Mechanisms of coronary endothelial dysfunction in diabetes

糖尿病冠状动脉内皮功能障碍的机制

基本信息

批准号：
7787083
负责人：
Ayako Makino
金额：
$ 1.97万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7787083
关键词：
Accounting Attenuated Award Blood Vessels Blood capillaries Cardiac Cardiovascular system Cell Communication Cells Chronic Complication Connexin 43 Connexins Coronary Coronary artery Data Development Diabetes Mellitus Diabetic mouse Down-Regulation Endothelial Cells Functional disorder Gap Junctions Gene Expression Genes Goals Heart Heart failure Hyperglycemia Hyperlipidemia Hypertension Lead Learning Link Maintenance Mentorship Molecular Morbidity - disease rate Muscle Cells Pathogenesis Pathway interactions Play Prostaglandins Regulation Research Personnel Research Project Grants Resistance Risk Risk Factors Role Testing Therapeutic Transgenic Mice Translational Research Vascular Diseases Vascular Endothelium-Dependent Relaxation Vascular blood supply Vascular resistance Work base capillary density diabetic diabetic patient glycosylation insight intercellular communication mortality mouse model novel therapeutic intervention overexpression peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase prevent protein expression public health relevance transcription factor

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular complications account for significant morbidity and mortality in diabetic patients. Diabetic coronary vascular disease has been recognized as a risk factor that may lead to heart failure. Endothelial cells play a major role in the maintenance of vascular tone and revascularization, while an endothelial dysfunction is commonly observed in diabetes. Gap junctions, formed by connexins (Cxs), provide important pathways for the cell-cell communication and Cx40 is known to be specially important in pathogenesis of hypertension and hyperlipidemia. It is, however, unclear whether Cx40 contributes to the development of coronary vascular complication in diabetes. The object of this application is to investigate the role of Cx40 in coronary endothelial dysfunction using diabetic mice. The hypothesis of this study is that chronic exposure of endothelial cells to hyperglycemia results in downregulated Cx40 protein expression, which increases coronary vascular resistance, decreases cardiac blood supply and increases mortality in diabetes. Three specific aims are proposed to test the hypothesis: 1) To examine whether exposure of coronary endothelial cells to hyperglycemia decreases capillary density and inhibits vascular function through downregulation of Cx40 protein expression; 2) To test whether overexpression of Cx40 gene in endothelial cells serves as a therapeutic approach for coronary endothelial dysfunction in diabetic mice; and 3) To determine whether Cx40 function in diabetes is controlled by enzymatic 0-linked glycosylation of Cx40's transcription factors and Cx40 itself. My long-term goal is to identify the mechanisms for diabetic coronary vascular dysfunction and to develop endothelial cell-based therapeutic strategies to reduce or prevent the progression of coronary vascular disease. To work under a mentorship of Dr. Wolfgang Dillmann provides a great opportunity to learn how to generate endothelial cell-based transgenic mouse model to investigate Cx40 function at the molecular level in diabetes. The purpose of this award is to obtain support for my independent research project and to facilitate my transition to become a fully independent investigator conducting basic and translational research in the field of cardiovascular pathophysiology. PUBLIC HEALTH RELEVANCE: Completion of this study will provide important insights into developing new therapeutic interventions for coronary vascular decease in diabetes.

描述（由申请人提供）：心血管并发症解释了糖尿病患者的发病率和死亡率的显着发病率和死亡率。糖尿病冠状动脉血管疾病已被认为是可能导致心力衰竭的危险因素。内皮细胞在维持血管张力和血运重建中起主要作用，而在糖尿病中通常观察到内皮功能障碍。连接蛋白（CXS）形成的间隙连接为细胞 - 细胞通信提供了重要的途径，并且CX40在高血压和高脂血症的发病机理中特别重要。但是，尚不清楚CX40是否有助于糖尿病中冠状动脉血管并发症的发展。该应用的目的是研究使用糖尿病小鼠在冠状动脉内皮功能障碍中的作用。这项研究的假设是，内皮细胞长期暴露于高血糖症会导致CX40蛋白表达下调，从而增加冠状动脉血管抗性，降低心血性血液供应并增加糖尿病的死亡率。提出了三个具体目的来检验假设：1）检查冠状动脉内皮细胞暴露于高血糖的暴露是否会通过下调CX40蛋白质表达来降低毛细血管密度并抑制血管功能； 2）测试内皮细胞中CX40基因的过表达是否是糖尿病小鼠冠状动脉内皮功能障碍的治疗方法； 3）确定糖尿病中的CX40功能是否通过CX40转录因子和CX40本身的酶促0连接的糖基化来控制。我的长期目标是确定糖尿病冠状动脉血管功能障碍的机制，并开发基于内皮细胞的治疗策略，以减少或防止冠状动脉血管疾病的发展。在Wolfgang Dillmann博士的指导下工作提供了一个很好的机会，可以学习如何生成基于内皮细胞的转基因小鼠模型，以研究糖尿病分子水平的CX40功能。该奖项的目的是获得对我的独立研究项目的支持，并促进我的过渡，成为一名完全独立的研究者，在心血管病理生理学领域进行基本和转化研究。公共卫生相关性：完成这项研究将为糖尿病中冠状动脉血管脱发的新治疗干预提供重要见解。