FAM83H (F)是目前发现的常显釉质发育不全的主要基因，其在釉质形成中的具体功能不明确，未见文献报道。所有F突变为集中于C端的突变，表明其C端结构与成釉细胞功能及釉质矿化密切相关。现有研究及我们前期研究提示，F与釉原蛋白等多个蛋白结合形成复合体，一方面调控复合体功能，对釉质形成发挥重要作用；另一方面，上游调节CK1α，影响CK1α与β-catenin调节平衡，对成釉细胞连接和极化及釉质矿化起重要作用。本项目拟进行以下研究：选用小鼠成釉细胞系，研究F特定突变、表达变化及CK1α调节，对复合体形成及各蛋白表达和功能，对成釉细胞功能和釉质形成及矿化信号通路的影响；构建小鼠CK1α调节及肾囊膜F突变牙胚移植模型，研究突变对复合体各蛋白时空表达、成釉细胞连接和极化、矿化信号通路及釉质形成的影响；并对细胞和动物模型进行挽救实验，寻找干预靶点。阐明F在釉质形成中的功能及突变致病的分子机制。

To date, FAM83H gene is a major contributor to the etiology of AI. The function of FAM83H during the formation of enamel has not been revealed and no reports focused on it. Until now, all identified mutations are located in the C-terminal of FAM83H and caused hypocalcified AI, which indicates that the C-terminal of FAM83H is important for the function of ameloblasts and enamel mineralization. The present studies and our preliminary studies indicated the following hypothesis：FAM83H combining with CK1α, keratin and amelogenin, functions as a complex. On one hand, it regulates the function of the complex; on the other hand, it upstream regulates CK1α and affects the regulation homeostasis between CK1α and β-catenin, and then plays roles on ameloblast adjunction, polarization and enamel mineralization. The present project plans to perform the following studies: (1)with mouse ameloblast cell line LS8, study the effects of expression alteration of Fam83h, specific Fam83h mutations, and the CK1α regulation on: the formation of the complex, the expression and function of the proteins, the function of ameloblasts and enamel formation as well as signaling pathway for mineralization; (2)with mouse models, study the effects of the CK1α regulation alteration and Fam83h mutations on: ameloblast adjunction and polarization, spatio-temporal expression of the proteins, signaling pathway for mineralization, enamel formation; (3) rescue on cell and mouse models, explore the potential intervention targets. The project aims to reveal the function of FAM83H during enamel formation and molecular mechanism of AI resulting from FAM83H mutations, and to provide new way for prevention and control of the disease.