Role of the Notch Pathway in Kidney Injury

描述（由申请人提供）。该提案的主要目标是探索Notch途径在慢性肾脏疾病和肾纤维化的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途径蛋白在慢性肾脏疾病和纤维化患者和动物模型中受到调节。在本申请中，我们提出进行系统分析以检查肾小管上皮Notch信号传导在基线和患病肾脏的成人肾脏中的作用。首先，我们将研究肾小管上皮Notch信号是否在成人肾脏稳态，衰老和修复中发挥任何作用。接下来，我们将分析哪种Notch受体和配体亚型负责损伤期间的肾损伤。第三个具体目标是明确Notch诱导上皮功能障碍和间质纤维化的分子机制。目前的提议将建立在我们最初的观察基础上，并探索Notch信号在基线和损伤模型中在成人肾脏中的作用。这些研究不仅有助于加深我们对肾上皮稳态的理解，而且有助于基于Notch的抑制剂治疗慢性肾脏疾病的潜在开发。

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 chronic kidney disease and kidney fibrosis. We found via large scale genome screening that Notch pathway proteins are regulated in patients and animal models chronic kidney disease and fibrosis. In this application we propose to perform a systematic analysis to examine the role of renal tubular epithelial Notch signaling in the adult kidney at baseline and diseased kidneys. First we will examine whether tubular epithelial Notch signaling plays any role in the adult kidney homeostasis, aging and repair. Next we will analyze which Notch receptor and ligand isoforms is responsible for the renal damage during injury. The third specific aim will define the molecular mechanism of Notch induced epithelial dysfunction and interstitial fibrosis. The current proposal will built on our original observation and explore the role of Notch signaling in the adult kidney both at baseline and in injury models. These studies will help not only deepen our understanding of renal epithelial homeostasis, but also aid the potential development of Notch based inhibitors for chronic kidney disease.