常染色体显性多囊肾病是最常见的单基因遗传性肾病，由PKD1或PKD2基因突变引起编码的PC1和PC2表达异常所致，二种蛋白均表达于肾小管上皮细胞的初级纤毛。初级纤毛致病假说是目前最为关注的共同发病通路。本项目申请者成功建立了多囊肾病PKD1基因敲入小鼠模型，通过蛋白组学的研究获得了多个囊肿相关差异表达蛋白，其中蛋白cordon-bleu（Cobl）经过前期研究，发现在多囊肾病肾小管上皮细胞中表达异常，并引起初级纤毛的结构和功能变化。但Cobl如何被调控？Cobl又是通过哪个途径来影响初级纤毛，其机制尚未明确。本项目拟明确PC1的异常是否通过Ca2+/CaM来调控Cobl表达；Cobl是否在SNX9作用下引起细胞骨架紊乱而导致初级纤毛异常。另外，在多囊肾病小鼠中通过阻断上述发病通路，观察对囊肿的影响。本项目的研究结果将丰富多囊肾病中初级纤毛的发病机制，为寻找干预靶标奠定一定的理论基础。

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic hereditary kidney disease. ADPKD is caused by mutations in either the PKD1 or the PKD2 gene, which encodes polycystin-1 (PC1) or polycystin-2 (PC2), respectively. Polycystins are both localized in the primary cilia of renal tubular epithelial cell. The etiology hypothesis of primary cilia is the common pathogenesis pathway of ADPKD. The applicant of this project successfully founded PKD1 gene knock-in mouse model. Several different expression proteins were found by the proteomics study. The results of former study indicated that cordon-bleu (Cobl) was abnormal expression in the renal tubular epithelial cells of ADPKD and affected the structure and function of primary cilia. However, it was not clear that the mechanisms of which pathway regulates the expression of Cobl and through which pathway Cobl can affect the primary cilia. The applicant plans to find out whether the abnormal expression of PC1 regulates Cobl through Ca2+/CaM and whether under the help of SNX9, Cobl can lead to the disorder of cytoskeleton and primary cilia. Moreover, we plan to observe the changes of cysts by blocking the above pathogenesis pathway in the PKD1 gene knock-in mouse model. From this project, more information about the pathogenesis of primary cilia and the therapeutic target will be obtained.