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

NPH 蛋白在控制 Hippo 信号传导中的作用 - 肾结核发病机制的新线索

• 批准号: 235379065
• 负责人: Professor Dr. Bernhard Schermer
• 金额: --
• 依托单位: Nephrologisches Forschungslabor
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/235379065?language=en
• 关键词: role; NPH; proteins; controlling; Hippo

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.

肾病综合征（NPH）是一种常染色体隐性遗传性囊性肾病，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。编码异质性肾胱氨酸蛋白家族的12个基因（NPHP 1 -12）的突变已被鉴定为这种进行性疾病的病因。然而，这些基因的功能还不清楚。基因产物主要定位于初级纤毛连同它们的基体/肾小管细胞的中心粒。纤毛是微管（MT）为基础的触角状细胞器，从人体的几乎所有细胞类型的表面延伸。纤毛轴丝从基体中出现，是一种修饰的中心粒，也是有丝分裂中的纺锤体组织中心。在肾脏中，纤毛从肾小管上皮细胞的顶端表面突出到肾小管的内腔中。作为感觉细胞器，它们将信号从管腔传递到肾小管细胞内部。我们小组以前的工作确定了NPH蛋白作为河马信号通路的调节剂。该途径首先在黑腹果蝇中被描述，并且由于其显示出以高度保守的方式控制细胞增殖和器官大小并且参与肿瘤发生而获得越来越多的关注。该项目的总体目标是了解河马信号通路在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，囊蛋白调节Hippo信号的潜在机制，并研究纤毛和Hippo信号的联系，（2）鉴定通过NPH和纤毛蛋白调节的依赖于NPH的转录靶点，和（3）分析体内去调节的Hippo信号传导在不同的囊性肾病小鼠模型中的作用，特别强调潜在的治疗选择。