前庭感觉上皮重度损伤与修复机制及Atoh1基因治疗研究

眩晕的发生与前庭毛细胞、支持细胞及神经支配受损密切相关。在前期动物实验中，我们发现了一类前庭感觉上皮严重损伤的病理类型：前庭毛细胞和支持细胞正常结构均消失，呈现为单层扁平上皮，但仍出现少量的新生毛细胞。目前对于其病理特点和修复机制尚缺乏系统研究，其干预研究也未见报道。结合我们既往研究，我们推测这些新生毛细胞和扁平上皮细胞可能由支持细胞或感觉上皮周围的移行上皮细胞分化而来，而Notch信号通路和下游因子Atoh1参与了此修复过程。本课题中，我们首先将评估其病理特点和神经支配改变；然后探讨Notch信号通路和Atoh1以及细胞有丝分裂在修复过程中的作用；并利用转基因小鼠进行支持细胞谱系示踪，以明确支持细胞的动态变化及新生毛细胞的来源；最后我们探索利用腺相关病毒介导Atoh1过表达，在重度损伤后的前庭感觉上皮中诱导毛细胞再生的可行性，为阐明前庭感觉上皮重度损伤的修复机制和研发其干预措施提供线索。

The occurrence of vertigo is closely associated with impairments of hair cells, supporting cells and innervations in the vestibular sensory epithelium. In our previous study, we found a type of vestibular sensory epithelial severe lesion, which was characterized by the loss of normal cytoarchitecture of both vestibular hair cells and supporting cells, and the replacement of monolayer flat cells. However, limited spontaneous regeneration of hair cells was found in the severely damaged vestibular sensory epithelium. So far, there is no systematic study on its damage and repair mechanism, and its intervention research has not been reported. Based on our previous studies, we hypothesize these new hair cells and flat epithelial cells may trans-differentiated from supporting cells or cells in the surrounding transitional epithelium, and Notch signaling and the downstream factor, Atoh1, may play a role in the repair process. In this study, we will firstly assess pathological features and changes of the innervation in the severely damaged vestibular sensory epithelium. Then we will study the mechanism of the repair, including Notch signaling factors, Atoh1 and cell mitosis. We will use transgenic mice for lineage tracing of supporting cells to identify the dynamic changes of supporting cells and the origin of new hair cells. Finally, we will over-express Atoh1 by using an adeno-associated virus, to induce hair cell regeneration in the severely damaged vestibular sensory epithelium. Our study will provide clues for illuminating the mechanisms of the damage and repair and developing interventions in the vestibular sensory epithelium after a sever lesion.