Hyperglycemia, aldose reductase, miRNA and cardiovascular disease in diabetes mellitus

项目总结/摘要 糖尿病（DM）的发病率不断增加，是一个主要的健康问题。糖尿病损害内皮细胞 功能，并作为不良血栓事件（心脏病发作和中风）的主要风险因素，导致 糖尿病患者的死亡率增加。血管性血友病因子（VWF）沿着NO和前列环素， 由内皮产生的调节急性动脉粥样硬化血栓形成的关键血液成分。患者 糖尿病患者VWF水平异常高，NO和前列环素水平低，可预测 不良动脉粥样硬化血栓形成事件。这些内皮细胞的异常调节的潜在机制是 衍生的血小板调节剂在DM中的作用仍然知之甚少。经过广泛的筛选和验证 使用尖端方法的检测，我们已经检测并确认了支持 通过一种有趣的假定高血糖诱导的miRNA途径调节DM患者的VWF。 这些结果导致我们的中心假设，即高血糖诱导的miRNA导致调节异常 内皮衍生的血小板调节剂，有助于增加血栓形成。我们将直接向 有三个具体目标。具体目标#1将重点关注高血糖症 调节内皮miRNA，目标#2将评估miRNA调节蛋白质的机制 参与VWF，NO和前列环素的产生和分泌，目标#3将集中在临床 这些发现在临床患者水平和使用体内小鼠模型的意义。我们有 聚集了一个VWF、miRNA和糖尿病领域的国际领导者团队， 目的。在短期内，我们将提供DM调节和失调的分子机制 内皮在健康和疾病中的作用从长远来看，我们将提供新的目标，以打击日益增加的 与DM相关的血栓形成。

PROJECT SUMMARY/ABSTRACT The increasing prevalence of diabetes mellitus (DM) is a major health concern. DM impairs endothelial cell function and serves as a major risk factor for adverse thrombotic events (heart attacks and strokes) leading to increased mortality in diabetic patients. Von Willebrand Factor (VWF) along with NO and prostacyclin, are key blood components, produced by the endothelium, that regulate acute atherothrombosis. Patients with diabetes mellitus, have abnormally high levels of VWF, and low levels of NO and prostacyclin, predictive for adverse atherothrombotic events. The underlying mechanisms for aberrant regulation of these endothelial derived platelet modulators, in DM remain poorly understood. After extensive screening and validation assays using cutting edge approaches we have detected and confirmed experimental results which support regulation of VWF in DM patients through an intriguing putative hyperglycemia induced miRNA pathway. These results have led to our central hypothesis that hyperglycemia induced miRNA leads to dysregulation of endothelial derived platelet modulators, contributing to increased thrombosis. We will directly address the hypothesis using three Specific Aims. Specific Aim #1 will focus on the mechanism by which hyperglycemia regulates endothelial miRNA, Aim #2 will assess the mechanism by which miRNAs regulates proteins involved in the production and secretion of VWF, NO and prostacyclin, and Aim #3 will focus on the clinical significance of these findings both at a clinical patient level and using in vivo mouse models. We have gathered a team of international leaders in VWF, miRNA and diabetes mellitus to complete these Specific Aims. In the short term we will provide molecular mechanisms for the regulation and dysregulation of DM endothelium in health and disease. In the long term we will provide novel targets to combat the increased thrombosis associated with DM.