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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

基本信息

批准号：
9481394
负责人：
JOHN HWA
金额：
$ 7.15万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9481394
关键词：
3&apos 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

项目摘要

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.

项目总结/文摘