Hyperglycemia, thromboxane and platelet activity in diabetes mellitus

描述（由申请人提供）：糖尿病是美国心血管疾病发病率和死亡率的主要原因。血小板功能增强参与了血管并发症的发病机制。我们最近观察到糖尿病患者血小板有显著的血栓素释放，特别是在高血糖期间，并且醛糖还原酶可能在促进血小板过度活跃中起重要作用。我们的目标是发现高血糖通过何种机制转化为血栓素释放，导致糖尿病血小板功能障碍。通过三个具体目标，我们将首先阐明醛糖还原酶在将这种高葡萄糖信号转导至血小板功能障碍中的作用（具体目标#1）。具体目标#2将确定这种信号传导过程是否可能导致糖尿病患者中经常观察到的阿司匹林不敏感性，具体目标#3将评估新发现的遗传变异如何影响对高血糖症和阿司匹林不敏感性的反应。在这项研究计划结束时，我们将确定并确认一个关键的代谢和信号传导成分，将急性和慢性高血糖症转化为增强的血小板活性。这些研究的结果可能支持进行临床试验，以确定哪种抗血小板药物组合对糖尿病患者预防心血管疾病最有益。

DESCRIPTION (provided by applicant): Diabetes mellitus is a major cause of cardiovascular morbidity and mortality in the United States. Enhanced platelet function participates in the pathogenesis of vascular complications. We have recently observed that there is significant thromboxane release from diabetic platelets particularly during hyperglycemia and that aldose reductase may play a significant role in promoting platelet hyperactivity. Our goals are to discover the mechanism by which hyperglycemia is transduced into thromboxane release contributing to diabetic platelet dysfunction. Through three Specific Aims we will initially addres the role of aldose reductase in transducing this high glucose signal to platelet dysfunction (Specific Aim #1). Specific Aim #2 will determine whether this signaling process may contribute to aspirin insensitivity that is often observed among diabetic patients, and Specific Aim #3 will assess how newly discovered genetic variants may influence both the response to hyperglycemia and aspirin insensitivity. At the conclusion of this research program we will have identified and confirmed a key metabolic and signaling component that transduces acute and chronic hyperglycemia into enhanced platelet activity. The results of these studies may support proceeding with clinical trials to determine what combination of antiplatelet agents would be most beneficial to protect against cardiovascular disease in diabetic patients.