Role of the Notch pathway in Kidney Injury

描述（由申请人提供）：本提案的主要目的是探索Notch通路在糖尿病肾病发展中起重要作用的假设。通过大规模基因组筛选，我们发现Notch通路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通路在糖尿病并发症的介导中起重要作用。本研究的具体目的是：目的一是表征葡萄糖诱导足细胞Notch通路激活的分子机制。在第二个特定目标中，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信号的遗传操纵来实现这一目标。在第三个特定目标下，我们将通过基因工程动物确定肾小球上皮Notch在介导糖尿病肾病发展中的体内功能作用。从长远来看，这项工作将阐明决定特定的、环境依赖的细胞反应的分子信号机制，如细胞凋亡和生长停滞，这些反应可能由不同细胞类型的高血糖引发。

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.