Hyperglycemia, thromboxane and platelet activity in diabetes mellitus

描述(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的血小板有显着的血栓素释放，特别是在高血糖时，而醛糖还原酶可能在促进血小板过度活动中起重要作用。我们的目标是发现高血糖转化为血栓素释放导致糖尿病患者血小板功能障碍的机制。通过三个具体的目标，我们将首先阐述醛糖还原酶在将这种高血糖信号转化为血小板功能障碍中的作用(具体目标#1)。具体目标2将确定这一信号传递过程是否可能导致糖尿病患者经常观察到的阿司匹林不敏感，而具体目标3将评估新发现的基因变异如何影响对高血糖和阿司匹林不敏感的反应。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成分，它将急性和慢性高血糖转化为增强的血小板活性。这些研究的结果可能会支持继续进行临床试验，以确定哪种抗血小板药物组合对预防糖尿病患者的心血管疾病最有利。

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.