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

肾病（NPH）是一种常染色体隐性囊性肾病，是儿童和年轻人终末期肾病（ESRD）最常见的遗传原因。与其他肾囊性疾病相比，NPH的肾脏大小正常甚至缩小。编码异质肾胱氨酸蛋白家族的12个基因（NPHP1-12）突变已被确定为导致这种进行性疾病的原因。然而，这些基因的功能尚不清楚。基因产物主要定位于肾小管细胞的初级纤毛及其基小体/中心粒。纤毛是基于微管（MT）的天线状细胞器，从人体几乎所有细胞类型的表面延伸出来。纤毛轴突从基体出现，这是一个经过修饰的中心粒，在有丝分裂中也起着纺锤体组织中心的作用。在肾脏中，纤毛从肾小管上皮细胞的顶端表面伸入肾小管的管腔。作为感觉细胞器，它们将信号从管腔传递到管状细胞内部。我们小组先前的工作确定了NPH蛋白是河马信号通路的调节因子。这一途径首次在果蝇中被描述，并因其以高度保守的方式控制细胞增殖和器官大小并参与肿瘤发生而受到越来越多的关注。该项目的总体目标是了解hippo信号通路在NPH分子发病机制中的功能，并揭示其对其他囊性肾病的贡献，重点是将hippo信号通路作为未来治疗策略的潜在靶点。在本项目中，我们将(1)研究通过NPH蛋白和其他纤毛、囊生蛋白调控Hippo信号传导的机制，研究纤毛与Hippo信号传导的联系；(2)鉴定通过NPH蛋白和纤毛蛋白调控的河马依赖的转录靶点；(3)分析在体内不同小鼠囊肾疾病模型中河马信号通路失调控的作用，并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.