yap/taz-lin28a通路促进听觉毛细胞再生修复的功能和机制研究

In human damage to inner ear hair cells (HCs) is irreversible, which causes hearing and balance disorders. In contrast, the zebrafish lateral line constantly renew and regenerate hair cells through of support cell (SC) amplification and HC differentiation. Understanding mechanisms that regulate HC regeneration using zebrafish may shed light on factors that promote regenerative ability of human hair cells. The applicant has used RNA-Seq to systematically investigated zebrafish lateral line regeneration and uncovered dynamic changes in the expression of signaling pathways during HC regeneration (PNAS 2014). One of them named lin28a is rapidly upregulated in lateral line post HC injury. Preliminary data indicates that yap/taz is activated to induced lin28a expression in HCs post injury. Overexpression of lin28a promotes while lin28a mutation inhibits hair cell regeneration. Mechanistic study shows that lin28a plays a critical role in balancing HC differentiation and SC amplification during regeneration. Lin28a inhibits expression of a group of HC differentiation genes. Furthermore, Wnt activation acts downstream of lin28a to enhance SC amplification. Our project aims to understand the cellular and molecular mechanisms of how yap/taz pathway regulates lin28a to promote hair cell regeneration in zebrafish, which will provide novel therapeutic targets for triggering regeneration of functional hair cells in human.

人类内耳听毛细胞不可再生导致听力疾病仍缺乏有效的治疗手段。斑马鱼侧线毛细胞与内耳听毛细胞在发育、结构和功能上非常类似，但是它具有极强的再生能力，是研究听毛细胞再生机制的理想模型，对于促进听力疾病再生治疗具有重要意义。申请人前期工作通过对侧线毛细胞损伤后再生过程不同时段的大规模转录组分析，发现了一系列与侧线毛细胞再生相关的基因和分子通路（PNAS 2014），其中基因lin28a的表达在毛细胞损伤后迅速增加，前期结果提示损伤信号首先激活yap/taz信号通路进而促进lin28a在毛细胞中高表达。进一步功能研究发现lin28a是调控再生过程中细胞分化和增殖平衡的关键因子， lin28a抑制一系列分化基因的表达，同时激活Wnt通路促进增殖。本课题将在此基础上进一步研究，yap/taz信号通路调控lin28a参与侧线毛细胞再生修复的细胞和分子机制，为临床上听毛细胞的再生治疗提供新的潜在治疗靶点。

斑马鱼侧线毛细胞与内耳听毛细胞在发育、结构和功能上非常类似，但不同的是斑马鱼毛细胞具有极强的再生能力，是研究听毛细胞再生机制的理想模型。申请人通过对侧线毛细胞损伤后再生过程不同时段的大规模转录组分析，发现了一系列与侧线毛细胞再生相关的基因和分子通路，其中基因lin28a的表达在毛细胞损伤后迅速增加。本项目进一步明确了在内耳干/祖细胞缺失的情况下听毛细胞仍然具有很强的再生能力，揭示了毛细胞损伤后yap激活lin28a表达使分化细胞重编程为干/祖细胞促进听毛细胞再生的机制，yap/lin28a促进干/祖细胞再生毛细胞的发现为临床上听毛细胞缺损引起的听力疾病提供了潜在的治疗靶点。