miR-34a调控SIRT1/TFEB抑制自噬参与老年性聋发病的机制研究及干预策略

Hair cell loss is one of the major pathological feature of age-related hearing loss (AHL). Our previous study has proved that miR-34a increased with aging, accompanied with hair cell loss and hearing loss. However, the detailed mechanism that miR-34a induces hair cell death is not fully understood. Recently, it is suggested that autophagy attenuates cisplatin and noise-induced hair cell damage. Therefore, we wonder whether miR-34a activation induces cochlear cell death and AHL via modulating autophagy. We then demonstrated that the blockage of autophagic flux occurred in aging cochlea of an AHL animal model. In HEI-OC1 cells line, overexpression of miR-34a inhibited autophagic flux by the blockage of autophagic degradation and induced cell death. Moreover, miR-34a modulated autophagy via suppressing TFEB nuclear translocation, after decreasing SIRT1 expression. Thus, we hypothesize that miR-34a activation with aging leads to cochlear cell death and AHL via modulating autophagy by controlling SIRT1 expression and TFEB nuclear translocation. The aim of this study is to elucidate the key mechanism that miR-34a induces hair cell loss in the pathogenesis of AHL via modulating autophagy through regulating SIRT1/TFEB using the tools including transgenic mice and adenovirus vector. Hopefully we could reveal the mechanism of AHL and provide novel therapeutic targets for the prevention and treatment of AHL.

老年性聋（AHL）重要的病理改变是耳蜗毛细胞的死亡。我们前期已证实miR-34a在AHL小鼠耳蜗呈年龄相关性升高，与毛细胞死亡及听力损失程度正相关，但miR-34a诱导毛细胞死亡的机制尚未阐明。新近有研究证实自噬可减轻噪声及顺铂造成的毛细胞损伤。那么，miR-34a是否通过调控自噬介导AHL耳蜗毛细胞死亡和AHL？机制是什么？我们随后发现自噬流在老年AHL小鼠耳蜗受抑制；体外实验显示miR-34a过表达抑制自噬流并诱导毛细胞死亡。深入探究发现miR-34a下调SIRT1，阻滞TFEB入核抑制自噬。我们提出假设：随年龄增长,激活的miR-34a通过SIRT1阻滞TFEB入核，降低自噬流，诱导毛细胞死亡及AHL的发生。本项目拟采用包括基因工程小鼠及腺病毒转染在内的多种手段，阐明miR-34a调控SIRT1/TFEB介导自噬在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。

老年性聋是三大老年人常见病之一。随着老龄化进程的进一步加快，这将会带来很严重的社会健康问题。但目前老年性聋的发病机制尚未明确。本课题围绕miR-34a，SIRT1和自噬与毛细胞死亡和老年性聋之间的关系中展开研究。在研究中发现，自噬确实在老年性聋耳蜗病变中有很明显的改变，不同于自噬流的升高和下降，这是自噬过程阻滞的表现，具有特殊性。自噬的变化由miR-34a和SIRT1参与调控，结合既往的研究我们对miR-34a和SIRT1对老年性聋的调控作用有了更全面的了解。自噬中的一个分支——线粒体自噬，在老年性聋进程中亦发挥重要的作用，线粒体自噬的下调会加快老年性聋的进程，并且与线粒体动态平衡相关。而SIRT1的上调有通过自噬在HEI-OC1细胞和C57BL/6小鼠中都能够提高毛细胞的存活率，延缓老年性聋的进程。这是一个有效的延缓老年性聋的方式。这为以后老年性聋的防治提供实验依据和思路。本课题着重在阐明miR-34a参与老年性聋的机制及如何利用找到的研究结果寻求延缓老年性聋的方法两个方面进行研究，并且拿到了相关的实验成果。