The Role of the Metabolic Milieu In Regulating Platelet Reprogramming in Humans

项目总结（见说明）： 该项目的重点是我们对血小板在糖尿病和一种关键的相关代谢疾病肥胖中成为促血栓形成的分子机制的认识上的差距。我们的研究具有重要的临床和转化意义，因为动脉粥样硬化血栓形成和其他血栓性综合征，包括静脉血栓形成和肺栓塞，是2型糖尿病（DM）和肥胖症的常见和病态并发症。虽然机制尚未确定，但有大量已发表的观察结果表明，血小板在这些条件下具有高反应性和胰岛素抵抗。犹他州大学血栓形成分子医学转化研究中心（U2 M2-TRCT）的一个中心主题假设，我们已经建立了该假设，以响应NHLBI的倡议， 在血栓形成和止血障碍中的翻译程序的一个重要方面是，代谢综合征患者的全身环境的变化导致血小板的重编程，导致血栓形成前和功能障碍活动。这一假设是基于U2 M2-TRCT研究人员在实验模型中对人类血小板和血小板进行研究所产生的大量初步数据。该项目将 在2型糖尿病和肥胖受试者中检查中心假设，在“人体模型”中提供严格的测试，补充项目1和2中的临床前研究以及项目4中的额外新临床分析。目标1将前瞻性地确定2型糖尿病和肥胖症患者是否发生血小板重编程，目标2将确定是否可以通过使用具有以下特征的药物进行干预来逆转血小板重编程： 二甲双胍具有独特的治疗作用，已在临床上得到广泛检查和使用。我们的研究将提供关键的翻译观察，这些观察将与项目1，2和4中的发现紧密结合，也将成为新兴翻译研究人员研究职业发展活动的重要工具。

PROJECT SUMMARY (See instructions): This project focuses on gaps in our knowledge regarding molecular mechanisms by which platelets become pro-thrombotic in diabetes and in a key associated metabolic condition, obesity. Our studies have major clinical and translational significance because atherothrombosis and other thrombotic syndromes, including venous thrombosis and pulmonary embolism, are common and morbid complications of type 2 diabetes mellitus (DM) and obesity. Although the mechanisms have not been defined, there are substantial published observations indicating that platelets are hyperreactive and insulin resistant in these conditions. A central thematic hypothesis in the University of Utah Molecular Medicine Translational Research Center in Thrombosis (U2M2-TRCT), which we have established in response to this NHLBI initiative to develop translational programs in thrombotic and hemostatic disorders, is that changes in the systemic milieu of patients with metabolic syndromes leads to reprogramming of platelets, resulting in prothrombotic and dysfunctional activities. This hypothesis is based on extensive preliminary data generated from studies of human platelets and platelets in experimental models by U2M2-TRCT investigators. This project will examine the central hypothesis in subjects with type 2 DM and obesity, providing a rigorous test in the "human model" that complements pre-clinical studies in Projects 1 and 2 and additional novel clinical analysis in Project 4. Aim 1 will prospectively determine if platelet reprogramming occurs in type 2 DM and obesity, and Aim 2 will determine if reprogramming can be reversed by intervention with an agent with a unique therapeutic profile that has been extensively examined and used in the clinic, metformin. Our studies will provide critical translational observations that will be tightly integrated with discoveries in Projects 1, 2, and 4, and will also be an important vehicle for research career development activities of new and emerging translational investigators.