A role for NPH proteins in controlling Hippo signaling - Novel clues to the pathogenesis of Nephronophthisis

肾单位病(NPH)是一种常染色体隐性遗传性囊性肾病，是儿童和青壮年终末期肾病(ESRD)最常见的遗传病因。与其他肾囊性疾病相比，NPH患者的肾脏大小正常，甚至缩小。编码异质性肾胱氨酸蛋白家族的12个基因(NPHP1-12)的突变已被确定为导致这种进行性疾病的原因。然而，这些基因的功能还没有被很好地理解。基因产物主要定位于原生纤毛及其肾小管细胞的基底体/中心粒。纤毛是一种基于微管(MT)的天线状细胞器，几乎从人体所有类型的细胞表面延伸出来。纤毛轴丝从基底体出现，这是一种改良的中心粒，在有丝分裂中也起着纺锤体组织中心的作用。在肾脏，纤毛从肾小管上皮细胞的顶面伸入肾小管腔内。作为感觉细胞器，它们将信号从管腔传递到管状细胞的内部。我们课题组以前的工作确定NPH蛋白是河马信号通路的调节蛋白。这一途径最早是在果蝇中被描述的，自从被证明以一种高度保守的方式控制细胞增殖和器官大小并参与肿瘤的发生以来，得到了越来越多的关注。本项目的主要目标是了解河马信号通路在NPH分子发病机制中的作用，并揭示其在其他囊性肾脏疾病中的作用，重点关注河马信号通路作为未来治疗策略的潜在靶点。在这个项目中，我们将(1)研究通过NPH蛋白和额外的纤毛、成囊蛋白调节河马信号的机制，并研究纤毛和河马信号的联系，(2)确定通过NPH和纤毛蛋白调节的河马依赖的转录靶标，以及(3)分析体内河马信号在不同囊性肾病小鼠模型中的作用，特别强调潜在的治疗方案。

Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease that constitutes the most frequent genetic cause for end-stage renal disease (ESRD) in children and young adults. In contrast to other renal cystic diseases kidney size in NPH appears normal or even reduced. Mutations of 12 genes (NPHP1-12) that encode for the heterogeneous nephrocystine protein family have been identified as causative for this progressive disorder. The function of these genes, however, is not well understood. The gene products predominantly localize to primary cilia together with their basal bodies/centrioles of renal tubular cells. Cilia are microtubule (MT)-based antenna-like organelles which extend from the surface of almost all cell types of the human body. The ciliary axoneme emerges from the basal body, a modified centriole that also functions as the spindle-organizing center in mitosis. In the kidney, cilia project from the apical surface of tubular epithelial cells into the lumen of the kidney tubules. As sensory organelles they transmit signals from the lumen to the inside of the tubular cells. Previous work of our group identified NPH proteins as regulators of the hippo signaling pathway. This pathway was first described in Drosophila melanogaster and has gained increasing attention since it was shown to control cell proliferation and organ size in a highly conserved manner and to be involved in tumorigenesis. The overarching goal of this project is to understand the function of the hippo signaling pathway in the molecular pathogenesis of NPH and to uncover its contribution to additional cystic kidney diseases with a focus on hippo signaling as a potential target of future therapeutic strategies. In this project we will (1) investigate the mechanism underlying the regulation of Hippo signaling through NPH proteins and additional ciliary, cystogenic proteins and study the connection of cilia and hippo signaling, (2) identify the hippo-dependent transcriptional targets regulated through NPHs and ciliary proteins, and (3) analyze the role of deregulated hippo signaling in vivo in different mouse models of cystic kidney disease with specific emphasis on potential therapeutic options.