ADPKD发病率高、危害大，除发生双肾等多器官囊肿性病变外，男性患者精子鞭毛结构高发异常，合并生殖障碍。本课题组前期应用定量蛋白质组学技术和生物信息学分析发现，PKD1可能通过调控NPHP4，在纤毛形成过程中发挥重要作用。基于上述发现，本课题拟使用临床样本、细胞模型和动物模型，筛查精子鞭毛异常男性患者PKD1/NPHP4的遗传变异，研究PKD1/NPHP4与精子鞭毛结构异常的相关性；利用纤毛形成体外模型和睾丸局部Nphp4基因过表达的Pkd1-/-诱导性敲除小鼠模型，进一步分析PKD1对NPHP4蛋白的相互作用及其对NPHP4的泛素化调控机制，结合PKD1、NPHP4和Hippo信号通路关键蛋白表达水平与动精子数量和纤毛（鞭毛）结构的关联分析，解析PKD1/NPHP4通路参与纤毛形成调控的分子机制，阐明ADPKD患者精子鞭毛结构异常的病理机制，为筛选疾病的临床干预靶点提供

ADPKD is one of the most serious diseases that affect human health with a high prevalence. Beside cystic lesions in kidney and other organs, infertility occurs in up to 60% of male ADPKD patients with marked sperm motility and flagellar structures defects. Our previous studies of iTRAQ and protein interaction network analysis in testicular tissue of ADPKD patients showed that PKD1 may regulate the expression of NPHP4. The differential expression proteins significantly enriched in "cilia formation" molecular interaction network. Based on the above findings, we will first compare the expressions and subcellular localizations of PKD1 and NPHP4 in the testicular tissues and sperm between healthy controls and ADPKD patients to illustrate the correlation of sperm flagella structural abnormalities and the aberrant expression of PKD1 or NPHP4. Second, we will investigate the expression of PKD1, NPHP4 and several key proteins in Hippo signal pathway when cillia are induced in ADPKD-iPS and PC12 cells. we will attempt to illustrate the interactions of those proteins and the possible ubiquitination mechanism involving in the regulation of PKD1 on NPHP4. Finally, in vivo study by Nphp4 overexpression experiments in Pkd1-/- gene knockout mice will further be used to explore the influence of PKD1, NPHP4 expressions upon the sperm motility and its flagellar structure. This project may improve our understanding of the molecular pathogenesis of spermatic flagellum structure defects in male patients with ADPKD.