E3泛素连接酶CHIP调控自噬在类风湿性关节炎发病中的免疫机制研究

Rheumatoid arthritis (RA) cannot be effected a radical cure as well as its high disability rate, which cause serious damage to public health and increase the burden on society. The disturbed T-cell function and homeostasis are the main pathogenesis of RA. So far, its pathogenesis has not been fully confirmed until now. There is still a lack of mechanism-based prevention and treatment for RA. Ubiquitin signaling and autophagy pathway are known to regulate aspects of T cells activities and play important role in immune regulation, with an emphasis on latest development in the crosstalk between ubiqutin signaling and selective autophagy. Our preliminary results demonstrated that E3 ubiquitin ligase CHIP is required for T-cell differentiation and activation, and it plays a role in the bone destruction of inflammatory arthropathy through regulating osteoblastogenesis and bone formation. Blocking of CHIP significantly attenuated disease in a CIA mouse model of RA and influenced the expression of autophagy genes. However, the exact mechanisms remain unclear. Using molecular and epigenetic tools, we propose to investigate the regulation of T-cell differentiation and activation by CHIP, clarify the relation between ubiqutin signaling and selective autophagy in CIA mouse model and RA patients. This study is expected to provide a theoretical basis for elucidating the molecular mechanisms of RA and to identify new approaches to prevent and treat RA.

类风湿性关节炎(RA)具有不可根治和致残率高等特点，严重危害公众健康，增加社会负担，RA发病与T细胞功能紊乱以及T细胞亚群数量失衡有关。其确切机制不明，至今仍缺乏有效的防治方法。蛋白质泛素化与自噬通路通过调控T细胞分化在免疫调节中发挥着重要作用，二者之间存在密切联系。我们前期研究发现，CHIP作为泛素化通路中一个关键的连接酶通过调控RA的T细胞分化和细胞因子的分泌，进而影响骨代谢参与炎性关节病骨质破坏的发生。阻断CHIP可调控细胞自噬变化和有效改善RA的症状。其确切分子机制不明。本研究拟采用分子生物学，表观遗传学等方法，在小鼠CIA模型和RA人群中，探讨CHIP对T细胞分化调控的分子机制，明确CHIP与细胞自噬之间的关系，为阐明RA发生机制提供理论基础，为临床防治RA提供新的方法。

类风湿性关节炎(RA)具有不可根治和致残率高等特点，严重危害公众健康，增加社会负担.，RA发病与T细胞功能紊乱以及T细胞亚群数量失衡有关。其确切机制不明，至今仍缺乏有效的.防治方法。蛋白质泛素化与自噬通路通过调控T细胞分化在免疫调节中发挥着重要作用，二者.之间存在密切联系。我们前期研究发现，CHIP作为泛素化通路中一个关键的连接酶通过调控RA.的T细胞分化和细胞因子的分泌，进而影响骨代谢参与炎性关节病骨质破坏的发生。阻断CHIP.可调控细胞自噬变化和有效改善RA的症状。其确切分子机制不明。本研究拟采用分子生物学，.表观遗传学等方法，在小鼠CIA模型和RA人群中，探讨CHIP对T细胞分化调控的分子机制，明确.CHIP与细胞自噬之间的关系，为阐明RA发生机制提供理论基础，为临床防治RA提供新的方法