Role of the Notch pathway in Kidney Injury

描述（由申请人提供）：本提案的主要目标是探索Notch通路在糖尿病肾病发展中起重要作用的假设。我们通过大规模基因组筛选发现，Notch途径蛋白在糖尿病肾病动物模型中受到调控。体外研究表明，高血糖环境激活Notch通路，这种激活导致肾小球细胞功能障碍。这些观察结果表明，Notch通路在介导糖尿病并发症中起着重要作用。该提案的具体目的是：目的一是表征足细胞中葡萄糖诱导的Notch通路激活的分子机制。在第二个具体目标中，我们将确定Notch通路激活在葡萄糖诱导的足细胞功能障碍中的作用。我们将通过Notch信号的遗传操作来实现这一目标。在第三个具体目标下，我们将通过使用基因工程动物来确定肾小球上皮Notch在介导糖尿病肾病发展中的体内功能作用。从长远来看，这项工作将阐明分子信号传导机制，确定特定的，上下文依赖的细胞反应，如细胞凋亡和生长停滞，可能是由高血糖症在不同的细胞类型触发。

DESCRIPTION (provided by applicant): The primary goal of this proposal is to explore the hypothesis that the Notch pathway plays an important role in the development of diabetic nephropathy. We found via large scale genome screening that Notch pathway proteins are regulated in animal models of diabetic nephropathy. In vitro studies showed that the hyperglycemic milieu activates the Notch pathway and this activation leads to the dysfunction of glomerular cells. These observations suggest that the Notch pathway plays an important role in mediating diabetic complications. The specific aims of the proposal are to: Aim one is to characterize the molecular mechanism of glucose induced Notch pathway activation in podocytes. In the second specific aims we will determine the role of Notch pathway activation in glucose induced podocyte dysfunction. We will achieve this aim via genetic manipulation of Notch signaling. Under the third specific aim we will determine the in vivo functional role of glomerular epithelial Notch in mediating the development of diabetic nephropathy via the use of genetically engineered animals. In the long-term, this work will elucidate molecular signaling mechanisms determining specific, context dependent cellular responses, such as apoptosis and growth arrest that may be triggered by hyperglycemia in different cell types.