DRP1依赖的线粒体自噬在老年性聋发病中的机制研究

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.

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。

习总书记提出：预防是最经济最有效的健康策略。预防衰老引起的疾病是国家重大需求。年龄相关性听力损失（Age-related hearing loss, AHL）就是一个预防为主，临床治疗获益不大的疾病。AHL患者众多，据2013年WHO数据显示，超过33%的65岁及以上老年人有听力下降的表现，到85岁以上，发病率则高达80%。听觉减退是痴呆的重要危险因素。治疗AHL及其导致的痴呆必将造成家庭及国家医疗巨大的负担。因此，阐明听觉衰老的发生机制，重视AHL的预防符合国家健康策略。 .耳蜗毛细胞的衰老是AHL的重要病理特征，迄今毛细胞衰老具体机制尚未阐明。线粒体功能障碍在多种细胞衰老中发现，包括毛细胞。我们在前期研究积累中发现自噬参与到毛细胞的死亡中，线粒体自噬是自噬的一个分支。那么是否毛细胞中线粒体功能改变是否与衰老过程中线粒体自噬有关呢？基于此本课题展开了探索，发现在AHL小鼠模型中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。DRP1可能是中间关键的调控分子。在氧化应激诱导的衰老听觉细胞里我们证实了DRP1调控线粒体自噬影响毛细胞衰老。DRP1受到miR-34a的调控。.本项目阐明了miR34a/DRP1在调控线粒体自噬中担任重要角色，参与毛细胞衰老及AHL的发生。本项目从毛细胞衰老的角度深入探讨了AHL与线粒体自噬的关系，为预防老年性聋的发病提供干预靶点。在基金的支持下，已发表了SCI论文4篇，参加全世界最大型耳科研究国际会议交流1次，培养博士和硕士各1名。