骨代谢疾病形成的核心因素是骨组织稳态的破坏，其中破骨细胞的过度激活或抑制都会影响骨组织稳态。TRAF1作为TRAFs家族的重要成员，参与免疫、炎症反应等多种细胞生物过程，但TRAF1能否调控破骨细胞的分化和功能以及相应的机制，尚未有研究报道。我们的前期研究表明，TRAF1的表达水平在破骨细胞分化过程中上升，并且TRAF1敲除后小鼠骨量显著上升，破骨细胞的分化受到明显抑制；该结果提示TRAF1参与了对破骨细胞分化和功能的调控。本研究拟采用TRAF1破骨前体细胞条件性敲除小鼠，通过体内动物实验和体外细胞实验，明确TRAF1对破骨细胞分化和功能的调控作用；然后利用RNA-seq、蛋白质互作组学等分子生物学技术筛选并验证TRAF1的下游靶蛋白，并进一步结合细胞水平和动物疾病模型的挽救实验，系统性地揭示TRAF1调控破骨细胞分化和功能的分子机制。本项目将为发掘新的骨代谢疾病的临床治疗靶点提供可能。

The core factor of the formation of bone metabolic diseases is the destruction of bone tissue homeostasis, in which over-activation or over-inhibition of osteoclasts will affect the bone tissue homeostasis. As an important member of the TRAFs family, TRAF1 participates in many cellular biological processes, such as immunity and inflammatory response. However, whether TRAF1 can regulate the differentiation and function of osteoclasts and the corresponding mechanism has not been reported yet. Our previous investigations revealed that the expression level of TRAF1 increased during the process of osteoclast differentiation. Besides, after TRAF1 knockout, bone mass increased markedly, and osteoclast differentiation was significantly inhibited; the results suggested that TRAF1 participated in the regulation of osteoclast differentiation and function. In this study, mice with conditional TRAF1 knockout in osteoclast precursor cells will be used to determine the regulatory effect of TRAF1 on osteoclast differentiation and function through animal experiments in vivo and cellular experiments in vitro. RNA-seq, proteomics of protein interaction and other molecular biology techniques will be employed to screen out and verify the downstream target protein of TRAF1. In addition, rescue experiments based on both cellular experiments and animal disease model will be performed to systematically reveal the molecular mechanism of TRAF1 regulating osteoclast differentiation and function. This project will provide the possibility for the exploration of new clinical therapeutic targets of bone metabolic diseases.