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

项目摘要/摘要 糖尿病(DM)的发病率越来越高，这是一个主要的健康问题。糖尿病损害内皮细胞 功能，是导致不良血栓事件(心脏病发作和中风)的主要危险因素 糖尿病患者死亡率的增加。血管性假血友病因子(VWF)、一氧化氮和前列环素 血管内皮细胞产生的调节急性动脉粥样硬化血栓形成的关键血液成分。患有疾病的患者 糖尿病，VWF水平异常高，NO和前列环素水平低，预示着 不良动脉粥样硬化血栓形成事件。这些内皮细胞异常调节的潜在机制 糖尿病患者对衍生的血小板调节剂仍知之甚少。经过广泛的筛选和验证 使用尖端方法的分析我们检测并确认了支持以下内容的实验结果 糖尿病患者中VWF的调节通过有趣的假定高血糖诱导的miRNA途径。 这些结果导致了我们的中心假设，即高血糖导致miRNA导致调节失调 血管内皮细胞衍生的血小板调节剂，导致血栓形成增加。我们将直接解决 假设使用了三个特定的目标。具体目标1将重点放在高血糖的机制上 调节内皮细胞miRNA，Aim#2将评估miRNAs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将重点放在临床上 这些发现在临床患者水平和使用活体小鼠模型的意义。我们有 聚集了一支由VWF、miRNA和糖尿病领域的国际领导者组成的团队，以完成这些特定的 目标。在短期内，我们将为DM的调节和失调提供分子机制 血管内皮细胞与健康和疾病从长远来看，我们将提供新的目标来打击日益增长的 血栓形成与糖尿病相关。

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.