Regulation of thrombospondin-1 expression by glucose

描述（由申请人提供）：血管并发症是糖尿病患者死亡的主要原因。然而，导致这些并发症的分子机制仍然知之甚少。我们最近报道，在2型糖尿病动物模型Zucker大鼠的大血管中，血栓反应蛋白-1 （TSP-1）的表达在基础条件和损伤反应中显著升高，表明该蛋白在该动物模型和糖尿病患者中加速动脉粥样硬化和增加再狭窄中起作用。TSP-1具有许多证据充分的致动脉粥样硬化特性，包括遗传和生化证据，也是最有效的抗血管生成药物之一，其功能与糖尿病并发症直接相关。我们的初步数据表明，TSP-1的表达在转录水平上受到葡萄糖的调节，并提出了这种激活的可能信号通路。我们将验证一种假设，即高糖急性刺激动脉平滑肌细胞（SMC）迅速激活的特定信号和转录分子机制介导大血管壁中TSP-1表达的增加，并在高血糖和加速动脉粥样硬化之间提供联系。该项目的总体目标是阐明葡萄糖在SMC中上调TSP-1表达的具体信号和转录机制，并测试血管壁中TSP-1表达的增加是否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。具体目标是：1。鉴定葡萄糖上调TSP-1基因的启动子区域和核因子；2. 确定葡萄糖调控TSP-1表达的信号通路；3. 在转基因小鼠模型中直接证明血管壁中TSP-1表达的增加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TSP-1的调控靶点，TSP-1是一种有效的抗血管生成和促动脉粥样硬化蛋白，可能导致血管性糖尿病并发症；2)为葡萄糖在SMC中作用的分子机制提供更多信息；3)直接证明TSP-1可能是糖尿病和血管并发症之间的联系。

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.