围绕纤毛的发生机制等内容，申请人新近在纤毛内蛋白运输机制及纤毛遗传病致病机理方面取得了重要进展。主要发现包括：(1)阐明纤毛遗传病致病蛋白NPHP2及B9D2在纤毛内的新型相互作用及运输机制；(2)揭示了Kinesin2家族蛋白在感知器官纤毛内的功能；(3)鉴定出部分导致多囊肾及感光细胞凋亡的关键基因；(4)建立人类TCS遗传疾病的动物模型，通过对WDR43基因的研究，阐述了rRNA转录缺陷导致TCS疾病的分子机制。上述研究成果发表在EMBO Journal，PNAS，Nat Cell Biol.及PLOS Genetics等国际重要刊物上，受到领域内同行的高度认可，论文被引用近150次。本申报项目是在前期工作基础上的深入，以斑马鱼、四膜虫等模式动物为材料，进一步探讨纤毛及相关疾病的关系与分子机理，为纤毛遗传疾病的治疗打下理论基础。

Focusing on the study of ciliogenesis, Dr. Chengtian Zhao has made significant progress on his fields. His main contributions include: (1) He first described the interaction between human NPHP-MKS disease proteins and IFT proteins and explained how these ciliopathy proteins are transported in the cilia; (3) He studied the function of Kinesin2 protein family, and described the different transport mechanisms existed in the cilia of various sensory organs; (1) By screening zebrafish mutants with polycystic kidney or photoreceptor degeneration defects, he has identified several genes that play fundamental roles during ciliary transport; (4) By studying a zebrafish mutant modeling human TCS disease, he identified wdr43 gene and established a new model to explain how this gene regulates neural crest development. The related papers were published in those high impact journals, including Nature Cell Biology, EMBO Journal, PNAS and PLOS Genetics, which has received extensive concern and has been cited many times. In this study, he will continue his research on this field and will use both zebrafish and tetrahymena as model animal to study the relationship between cilia and human ciliopathy diseases.

纤毛是一种普遍存在于多种动物细胞中的细胞器，在细胞迁移、分化、信号转导等方面发挥重要作用，同时其发育缺陷也是多种遗传疾病的重要致病原因。本项目以斑马鱼、四膜虫及衣藻等为模式生物，筛选鉴定了一批与纤毛发生相关的基因，并对其进行了功能研究。目前的主要研究进展包括：1）通过生物信息学，原位杂交及生化等方法，筛选出近30个与纤毛发生相关的基因；2）通过对Kif3基因的研究，发现其在感光细胞凋亡过程中的重要功能；3）分离鉴定出zmynd10基因，通过对其研究，发现运动纤毛相关基因缺陷导致胚胎体轴发育弯曲的分子机制；4）发现lrrc23等辐条蛋白在斑马鱼胚胎耳石发育中的重要功能；5）以衣藻、四膜虫等为模式生物，分离鉴定出一批影响纤毛运动的关键辐条蛋白，并对其生化功能进行了分析。上述部分成果发表在JBC，JGG等杂志上，另有部分成果仍在审稿或整理中。通过对这些基因的研究，使我们进一步加深了对纤毛，尤其是运动纤毛的功能认识，对进一步了解人类纤毛相关疾病的发病机理具有重要帮助。