Wnt和Notch信号调控椭圆囊Lgr5阳性前体细胞再生毛细胞的研究

Sensory hair cells are required for auditory and vestibular function, and their loss leads to hearing loss and balance dysfunction. In cochleae, my previous studies have reported the Wnt responsive cell Lgr5+ cells are hair cell progenitors and Wnt signals can regulate these Lgr5+ hair cell progenitors; while in utricle, Notch inhibition has been reported to promote the supporting cell differentiate into hair cell. Canonical Wnt signaling is a well-conserved pathway that is critical for the self-repair of many organs. However our insights into the role of Wnt signaling pathway and Wnt responsive cells in utricle self-repair are still very limited. This project has been designed to systematically investigate the role of Lgr5+ cells in utricle self-repair and the mechanism regulating it, with the goal to promote hair cell regeneration from Lgr5+ cells, thus partially recover the balance function. In this project we propose to fulfill the following aims: Aim1: we will characterize the proliferation, the differentiation and the hair cell regeneration capacity of Lgr5+ cells in neonatal and adult utricle hair cell damage model both in vitro and in vivo; Aim2: based on the result of aim1, we will investigate how Wnt and Notch signal regulate the proliferation and differentiation of Lgr5+ cells, thus promote hair cell regeneration from Lgr5+ cells in neonatal and adult utricle hair cell damage model both in vitro and in vivo; Aim3: we will investigate the function of new regenerated hair cell original from Lgr5+ cells; Aim4: we will investigate the correlative recovery of balance function induced by hair cell regeneration with VSEP. The goal of this study is to establish the experimental foundation for the clinical treatment of balance dysfunction by stem cell therapy.

感觉毛细胞在听觉和平衡功能中起了重要作用，毛细胞缺失会导致听力损失和平衡障碍。在耳蜗中申请人之前的研究表明Wnt相关细胞Lgr5阳性细胞是毛细胞前体细胞，Wnt信号可以促进其增殖;而在椭圆囊中Notch信号可以调控支持细胞分化为毛细胞。目前Wnt信号和Wnt相关细胞在椭圆囊自我修复中的作用及调控机制还不清楚。本项目将研究Lgr5阳性细胞在椭圆囊自我修复中的作用及调控机制，拟通过这两种信号的共调控促进Lgr5阳性细胞再生具有功能的毛细胞，从而部分恢复平衡功能。拟实现目标：一在新生和成年小鼠离体和活体椭圆囊毛细胞损伤模型中，研究Lgr5阳性细胞增殖，分化及再生毛细胞的能力；二研究如何通过这两种信号的调控促进Lgr5阳性细胞再生毛细胞；三研究来源于Lgr5阳性细胞的新生毛细胞功能；四检测通过这两种信号促进毛细胞再生所导致的平衡功能恢复。本项目将为临床上应用毛细胞前体细胞恢复平衡功能奠定实验基础。

感觉毛细胞在听觉和平衡功能中起了重要作用，毛细胞缺失会导致听力损失和平衡障碍。在耳蜗中申请人之前的研究表明 Wnt 相关细胞 Lgr5 阳性细胞是毛细胞前体细胞，Wnt 信号可以促进其增殖；而在椭圆囊中 Notch 信号可以调控支持细胞分化为毛细胞。目前Wnt 信号和 Wnt 相关细胞在椭圆囊自我修复中的作用及调控机制还不清楚。本项目主要研究在新生和成年小鼠离体和活体椭圆囊毛细胞损伤模型中Lgr5阳性前体细胞增殖和分化及再生毛细胞的能力，接着以此为基础研究如何通过Wnt和Notch信号通路的共调控促进Lgr5阳性前体细胞再生毛细胞。在本研究中我们发现在椭圆囊毛细胞受到损伤后可以激活Lgr5+支持细胞的表达，并且这些细胞可以作为毛细胞的前体细胞；激活Wnt信号通路并且抑制Notch信号通路可以促进毛细胞的再生，再生的毛细胞具有成熟毛细胞的标志。本项目将为临床上应用毛细胞前体细胞恢复平衡功能奠定实验基础，在不久的将来如果可以通过信号通路的调控显著促进前体细胞再生毛细胞，这就具有巨大的临床应用价值，也向着在临床治疗上应用这些毛细胞前体细胞恢复平衡功能的长期目标前进了一大步。相关研究成果以第一或者通讯作者发表在包括国际著名学术期刊Nature Communication，Frontiers in Molecular Neuroscience等在内的42篇SCI文章上，其中影响因子大于10的文章2篇，5-10分的文章25篇，另外作为主编著有一本论著。