Proatherogenic effect of thrombospondins in diabetes

描述(由申请人提供)： 加速的动脉粥样硬化和微血管并发症是糖尿病患者死亡和住院人数最多的原因。然而，导致这些并发症的分子机制仍然知之甚少。由于我们的工作由NIDDK K01奖支持了3年，我们最近报道，在基础状态和损伤反应中，血栓反应蛋白-1(TSP-1)在2型糖尿病动物模型Zucker大鼠的大血管中显著升高，这表明该蛋白在该动物模型和糖尿病患者加速的动脉粥样硬化和增加的再狭窄中发挥了作用。TSP-1具有大量有文献记载的致动脉粥样硬化特性，包括遗传和生化证据。这种蛋白质也是最有效的抗血管生成剂之一，这一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控，这为应用于动脉粥样硬化的小鼠模型提供了一个新的方向。申请者正在提交一份竞争性的续期拨款申请，以支持她在一种新的实验方法--小鼠动脉粥样硬化模型--方面的培训。该计划的总体目标是阐明葡萄糖在大血管主要细胞类型中上调TSP-1表达的特定转录机制，并验证TSP-1在小鼠模型血管壁的高表达有助于动脉粥样硬化病变和新生内膜形成的假说。该项目的长期目标是揭示导致糖尿病血管并发症发展的高血糖诱导的分子机制。其具体目的是：1.确定TSP-1基因的启动子区域和参与葡萄糖和创伤后TSP-1转录上调的核因子；2.在转基因小鼠模型中直接证明TSP-1在血管壁上的表达增加有助于动脉粥样硬化病变的发生和损伤后新生内膜的形成。这些实验的结果将：1)确定调节TSP-1表达的靶点，TSP-1是一种可能导致血管糖尿病并发症的强大的抗血管生成和促动脉粥样硬化蛋白；2)提供关于葡萄糖影响血管细胞的分子机制的更多信息；以及3)直接证明TSP-1可能在糖尿病和血管并发症之间起联系作用。

DESCRIPTION (provided by applicant): Accelerated atherosclerosis and microvascular complications account for the greatest numbers of deaths and hospitalizations in diabetic patients. However, the molecular mechanisms responsible for these complications remain poorly understood. As a result of our work on the project supported for 3 years by a K01 award from NIDDK, 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. This protein is also one of the most potent anti-angiogenic 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 a new direction for the applicant - use of a mouse model of atherosclerosis. The applicant is submitting a competing renewal of the grant to support her training in a new experimental approach - mouse model of atherosclerosis. The overall goal of the proposed program, which represents a competing renewal application, is to elucidate specific transcriptional mechanisms responsible for the upregulation of TSP-1 expression by glucose in major cell types of large blood vessels and to test the hypothesis that increased expression of TSP-1 in the vascular wall of a mouse model contributes to the development of atherosclerotic lesions and neointima formation. The long-term objective of the project is to uncover the hyperglycemia-induced molecular mechanisms that lead to development of diabetic vascular complications. The Specific Aims are: 1. To identify the promoter region of the TSP-1 gene and nuclear factors responsible for the transcriptional up-regulation of TSP-1 expression by glucose and wounding; 2. 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 and neointima formation in response to injury. The results of these experiments will: 1) identify targets for the regulation of expression of TSP-1, a potent anti-angiogenic and pro-atherogenic protein that may contribute to vascular diabetic complications; 2) provide additional information about the molecular mechanisms for the effects of glucose in vascular cells; and 3) demonstrate directly that TSP-1 may serve as a link between diabetes and vascular complications.