Proatherogenic effect of thrombospondins in diabetes

描述(申请人提供)：进行性动脉粥样硬化和血管成形术后的再狭窄在糖尿病患者中更常见，并且发生在比非糖尿病患者更早的年龄，动脉粥样硬化的后果(中风、冠状动脉和外周血管疾病)是糖尿病人群死亡的主要原因。凝血酶原蛋白(TSPs)是一个多功能蛋白家族，可与多种基质蛋白和细胞表面受体相互作用。只有非常有限的信息将TSP与糖尿病和动脉粥样硬化联系起来。这种情况随着最近一项大规模遗传关联研究(GeneQuest)的完成而改变，该研究发现TSP-1、TSP-2和TSP-4的单核苷酸多态(SNP)不仅与早发性冠状动脉疾病有关，而且是所分析的80多个SNP中唯一与疾病高度相关的3个。这些观察结果促使我们评估高糖对血管细胞释放TSP的影响，并观察到显著增加。基于这些发现，我们推测，高糖暴露下血管细胞产生TSP的变化可能导致糖尿病动脉粥样硬化病变的加速发展。现在，通过研究变异体之间的功能差异，可以深入了解TSPs可能导致糖尿病动脉粥样硬化病变的机制。因此，本项目的总体目标是阐明TSP在糖尿病动脉粥样硬化病变加速发展中的作用，并确定不同形式TSP促动脉粥样硬化作用的分子基础。其具体目的是：1.建立葡萄糖调节血管细胞TSP表达的机制。2.检测糖尿病Zucker大鼠血管壁、心脏和脑组织中TSP的表达，探讨糖尿病大鼠和正常Zucker大鼠血管损伤后TSP表达模式的差异。3.确定TSP编码区SNP致动脉粥样硬化作用的分子机制和结构基础。导师研究科学家发展奖将极大地帮助Olga I.Stenina博士成功地过渡到糖尿病及其心血管并发症领域的独立研究人员。

DESCRIPTION (provided by applicant): Progressive atherosclerosis and restenosis following angioplasty are more common and occur at an earlier age in diabetic than in nondiabetic patients, and the consequences of atherosclerosis (stroke, coronary artery and peripheral vascular disease) are the primary causes of mortality in the diabetic population. The thrombospondins (TSPs) are a family of multifunctional proteins that interact with numerous matrix proteins and cell surface receptors. Only very limited information had linked the TSPs with diabetes and atherosclerosis. This has changed with the recent completion of a large scale genetic association study (GeneQuest) which found that single nucleotide polymorphisms (SNP) in TSP-1, TSP-2 and TSP-4 were not only associated with premature coronary artery disease, but were the only three of more than 80 SNP analyzed that were highly correlated with disease. These observations prompted us to assess the effects of high glucose on TSP release from vascular cells, and a significant increase was observed. Based upon these findings, we hypothesize that changes in TSP production by vascular cells exposed to high glucose may lead to the accelerated development of atherosclerotic lesions in diabetes. Now, by studying the functional differences between the variants, insights can be gained into the mechanisms by which the TSPs may induce atherosclerotic lesions in diabetes. Accordingly, the overall goal of this project is to elucidate the role of the TSPs in the accelerated development of atherosclerotic lesions in diabetes and to identify the molecular basis for the proatherogenic effects of the variant forms of TSP. The Specific Aims are: 1. To establish the mechanism by which glucose regulates TSP expression in vascular cells. 2. To characterize the expression of TSPs in the vascular wall, heart and brain of diabetic Zucker rats and to establish differences between diabetic and control Zucker rats in TSP expression patterns in response to vascular injury. 3. To identify the molecular mechanisms and the structural basis for the proatherogenic effects of the SNP in the coding regions of the TSPs. The mentored Research Scientist Development Award would greatly assist Dr. Olga I. Stenina in making a successful transition to an independent researcher in the field of diabetes and its cardiovascular complications.