DRP1依赖的线粒体自噬在老年性聋发病中的机制研究

耳蜗毛细胞的衰老是老年性聋（AHL）的重要病理特征，迄今毛细胞衰老具体机制尚未阐明。在心脏衰老及多种神经退行性疾病中已证实线粒体自噬障碍造成故障的线粒体累积，导致线粒体质量下降和功能障碍，从而损伤细胞正常生理功能和诱导衰老。那么，线粒体自噬障碍是否会引起耳蜗毛细胞衰老？我们前期研究在AHL小鼠模型中发现线粒体自噬在耳蜗细胞中呈现年龄相关性下降，进一步抑制线粒体自噬可加速AHL的进程。在氧化应激诱导的衰老听觉细胞模型里我们发现下调DRP1抑制线粒体自噬可加速毛细胞衰老，上调DRP1可延缓毛细胞衰老。据此我们提出假设：随年龄增长，DRP1下调抑制线粒体自噬，从而导致线粒体功能障碍，最终造成毛细胞衰老、死亡及AHL的发生。本项目拟采用基因工程小鼠、基底膜培养、听觉细胞系等工具，阐明DRP1调控线粒体自噬在毛细胞衰老和AHL发生发展中的关键作用及机制，为防治AHL提供新思路及干预靶点。

The cochlear hair cell senescence contributes to age-related hearing loss (AHL). The mechanism of hair cell senescence remains unknown. In the pathogenesis of cardiac aging and neurodegenerative disease, mitophagy inhibition accumulates dysfunctional mitochondrion leading to the decline of mitochondrial quality and function, that have a negative effect on the cellular function. However, whether mitophagy impairment is involved in the senescence of hair cells remains unknown. In our previous study, mitophagy showed an age-related decline in cochlear cells of AHL mice, and further inhibition of mitophagy accelerated AHL progression. In the hydrogen peroxide-induced senescence auditory cell, we found that the down-regulation of DRP1 inhibited mitophagy, thereby senescence accelerated . On the contrary, the up-regulation of DRP1 delayed hair cell senescence. Based on this, we hypothesize that during aging, DRP1 down-regulation inhibits mitophagy, leading to mitochondrial dysfunction, which ultimately leads to hair cell senescence, even cell death and AHL. This study intends to clarify the key role and mechanism of DRP1 regulation of mitophagy in the senescence of the hair cell and the development of AHL with transgenic mice, cochlear tissue culture and auditory cell line. Hopefully, we could provide novel therapeutic targets for the prevention and treatment of AHL.