噪声介导COX2激活抑制Nrf2/ARE信号通路在促进耳蜗毛细胞死亡中的作用机制及干预研究

Inflammation/immune-mediated cochlear damage was proposed as an important contributor to NIHL. Previous studies have been demonstrated that the inflammatory response after acoustic injury was caused by activation and recruitment of circulating immune cells in the cochlea, however, recent studies have shown that the immune/inflammation-related gene expressed in the cochlear resident cells in the organ of Corti were also involved in the pathogenesis of NIHL. We recently revealed that COX2 is expressed in the mouse cochlea and its up-regulation in sensory hair cells after noise exposure promotes noise-induced hair cell death. However, the signal pathways involved in this process remains unknown. In the present study, we propose to investigate the effect of COX2-mediated inhibition of Nrf2/ARE pathway on the hair cell death after noise over-exposure. We will also explore the potential way to preserve cochlear sensory hair cells by inhibiting COX2 expression and/or promoting Nrf2 activation. This study may provide new evidence and novel targets on the therapeutic interventions of NIHL.

炎性损伤是噪声性聋(NIHL)发生的重要机制。以往研究认为噪声暴露后耳蜗内炎性细胞渗入介导的炎症反应是耳蜗炎性损伤的主要原因，新近研究发现耳蜗Corti器细胞自身表达的炎症相关分子在NIHL发病机制中可能起更重要作用。我们前期研究发现环氧化酶2（COX2）在小鼠耳蜗Corti器表达并在噪声暴露后促进耳蜗毛细胞死亡中起重要作用，然而其作用机制仍不清楚。本课题拟采用耳蜗细胞体外培养、Cox2基因敲除小鼠、Nrf2基因敲除小鼠模型研究噪声介导COX2激活通过抑制Nrf2/ARE信号通路参与耳蜗毛细胞死亡的机制，并通过对COX2/Nrf2/ARE信号传导中关键分子的干预，以期实现噪声暴露后维持耳蜗毛细胞的存活，为预防和治疗NIHL提供新的依据和靶点。

炎性损伤是噪声性聋(NIHL)发生的重要机制。新近研究发现耳蜗Corti器细胞自身表达的炎症相关分子可能在NIHL发病机制中起重要作用。我们前期研究发现炎症因子环氧化酶2（COX2）在小鼠耳蜗Corti器表达并在噪声暴露后促进耳蜗毛细胞死亡中起重要作用，然而其作用机制仍不清楚。本课题研究发现COX2组成性表达于小鼠耳蜗支持细胞及神经细胞内，而不同噪声损伤模式中耳蜗Corti 器内COX2 表达变化并不相同，强噪声暴露可显著增加耳蜗内COX2 表达。抑制COX2表达则可明显降低耳蜗毛细胞内氧自由基（ROS）水平，减少毛细胞死亡。进一步研究发现，COX2表达抑制后可显著增强噪声暴露后耳蜗内抗氧化反应元件Nrf2蛋白水平。同时，我们研究发现不同于噪声性耳聋，体外抑制COX2表达，并不能阻止顺铂诱导的耳蜗毛细胞损伤。我们的研究结果表明，噪声暴露后耳蜗内COX2表达变化可显著影响耳蜗毛细胞内氧化应激水平，并可能通过抑制Nrf2 活性表达影响耳蜗毛细胞存活。另外，我们的实验结果也表明COX2在不同耳蜗损伤模型中所起作用可能不同。