Role of the Notch Pathway in Kidney Injury

描述(由申请人提供)。这项建议的主要目的是探索Notch通路在慢性肾脏疾病和肾脏纤维化的发展中发挥重要作用的假设。我们通过大规模的基因组筛选发现，Notch途径蛋白在患者和动物模型、慢性肾脏疾病和纤维化中受到调控。在这项应用中，我们建议进行一项系统的分析，以检查肾小管上皮细胞Notch信号在成人肾脏基线和病变肾脏中的作用。首先，我们将研究肾小管上皮细胞Notch信号是否在成人肾脏的动态平衡、衰老和修复中发挥作用。接下来，我们将分析哪些Notch受体和配体亚型与损伤过程中的肾脏损伤有关。第三个具体目标将确定Notch诱导的上皮功能障碍和间质纤维化的分子机制。目前的建议将建立在我们最初的观察基础上，并探索Notch信号在成人肾脏基线和损伤模型中的作用。这些研究不仅有助于加深我们对肾上皮细胞动态平衡的了解，而且有助于开发基于Notch的抑制剂治疗慢性肾脏疾病。 公共卫生相关性：美国约有2000万人患有慢性肾脏疾病(CKD)。慢性肾脏病与心血管死亡率增加约5倍有关。仅在美国，终末期肾病(ESRD)患者的患病率就达到了50多万人，并在全球以5%-6%的速度增长。达到ESRD的患者的5年生存率约为20%，这比许多不同的实体瘤更差。这些数据突显了全球医学界当前问题的重要性和紧迫性。在表型和组织学水平上，慢性肾脏疾病的发展遵循非常相似的路径。肾脏纤维化是导致终末期肾病的最终共同途径。我们的研究旨在了解肾脏纤维化的分子机制。

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. PUBLIC HEALTH RELEVANCE: Approximately 20 million people in the US suffer from chronic kidney disease (CKD). CKD is associated with an approximately 5-fold increase in cardiovascular mortality. The prevalence of patients with end-stage renal disease (ESRD) reaches more than half a million people in the U.S. alone, and increases at a rate of 5-6% worldwide. The 5-year survival of patients who reaches ESRD is around 20%, which is worse than many different solid tumors. These data highlight the importance and urgency of the current problem in the medical community on a global scale. On phenotypic and histological levels, chronic kidney disease development follows a very similar path. Fibrosis of the kidney is the final common pathway leading to ESRD. Our studies aim to understand the molecular mechanism of kidney fibrosis.