著变化。 因此，我们假设T2 DM和MS的代谢环境增加了血小板对葡萄糖的利用和线粒体代谢，从而诱导线粒体氧化应激，导致血小板激活。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说，其特征是线粒体解偶联、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，并将检验以下假设：操纵这些机制(即，对血小板超氧化物歧化酶2、UCP2和Mfn2的KO)足以调节血小板的活性。在目标3中，我们将确定在T2 DM和MS患者中，增加的血小板葡萄糖利用率对血小板过度激活的贡献。 在糖尿病小鼠模型的研究中，糖尿病小鼠的血小板葡萄糖转运基因减少或增加。 总的来说，这些研究将为肥胖症和糖尿病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.