转录因子E2F1在年龄相关性听力损失中的作用及机制研究

The incidence of Age-related hearing loss (ARHL) is high. The pathogenesis of AHL is still unknown. The most prominent histopathological change in the inner ear of aged patients who had ARHL was a decrease in the population of the spiral ganglion cells (SGCs). Apoptosis is the important mechanism of age-related cochlear injury. E2F1 could constitute a common convergence point of the apoptosis pathways. Our previous work confirmed E2F1-CDK1 signaling pathway involved in SGC apoptosis by co-administration of kanamycin and furosemide in the guinea pigs. We observed E2F1 expression increased obviously in the SGCs of older age C57BL/6J mice. The roles of the E2F1 in age-related SGC death have not been addressed. In this study, we will observe the changes in the expression of E2F1 and related signal molecules in the SGCs of C57BL/6J mice, which are useful for studying ARHL features. The CBA/J mice would be applied as the control strain. We will interfere the E2F1 expression to identify its important role, and further validate the protective effect of CR8 on SGCs. This study will provide new ideas for SGC protection and promote the transformation process of auditory neuron protection from laboratory research to clinical application.

年龄相关性听力损失（ARHL）的发病率高，发病机制未明。耳蜗内毛细胞和螺旋神经节细胞（SGC）的丢失是ARHL的主要原因，而最显著的病理变化是SGC的丢失。已有研究证实，细胞凋亡是年龄相关性耳蜗损伤的重要机制，转录因子E2F1构成了多种凋亡途径的共同的交汇点。我们前期研究证实E2F1参与卡那霉素和速尿联合致聋豚鼠引起的SGC凋亡；E2F1在高月龄C57BL/6J小鼠SGC的表达增高。而E2F1在年龄相关性SGC丢失的作用未见报道。本实验拟利用C57BL/6J小鼠作为ARHL模型，利用CBA/J小鼠作为对照，研究E2F1及相关信号分子在年龄相关性SGC丢失中的表达变化，通过基因干预E2F1的表达证实其重要作用，并进一步检测CR8对SGC的保护作用。为保护SGC、对抗ARHL提供新的思路，推动听觉神经元保护药物从实验室研究至临床应用的转化进程。

年龄相关性听力损失（ARHL）的发病率高，发病机制未明。耳蜗内毛细胞和螺旋神经节细胞（SGC）的丢失是ARHL的主要原因，而最显著的病理变化是SGC的丢失。已有研究证实，细胞凋亡是年龄相关性耳蜗损伤的重要机制，转录因子E2F1构成了多种凋亡途径的共同的交汇点。我们前期研究证实E2F1参与卡那霉素和速尿联合致聋豚鼠引起的SGC凋亡；E2F1在高月龄C57BL/6J小鼠SGC的表达增高。而E2F1在年龄相关性SGC丢失的作用未见报道。本实验拟利用C57BL/6J小鼠作为ARHL模型，利用CBA/J小鼠作为对照，研究E2F1及相关信号分子在年龄相关性SGC丢失中的表达变化，通过基因干预E2F1的表达证实其重要作用。我们发现随月龄增加C57BL/6J小鼠听阈下降、耳蜗SGC丢失，转录因子E2F1、CDK1、 Bcl-2表达增加。通过腺相关病毒过表达E2F1的3月龄CBA小鼠较正常3月龄CBA小鼠SGC减少，而通过腺相关病毒抑制E2F1表达后的C57BL/6J小鼠较正常3月龄C57BL/6J小鼠SGC丢失减少。证实E2F1在年龄相关性SCG凋亡中发挥重要作用过。为保护SGC、对抗ARHL提供了新的思路。