显性遗传性多囊肾病（ADPKD）是一种由PKD1或PKD2基因突变所致的肾脏疾病，目前临床上无针对ADPKD的有效治疗方案。但研究发现ADPKD病程严重程度在相同遗传突变背景的家庭成员之间有重大临床差异，提示表观遗传调控可能是导致PKD病人间表型多样性的新机制。我们前期研究发现表观遗传调控因子赖氨酸甲基转移酶Smyd2可促进ADPKD囊肿的形成，进一步研究发现微管蛋白是Smyd2新的作用底物，而微管蛋白是真核生物细胞骨架和初级纤毛的主要组成成分，提示Smyd2在纤毛形成以及细胞有丝分裂中发挥重要作用。本项目拟研究Smyd2在纤毛形成以及ADPKD病理中的作用，以期找到Smyd2参与ADPKD病程的更多机理。本项目是第一个探讨微管蛋白甲基化在纤毛病中作用的研究，将会对包括ADPKD在内的纤毛相关性疾病产生重要影响，也将为开发ADPKD新的治疗策略提供重要依据。

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disease, which is caused by mutations in one of two genes, PKD1 or PKD2 encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. So far, there is no any effective treatment for ADPKD . There is an urgent need for all PKD researchers to understand novel mechanisms and then discover the novel treatment for ADPKD. However, ADPKD cannot be fully understood in terms of the constrained genetic setting, especially, in families with the same genetic mutations but variable disease severity. Epigenetic regulation has emerged as a critical driver of cell fate and survival that targets many pathways. Especially, epigenetic drift can occur even in genetically identical humans, which may be an alternative means of explaining PKD-associated alterations. In our recent study, we found that lysine methyltransferase Smyd2, an epigenetic regulator, promotes cyst formation in ADPKD via the methylation of its novel non-histone substrates, STAT3 and NF-κB. Our preliminary study that tubulin, a major component of the eukaryotic cytoskeleton and primary cilia, may also be a novel substrate of Smyd2, suggesting a role of Smyd2 in ciliopathy. In this study, we will investigate the roles and mechanisms of Smyd2 in the ciliogenesis of ADPKD .We will also investigate the roles of Smyd2 mediated tubulin methylation in mitosis, cytokinesis and abnormal centrosome amplification in different ADPKD mouse models. In addition, we will determine the changes of the methylation of tubulin and the epigenetic signatures in ADPKD samples compared to those in normal human kidney samples. This is the first study to investigate the methylation of α-tubulin on ciliogenesis, which should have high impact on ciliopathy related human diseases, including ADPKD, and should also provide rationale for the development of the novel therapeutic strategy for ADPKD.