NPHP-related polycystic kidney disease in man and mice

人和小鼠中与 NPHP 相关的多囊肾病

基本信息

批准号：
77903122
负责人：
Professor Dr. Heymut Omran
金额：
--
依托单位：
Klinik für Kinder- und Jugendmedizin - Allgemeine Pädiatrie
依托单位国家：
德国
项目类别：
Clinical Research Units
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/77903122?language=en
关键词：
NPHP related polycystic kidney disease

项目摘要

Our recent demonstration, that mutations of orthologous genes result in cystic kidney disease in mice and man, gives now a unique opportunity to study pathogenesis and therapy. We have shown that recessive hypomorphic mutations of NPHP3 cause cystic kidney disease (adolescent nephronophthisis) in children and adults, whereas more severe NPHP3 mutations result in either lethal congenital disease (heterotaxia) and/or renal-hepaticpancreatic dysplasia syndrome. Likewise we demonstrated that orthologous mutations in mice result in similar renal phenotypes. We recapitulated these distinct renal disorders and generated three distinct mouse models with stable expression of phenotypes: i) hypomorphic Nphp3pcy/pcy mutant mice (adult onset); ii) Nphp3ko/ko deficient mice (congenital disease); iii) compound mutant Nphp3ko/pcy mice (early onset). In addition we have contributed to the understanding that NPHP proteins function as gatekeepers at the ciliary base. Now we will utilize our mouse models as well as patient material to decipher the specific function of NPHP proteins on the cellular level. For that purpose we will perform immuno- EM and high resolution IF to study the NPHP protein network at the ciliary gate and analyze the functional sequelae of NPHP mutations for the ultrastructure of the ciliary necklace as well as the y-connectors using transmission and freeze fracture EM. In addition we will analyze in mutant and control cilia to determine which ciliary proteins are affected by altered NPHP gate function in man and mice.

我们最近证明，直系同源基因的突变会导致小鼠和人类的囊性肾病，这为研究发病机制和治疗提供了独特的机会。我们已经证明，NPHP3 的隐性亚形性突变会导致儿童和成人的囊性肾病（青少年肾痨），而更严重的 NPHP3 突变会导致致命的先天性疾病（异位性）和/或肾肝胰腺发育不良综合征。同样，我们证明小鼠的直系同源突变会导致相似的肾脏表型。我们概括了这些不同的肾脏疾病，并生成了三种具有稳定表达表型的不同小鼠模型：i) 低等态 Nphp3pcy/pcy 突变小鼠（成年发病）； ii) Nphp3ko/ko 缺陷小鼠（先天性疾病）； iii) 复合突变型 Nphp3ko/pcy 小鼠（早发）。此外，我们还有助于理解 NPHP 蛋白在纤毛基部发挥着守门人的作用。现在，我们将利用我们的小鼠模型以及患者材料来破译 NPHP 蛋白在细胞水平上的特定功能。为此，我们将进行免疫电镜和高分辨率 IF 来研究睫状门处的 NPHP 蛋白网络，并使用透射和冷冻断裂分析 NPHP 突变对睫状链超微结构以及 y 连接器的功能后遗症EM。此外，我们将分析突变体和对照纤毛，以确定哪些纤毛蛋白受到人和小鼠中 NPHP 门功能改变的影响。