Reprogrammed Platelets: Effectors of Thrombosis in Metabolic Syndromes

犹他大学分子医学血栓翻译研究中心(U2M2-TRCT)的广泛目标是分析代谢紊乱(肥胖、糖尿病和代谢综合征)患者血栓形成风险的新的临床和分子决定因素。U2M2-TRCT联合了一组在血栓形成和代谢失调方面具有广度和专业知识的基础和临床研究人员。我们的研究将测试这一主题假设，即系统环境中的新陈代谢变化对血小板前体和血小板本身进行重新编程，导致这些关键细胞的血栓活性改变。为了审查这一中心主题，我们提出了四个研究项目和四个核心，并由一批成熟的和新出现的调查人员进行研究，这些调查人员具有经过证明的生产性互动的记录。其智力基础如下：项目1“代谢环境对血小板重编程的分子调控”描述了血小板中的重编程事件，并剖析了microRNA影响代谢综合征中血小板表型的机制；项目2“血小板重编程的代谢调控”将确定对葡萄糖转运体和线粒体功能调节剂的遗传操作如何调节血小板的重编程事件和功能活动；项目3“代谢环境在调节人类血小板重编程中的作用”，前瞻性地检查了2型糖尿病的代谢环境引起的血小板重编程和血小板高反应性。项目3还将确定代谢失衡的治疗纠正是否逆转了血小板重新编程和过度活动；项目4，人类肥胖和糖尿病中的血小板重新编程，将评估暴露于急性甘油三酯乳剂输注的受试者、肥胖受试者在减肥手术前后以及参加Framingham心脏研究的患者的血小板重新编程和功能。在代谢综合征患者中筛选早期翻译mRNA纳米芯片是项目4的一个关键特征。我们的翻译研究将共同探索血栓形成和代谢综合征的新范式，并将成为研究生涯发展的独特平台。

The broad objective of the University of Utah Molecular Medicine Translation Research Center in Thrombosis (U2M2-TRCT) is to dissect novel clinical and molecular determinants of thrombotic risk in patients with metabolic disorders (obesity, diabetes, and the metabolic syndrome). The U2M2-TRCT unites a group of basic and clinical investigators with breadth and expertise in thrombosis and metabolic dysregulation. Our studies will test the thematic hypothesis that metabolic changes in the systemic milieu reprogram platelet precursors and platelets themselves, resulting in altered thrombotic activities of these critical cells. To examin this central theme, we propose four research projects and four cores and studies by a cadre of established and emerging investigators with proven track records of productive interactions. The intellectual infrastructure is as follows: Project 1, The Molecular Regulation of Platelet Reprogramming by the Metabolic Milieu, characterizes reprogramming events in platelets and dissects the mechanisms by which microRNAs influence platelet phenotypes in metabolic syndromes; Project 2, Metabolic Regulation of Platelet Reprogramming, will determine how genetic manipulation of glucose transporters and modulators of mitochondrial function regulate reprogramming events and functional activities of platelets; Project 3, The Role of the Metabolic Milieu in Regulating Platelet Reprogramming in Humans, prospectively examines platelet reprogramming and platelet hyperreactivity imposed by the metabolic milieu of type 2 diabetes. Project 3 will also determine if therapeutic correction of metabolic imbalances reverses platelet reprogramming and hyperactivity; Project 4, Platelet Reprogramming in Human Obesity and Diabetes, will evaluate platelet reprogramming and function in subjects exposed to acute triglyceride emulsion infusion, obese subjects before and after bariatric surgery, and patients enrolled in the Framingham Heart Study. Screening of an early-phase translation mRNA nanochip in humans with metabolic syndromes is a key feature in Project 4. Together, our translational studies will explore new paradigms in thrombosis and metabolic syndromes, and will be a unique platform for research career development.