FGFR3在纤维环/椎间盘退变及修复中作用与机制研究

椎间盘退变（DD）发生率高，严重危害健康，因机制不全清楚，缺乏有效生物治疗。纤维环（AF）在椎间盘稳态维持、退变及修复中起重要作用,但对其退变与修复机制包括修复细胞来源及治疗措施研究较少。近年来发现DD与衰老、纤毛结构/功能密切相关。我们近期发现FGFR3敲除鼠、斑马鱼及兔均有椎间盘退变，敲除鼠有AF细胞衰老与纤毛长度改变，FGFR3与纤毛相关蛋白KIF2A有结合,且FGFR3可能是一种新的间充质干细胞标记分子。我们推测FGFR3可能经纤毛、KIF3A/Gli2/P16途径拮抗AF细胞衰老，且FGFR3+MSCs可能参与DD及AF损伤修复。本课题将综合利用遗传工程斑马鱼及小鼠、培养椎间盘/AF细胞等模型以及活体影像、谱系示踪、基因编辑等技术，阐明FGFR3在AF/椎间盘退变及修复中的作用与机制，为从调节FGFR3活性及补充FGFR3+干细胞角度开发防治AF及椎间盘退变的措施提供实验依据。

The incidence of intervertebral disc degeneration (DD) has been increasing in modern society, severely endangering the health. The mechanism for intervertebral disc degeneration is not clear, which causes lack of effective biological treatments. Annulus fibrosus (AF) is critical for maintaining the homeostasis of intervertebral discs. However, there are few studies on the mechanisms of the degeneration and repair of AF and treatment measures for AF degeneration. The cells involved in AF/discs repair are not clear either. During recent years, DD has been found to be closely related to senescence, which is associated with abnormal cilium structure / function. Recently we have found that mice, zebrafish and rabbits with FGFR3 deficiency all have degeneration of intervertebral disc and AF. Our preliminary data indicate FGFR3 can slow down cell senescence through regulating cilia length, and FGFR3 may be a new marker of mesenchymal stem cells. We speculate that FGFR3 plays an important role in intervertebral disc, especially in AF homeostasis. FGFR3 may antagonize AF cell senescence through cilia and KIF3A/Gli2/P16 pathway, and FGFR3 positive mesenchymal stem cells may participate in DD and AF repair. In this project, we will comprehensively use genetically engineered zebrafish and mice, and multiple state-of-art techniques such as cultured intervertebral disc, and two-photon microscope based dynamic imaging , in vivo gene editing , genetic lineage tracing, etc. to elucidate the role and mechanism of FGFR3 in AF/ intervertebral disc degeneration and the cells involved in the repairing of injured discs/AF , which will provide experimental basis for developing treatment measures of AF/ intervertebral disc degeneration through regulating FGFR3 activity and application of FGFR3 positive MSCs.