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血小板中有明显的血栓素释放，特别是在高血糖期间，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转化为血栓素释放导致糖尿病血小板功能障碍的机制。通过三个特定目标，我们将首先解决醛糖还原酶在将这种高糖信号转导到血小板功能障碍中的作用（特定目标#1）。特异性目标#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，特异性目标#3将评估新发现的遗传变异如何影响对高血糖和阿司匹林不敏感的反应。在这个研究项目结束时，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血小板活性增强。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. PUBLIC HEALTH RELEVANCE: Platelet hyperactivity in diabetic patients plays an important role in the development of cardiovascular disease. We will now explore the glucose specific mechanisms for this increase in thrombosis, by complementing human, mouse and tissue culture cell systems. Our proposed biochemical, genetic and signaling studies may assist in the development of new antiplatelet drugs for diabetic patients, in combating cardiovascular disease.