Regulation of thrombospondin-1 expression by glucose

葡萄糖对血小板反应蛋白-1 表达的调节

基本信息

批准号：
7437338
负责人：
OLGA I STENINA
金额：
$ 27.2万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7437338
关键词：
Accounting Acute Address Affect Angiogenesis Inhibitors Angiogenic Proteins Angioplasty Animal Model Animals Antioxidants Aorta Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Biochemical Genetics Blood Glucose Blood Vessels Carotid Arteries Cells Cessation of life Chemosensitization Clinical Trials Complication Complications of Diabetes Mellitus Condition Control Animal Data Development Diabetes Mellitus Diabetic Angiopathies Doctor of Philosophy Endothelial Cells Epidemiology Epitopes Fibroblasts Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Transcription Glucose Goals Hexosamines Hyperglycemia In Vitro Injury Insulin Intervention Lead Link Mediating Mediator of activation protein Membrane Methods Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Numbers Pathway interactions Patients Play Production Promoter Regions Property Protein Overexpression Proteins Reactive Oxygen Species Regulation Reporting Research Personnel Risk Factors Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Stabilizing Agents Stroke THBS1 gene Testing Therapeutic Therapeutic Intervention Thrombospondin 1 Transcriptional Activation Transgenic Mice Transgenic Organisms Up-Regulation Vitamin E Zucker Rats atherogenesis base blood glucose regulation cell type diabetic diabetic rat follow-up genetic regulatory protein glycosylation impaired glucose tolerance insight macrovascular disease mouse model prevent programs promoter research study response response to injury restenosis

项目摘要

Description (provided by applicant): Vascular complications account for the greatest numbers of deaths in diabetic patients. However, the molecular mechanisms responsible for these complications remain poorly understood. We recently reported that the expression of thrombospondin-1 (TSP-1) is strikingly elevated in large vessels of Zucker rats, an animal model of type 2 diabetes, both in basal conditions and in response to injury, suggesting a role for this protein in the accelerated atherosclerosis and increased restenosis in this animal model and diabetic patients. TSP-1 has a number of well-documented proatherogenic properties, including genetic and biochemical evidence, and is also one of the most potent antiangiogenic agents, a function directly relevant to diabetic complications. Our preliminary data indicated that TSP-1 expression is regulated by glucose at the transcriptional level and suggested possible signaling pathways for this activation. We will test the hypothesis that specific signaling and transcriptional molecular mechanisms rapidly activated by acute stimulation of arterial smooth muscle cells (SMC) with high glucose mediate the increased expression of TSP-1 in the wall of large blood vessels and provide a link between hyperglycemia and accelerated atherogenesis. The overall goal of the proposed project is to elucidate specific signaling and transcriptional mechanisms responsible for the upregulation of TSP-1 expression by glucose in SMC and to test whether that increased expression of TSP-1 in the vascular wall contributes to the development of atherosclerotic lesions. The long-term objective is to uncover the hyperglycemia-induced molecular mechanisms that lead to development of vascular complications. Specific Aims are: 1. To identify the promoter region of the TSP-1 gene and nuclear factors responsible for the upregulation of TSP-1 by glucose; 2. To identify signaling pathways involved in regulation of TSP-1 expression by glucose; 3. To demonstrate directly in the transgenic mouse model that increased expression of TSP-1 in the vascular wall contributes to the development of atherosclerotic lesions. The results of these experiments will: 1) identify targets for the regulation of TSP-1, a potent antiangiogenic and proatherogenic protein that may contribute to vascular diabetic complications; 2) provide additional information about the molecular mechanisms of the effects of glucose in SMC; and 3) demonstrate directly that TSP-1 may serve as a link between diabetes and vascular complications.

描述（由申请人提供）：血管并发症解释糖尿病患者死亡人数最多。但是，导致这些并发症的分子机制仍然很少理解。我们最近报道说，在扎克大鼠的大容器中，血小板传播-1（TSP-1）的表达显着升高，扎克大鼠是一种基础条件和损伤的一种动物模型，这表明该蛋白在加速性动脉粥样硬化中的作用，并在这种动物模型和糖尿病患者中增加了动脉粥样硬化和增加。 TSP-1具有许多有据可查的促孕剂特性，包括遗传和生化证据，也是最有效的抗血管生成剂之一，这是与糖尿病并发症直接相关的功能。我们的初步数据表明，TSP-1表达在转录水平上受葡萄糖的调节，并提出了这种激活的可能信号传导途径。我们将检验以下假设：特异性信号传导和转录分子机制通过急性刺激动脉平滑肌细胞（SMC）迅速激活，高葡萄糖介导了大血管壁上TSP-1的表达增加，并提供了高血糖症和高血糖和加速动脉粥样硬化之间的联系。拟议项目的总体目标是阐明导致SMC中葡萄糖上调TSP-1表达上调的特定信号传导和转录机制，并测试在血管壁中TSP-1的表达是否增加有助于动脉粥样硬化病变的发展。长期目标是揭示导致血管并发症发展的高血糖诱导的分子机制。具体目的是：1。确定TSP-1基因的启动子区域和负责通过葡萄糖上调TSP-1的核因子； 2。确定葡萄糖调节TSP-1表达的信号通路； 3。直接在转基因小鼠模型中证明，增加了血管壁中TSP-1表达的表达有助于动脉粥样硬化病变的发展。这些实验的结果将：1）确定调节TSP-1的靶标，TSP-1是一种有效的抗血管生成和促性疗法蛋白，可能导致血管糖尿病并发症； 2）提供有关SMC葡萄糖作用的分子机制的其他信息； 3）直接证明TSP-1可以作为糖尿病与血管并发症之间的联系。