SIRT1调控线粒体分裂及线粒体自噬抵抗顺铂耳毒性的机制研究

顺铂致耳蜗毛细胞死亡是其耳毒性的主要病理机制，目前尚无有效的干预靶点。我们在前期多种细胞和动物模型中已证实SIRT1可减轻顺铂致毛细胞损伤，但具体机制尚未阐明。线粒体自噬通过清除功能障碍的线粒体发挥维持线粒体稳态的作用。线粒体自噬功能抑制已证实参与众多线粒体功能障碍所致疾病的发生发展。我们在HEI-OC1毛细胞中发现顺铂通过抑制线粒体自噬影响线粒体功能，进而造成细胞死亡；激活SIRT1促进HEI-OC1毛细胞的线粒体分裂及线粒体自噬，从而发挥保护毛细胞的作用。因此我们提出科学假设：SIRT1通过调控线粒体分裂及线粒体自噬抵抗顺铂耳毒性。本项目拟采用耳蜗毛细胞系、耳蜗组织培养、基因工程小鼠等多种实验工具，阐明线粒体分裂及线粒体自噬在顺铂耳毒性中的关键作用及SIRT1的调控机制，为防治顺铂耳毒性提供治疗靶点。

Promoting cochlear hair cells death is the main pathological mechanism of cisplatin-induced ototoxicity, and presently there is no effective intervention target. We have previously demonstrated that SIRT1 attenuates cisplatin-induced hair cell damage in a variety of cell and animal models, but the specific mechanism has not been elucidated. Mitophagy plays a role in maintaining mitochondrial homeostasis by clearing dysfunctional mitochondria. Inhibition of mitophagy has been shown to be involved in the development of many diseases caused by mitochondrial dysfunction. We found that cisplatin disturbed mitochondrial function by inhibiting mitophagy in HEI-OC1 auditory cells, which led to cell death. Activation of SIRT1 promoted mitochondrial fission and mitophagy of HEI-OC1 auditory cells, thereby protecting hair cells. Therefore, we propose a scientific hypothesis: SIRT1 resists cisplatin ototoxicity by regulating mitochondrial fission and mitophagy. This project intends to use the inner ear hair-lik cell line, cochlear tissue culture, transgenic mice and other experimental tools to clarify the key role of mitochondrial fission and mitophagy in cisplatin ototoxicity and the regulatory role of SIRT1, thus providing a therapeutic target for cisplatin ototoxicity.