支持细胞发育障碍介导巨噬细胞活化参与GJB2基因突变相关遗传性耳聋发生的机制研究

支持细胞发育障碍继发耳蜗感觉上皮细胞大量快速死亡是GJB2基因突变致聋主要的病理变化，其机制尚不明确。研究发现巨噬细胞活化及吞噬参与多种内耳损伤。我们在Gjb2敲除小鼠中发现，感觉上皮细胞死亡前期活化的巨噬细胞在基底膜底部大量聚集，推测巨噬细胞活化及吞噬参与Gjb2敲除小鼠感觉上皮细胞的大量快速死亡。本课题拟应用空间及时间特异性Gjb2敲除小鼠及巨噬细胞分化、功能缺陷、数量异常转基因小鼠，联合体外细胞共培养及耳蜗培养，研究巨噬细胞活化在GJB2突变感觉上皮细胞快速大量死亡中的作用，探讨GJB2突变支持细胞发育障碍导致IRF-7相关炎症通路激活介导巨噬细胞活化及吞噬的具体机制，从而进一步探索，通过干预内耳巨噬细胞活化及对内耳感觉上皮细胞的吞噬，在维持内耳感觉上皮细胞形态避免基底膜疤痕形成的基础上重建Cx26的基因治疗策略，为实现基于机制的GJB2相关遗传性耳聋干预提供新的思路。

The rapid degeneration of cochlear sensory epithelial cells secondary to the supporting cell developmental disorders is an important pathological change caused by GJB2 gene mutation, and its mechanism is still unclear. Previous studies have found that macrophage activation and phagocytosis are involved in the development of several inner ear injuries. We found in the Gjb2 knockout mouse model that the activation macrophages accumulate under the sensory epithelia in the early stage of sensory epithelial cell death. We hypothesized that macrophage activation and phagocytosis are involved in the rapid degeneration of sensory epithelial cells in mice with GJB2 mutations. This study intends to apply space-specific and time-specific Gjb2 knockout mouse models and macrophage differentiation, functional defects, abnormal number of transgenic mouse models, combined with in vitro cell co-culture and cochlear culture, to study the role of macrophage activation in GJB2 gene mutation-related hereditary deafness, and to explore the specific mechanism of supporting cell developmental disorders leading to IRF-7-related inflammatory pathway mediated macrophage activation. On this basis, we further explored the method of reconstructing Cx26 based on maintaining inner ear sensory epithelial cells by intervening in the activation of inner ear macrophages, reducing the phagocytosis of inner ear sensory epithelial cells, and provides a new strategy for implementing mechanism-based GJB2-related hereditary deafness interventions.