ErbB4/Atoh1信号通路在耳蜗毛细胞发育中的作用及其机制研究

位于耳蜗基底膜的毛细胞是哺乳动物的听觉感受细胞，其损伤后可导致感音神经性耳聋，对毛细胞发育机制的研究可为毛细胞再生和感音神经性耳聋的治疗提供新的方向。ErbB4受体是再生医学的重要干预靶点，可成功介导心肌再生。其在耳蜗中特异性表达于毛细胞，但仍不清楚ErbB4在内耳的功能。我们的前期研究提示，耳蜗毛细胞ErbB4受体可产生入核信号分子s80HER，调节泛素连接酶Huwe1和WWP1的表达水平，进而影响Atoh1和ErbB4本身的泛素化降解；通过对Atoh1蛋白水平的精确调控，防止持续高表达的Atoh1激活JNK通路，进而导致毛细胞的不可逆死亡。本研究拟利用耳蜗基底膜体外培养模型以及耳蜗毛细胞ErbB4特异性阻断或激活的小鼠模型，从泛素蛋白酶体通路、JNK通路等方面入手，阐明ErbB4/Atoh1信号通路在毛细胞发育过程中的作用和机制，从而为感音神经性耳聋的治疗提供新的理论依据和分子靶点。

Cochlear hair cells are sensory receptors for the auditory system in mammals, and its damage can lead to permanent sensorineural hearing loss. Studies on hair cell developmental mechanisms will provide valuable information for the regeneration of hair cells and the treatment of sensorineural hearing loss. ErbB4 is an important therapy target in regenerative medicine and has already expressed remarkable ability for myocardial regeneration. ErbB4 specially presents in hair cells in the organ of Corti. However, the function of ErbB4 in hair cells remains unclear. Our previous studies indicated that ErbB4 could regulate the expression of ubiquitin protein ligases Huwe1 and WWP1 via nuclear factor s80HER and thus the degradation of Atoh1 and ErbB4 itself by ubiquitination. ErbB4 regulation of Atoh1 could prevent the activation of JNK pathway and hair cell death from continual high expression of Atoh1. Based on the findings, we intent to study the central role of ubiquitin-proteasome pathway and JNK pathway in the mechanism of ErbB4/Atoh1 signal pathway by using both in vitro culture model of cochlea organ and ErbB4 -blocked or –activated mouse models. The aim of this study is to illustrate the function and mechanism of ErbB4/Atoh1 signal during cochlear hair cell development, and provide theoretical basis and new molecular targets in treatment of sensorineural hearing loss.