感音神经性聋主要由耳蜗毛细胞的不可逆损失造成。申请人主要从事内耳毛细胞再生与保护及内耳干细胞调控机制的研究。主要学术成果包括：1发现两种可被Wnt信号通路调控的内耳干细胞群体，Lgr5和Axin2阳性内耳干细胞；2在活体小鼠耳蜗中发现毛细胞损伤后，内耳干细胞可以再生毛细胞；3在活体小鼠中发现Wnt信号和XIAP对内耳毛细胞的保护作用及机制。近5年来发表SCI论文31篇，总影响因子213.8。目前在小鼠毛细胞损伤模型中，内耳干细胞在耳蜗修复中的作用及多种信号通路对其的协同调控机制还不清楚。本项目首先将研究在小鼠毛细胞损伤模型中内耳干细胞增殖，分化和再生毛细胞的能力，接着研究如何通过多种信号通路的协同调控促进其再生毛细胞，同时研究协同调控后来源于内耳干细胞的新生毛细胞的功能，并检测通过协同调控促进毛细胞再生所导致的听觉功能恢复。本项目将为临床上应用内耳干细胞治疗听力损失奠定理论和实验基础。

The main reason for sensorineural hearing loss is the irreversible loss of sensory hair cells. The applicant’s research focus on the hair cell regeneration, protection and the mechanism regulating the inner ear stem cells. My previous studies have reported: 1) two Wnt responsive inner ear stem cell populations: Lgr5+ cells and Axin2+ cells, both of which can regenerate hair cell and be regulated by Wnt signaling pathway; 2) there is hair cell regeneration after hair cell damage in the neonatal mice cochlea in vivo and Lgr5+ inner ear stem cells contribute to the new regenerated hair cell; 3) activation of Wnt signaling could protect the hair cell against the neomycin-induced damage. In recent five years, the applicant published 31 SCI paper, the total impact factor is 213.8. By far in neonatal mice cochlear hair cell damage model, the role of inner ear stem cells in cochlear self-repair and the mechanism regulating these inner ear stem cells remains unclear. Based on the previous studies, in this project first we will characterize the proliferation, differentiation and hair cell regeneration capacity of Lgr5+/Axin2+ inner ear stem cells in hair cell damage model both in vitro and in vivo. Secondly, we will systematically investigate the roles of multiple signaling pathways, including Wnt，Notch，FGF，Shh，Hippo in regulating the proliferation and differentiation of Lgr5+/Axin2+ inner ear stem cells, and thus promote the hair cell regeneration. At meanwhile, we will investigate the function of new regenerated hair cells originated from Lgr5+/Axin2+ inner ear stem cells and investigate the correlative hearing restoration induced by hair cell regeneration with ABR and DPOAE. The goal of this study is to establish the experimental foundation for the clinical treatment of sensorineural hearing loss by stem cell therapy.