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

糖尿病中的高血糖、醛糖还原酶、miRNA 与心血管疾病

• 批准号: 9334914
• 负责人: JOHN HWA
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334914
• 关键词: 3' Untranslated Regions; Acute; Address; Adhesions; Adult; Affect; Aldehyde Reductase; American; Animal Model; Apoptosis; Area; Biological Assay; Blood; Blood Platelets; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cells; Chemicals; Chronic; Clinic; Clinical; Clinical Data; Collaborations; Complementary therapies; Complex; Data; Development; Diabetes Mellitus; Disease; Endothelial Cells; Endothelium; Event; Functional disorder; Funding; Genes; Genetic; Goals; Health; Human; Hyperactive behavior; Hyperglycemia; Impairment; International; Knock-out; Link; Mediating; MicroRNAs; Modification; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Nitric Oxide Synthase; Pathologic Processes; Pathway interactions; Patient Recruitments; Patients; Plasma; Play; Population; Positioning Attribute; Prediabetes syndrome; Predictive Factor; Prevalence; Production; Prostaglandins I; Proteins; Regulation; Risk Factors; Risk Reduction; Stroke; TP53 gene; Testing; Thrombosis; Validation; atherothrombosis; c-myc Genes; cardiovascular risk factor; cerebrovascular; clinically significant; combat; cyclooxygenase 2; diabetic; diabetic patient; effective therapy; endothelial dysfunction; fasting glucose; in vivo; insight; mortality; mouse model; neuron loss; new therapeutic target; novel; overexpression; patient population; screening; statistics; targeted treatment; von Willebrand Factor

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.

项目概要/摘要 糖尿病（DM）患病率的增加是一个主要的健康问题。 DM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）的主要危险因素，导致 导致糖尿病患者死亡率增加。血管性血友病因子 (VWF) 与 NO 和前列环素一起， 由内皮产生的关键血液成分，可调节急性动脉粥样硬化血栓形成。患者患有 糖尿病，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事件。这些内皮细胞异常调节的潜在机制 衍生的血小板调节剂在糖尿病中的作用仍然知之甚少。经过广泛的筛选和验证 使用尖端方法进行分析，我们检测并确认了支持的实验结果 通过一个有趣的假定高血糖诱导的 miRNA 途径调节 DM 患者的 VWF。 这些结果引出了我们的中心假设：高血糖诱导的 miRNA 会导致失调 内皮衍生的血小板调节剂，导致血栓形成增加。我们将直接解决 使用三个具体目标的假设。具体目标#1 将重点关注高血糖的机制 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 将侧重于临床 这些发现在临床患者水平和使用体内小鼠模型方面都有重要意义。我们有 聚集了 VWF、miRNA 和糖尿病领域的国际领导者团队来完成这些具体任务 目标。短期内我们将提供 DM 调节和失调的分子机制 健康和疾病中的内皮细胞。从长远来看，我们将提供新的目标来应对日益增加的 与 DM 相关的血栓形成。