柱细胞发育障碍在GJB2基因缺失突变耳聋中的发生机制及干预

GJB2基因（编码Connexin26蛋白）缺失突变是导致遗传性非综合征型耳聋最常见的原因，目前临床上对该疾病只能诊断，尚无基于机制的治疗。本研究组前期研究发现耳蜗发育过程中Corti隧道未开放是GJB2基因缺失突变导致非综合征型遗传性耳聋的关键事件，然而柱细胞发育障碍的机制仍不清楚。本项目提出恢复柱细胞正常发育早期干预治疗GJB2相关遗传性聋的策略。拟应用Connexin26基因敲除小鼠模型，研究耳蜗发育过程中钙离子超载激活Calpain，通过调控Fgfr3信号通路参与柱细胞微管支架蛋白形成的机制；同时通过发育早期双靶向转染GJB2基因及FGF2，恢复Connexin26表达及逆转Fgfr3信号异常通路，以期实现在重建Corti器形态基础上挽救Connexin26通道功能。本课题旨在揭示Connexin26缺陷导致非综合性遗传性耳聋的机制并为干预策略提供理论基础和实验依据。

GJB2 gene (encoded Connexin26, Cx26) mutation was the most common causes for nonsyndromic hereditary deafness. There is no mechanism based therapy on this disease and could only diagnose at present. Our previous research revealed that the tunnel of Corti remained close during inner ear development is the major event present in GJB2 gene mutation caused nonsyndromic inherited deafness，however，the mechanisam of pillar cell dysplasia is still unknow.In this study, we propose the strategy that maintaining the normal development of pillar cell is essential for the early intervention. We propose to investigate the mechanism of calcium overload induced calpain activity mediated pillar cell dysplasia during cochlea developmental stage，as well as the role of Fgfr3 signal pathway in microtubule cytoskeleton formation in pillar cell using a Cx26 knockout mouse model. We will also explore the potential way of reversing the Fgfr3 signal pathway and to recover the expression of Cx26 by GJB2 gene and FGF2 transfection in the early developmental stage. Our ultimate goal is to double target for rebuilding the morphology of the organ of Corti and to rescue the channel function of Cx26. This study may provide novel targets on the therapeutic interventions and mechanisms of nonsyndromic inherited deafness caused by Cx26 deficiency.