CD4+ T细胞的嘌呤代谢异常对内耳听觉功能的影响及其作用机制

内耳免疫反应可导致感音神经性耳聋的发生，感音神经性聋主要是耳蜗毛细胞不可逆损失造成的。研究表明介导固有免疫反应的巨噬细胞在毛细胞存活中发挥了重要作用，但适应性免疫反应在内耳听觉功能中的作用尚无深入研究。申请人之前的研究表明小鼠CD4+ T细胞中敲除Miga2可导致嘌呤代谢紊乱，前期数据表明Miga2TKO小鼠出现听力下降症状，WT小鼠注射黄嘌呤可导致听力下降。但是CD4+ T细胞对毛细胞存活的具体作用还不清楚。本项目将通过Miga2TKO基因敲除小鼠研究CD4+ T细胞对毛细胞存活的调控作用及机制，拟实现以下目标：一、Miga2TKO小鼠在不同时间点的听觉功能及毛细胞存活；二、Miga2TKO小鼠耳蜗内的代谢紊乱对毛细胞存活的影响；三、CD4+ T细胞调控毛细胞存活的具体机制。本项目将为临床上通过免疫治疗感音神经性耳聋提供科学依据和理论基础。

Immune response in the inner ear can lead to sensorineural deafness, which is mainly caused by irreversible loss of hair cells in the cochlea.Studies have shown that macrophages, which mediate the innate immune response, play an important role in hair cell survival, but the role of adaptive immune response in inner ear auditory function has not been thoroughly studied.Previous studies of the applicant showed that depletion of Miga2 in CD4+ T cells in mice could lead to the disorder of puine metabolism. Preliminary data showed that hearing loss was observed in Miga2TKO mice, and hearing loss was observed by injection of xanthine in WT mice.But the specific role of CD4+ T cells in hair cell survival is unclear.This project will study the regulatory effect and mechanism of CD4+ T cells on hair cell survival through Miga2TKO knockout mice, aiming to achieve the following objectives:Ii. Effects of metabolic disorders in Miga2TKO mice cochlea on hair cell survival;Iii. Specific mechanism of CD4+ T cells regulating hair cell survival.This project will provide scientific basis and theoretical basis for the clinical treatment of sensorineural deafness by immunotherapy.