纤毛是真核生物特有的细胞器，在动物细胞表面广泛分布。纤毛组装缺陷及功能异常导致波及多种器官的人类疾病。由于纤毛研究起步晚，其基础理论研究、相关疾病认定和治疗都相对落后。近几年临床病理学研究发现，在多种组织来源的癌症中均存在纤毛组装抑制。癌细胞抑制纤毛组装这一现象暗示，纤毛在癌症发生发展过程中可能存在作用。本项目前期研究鉴定了癌细胞抑制纤毛组装的关键蛋白OFD1，敲低OFD1，可以诱导细胞恢复纤毛生成。有意思的是，在正常细胞中，纤毛生成诱导细胞退出分裂进入休眠期；在大部分癌细胞中，纤毛生成不能诱导细胞进入休眠期，却会导致细胞死亡。本项目将明确癌细胞抑制纤毛组装的具体分子机制，解析纤毛调控细胞分裂周期和细胞死亡的关键通路，并探讨OFD1作为新的癌症治疗靶点的可能性。通过以上研究将加深我们对纤毛组装/去组装调控机制的理解，拓展对纤毛相关疾病的认识，并为癌症治疗提供新的手段。

Cilia are cellular organelles ubiquitously protruding from the surfaces of almost all types of cells in mammal. The assembly/disassembly defects or functional disorders of cilia lead to a numbers of human diseases affecting multiple organs, collectively known as ciliopathies. Compared to other cellular organelles, the studies of cilia were neglected for many years. The basic knowledges of cilia and ciliopathies remains largely unknown. Recently, pathological studies of cancer tissues show that cells from several major types of cancers loss cilia expression, though the correlated normal tissues always have cilia. These results suggest that cilia may have functions in tumorigenesis and tumor development. Our preliminary results indicated that OFD1 may play critical inhibitory roles in ciliogenesis in cancers, and that the depletion of OFD1 by RNAi induced cilia formation and attenuated cell proliferation. Interestingly, we also found that ciliogenesis led to cell cycle exit and entering into quiescence of normal cells, but led to cell death of most cancer cells. In the proposed study, we will dissect the mechanisms of OFD1 regulated ciliogenesis in cancers, investigate the molecular pathways of cilia-controlled cell cycle regulation and cell death, and finally confirm the possibility of OFD1 to be a novel cancer target. The proposed studies will acquire insightful understandings of cilia and the basic knowledge of ciliopathies, and provide promising method for cancer therapy.