微环境对内耳毛细胞的保护作用及其分子机制研究

Deafness is a major public health problem, affecting nearly 30 million people in China. This disease is mainly caused by the loss of sensory hair cells in cochlea. Auditory hair cell regeneration provides great promise for treatment of the disorder. However, there are still enormous challenges lie ahead before the translation of bench results to final clinical applications. A growing body of evidence has shown that inner ear microenvironment protects hair cells against environmental insults, but the specific mechanisms are still poorly understood. Our previous studies showed that stromal cells and endothelial cells can effectively improve the chemoresistance of neighboring cells through MAPK, CXCR4, CTGF, and miRNA signaling pathways. Here, we propose that these pathways may also participate in the microenvironment-mediated protection of hair cells. The overall aim of this investigation is to elucidate the mechanism of this microenvironmental protection and explore the strategy for intervention of stress-induced hair cell impairment. For this purpose, we will further investigate the communication between hair cells and the microenvironmental components by using in vitro co-culture system, high-throughput gene/protein analysis platform, and also experimental animals. The success of this study will provide new insights into the pathophysiology of deafness and also a step toward therapeutic intervention for the disease.

内耳毛细胞是重要的听觉感受器，毛细胞的损伤会导致不可逆的听力下降。寻找毛细胞再生的方法是近年来听觉医学领域最被关注的热点之一，但是现阶段实验研究结果向临床转化应用依旧面临巨大挑战。最近我们和其他研究者发现内耳微环境在应激条件下对毛细胞具有一定的保护作用，但涉及的具体机制尚不明确。该项结果提示我们有可能应用潜在方法在病人进行药物治疗前首先实现对内耳微环境的调控，从而控制药物性耳聋的发生。本课题在前期研究中发现基质细胞和内皮细胞能通过介导MAPK、CXCR4、CTGF、及miRNA等信号途径有效提高其他细胞的耐药性。为此我们推测这些通路可能也参与了微环境对毛细胞的保护作用。本项目拟通过建立体外共培养体系、结合高通量基因/蛋白分析平台、及实验动物模型，进一步明确微环境保护毛细胞损伤作用，阐释其中的分子机制，为耳聋的防治提供新的思路和理论依据。

内耳毛细胞是重要的听觉感受器，毛细胞的损伤会导致不可逆的听力下降，寻找毛细胞损失原因和探索毛细胞再生的方法是近年来听觉医学领域最被关注的热点之一。在本课题实施中，我们进一步分析了线粒体单体型对于亚洲12S rRNA 1555 A>G突变家庭的耳聋易感性，发现线粒体单倍型B增加东亚地区携带12S rRNA 1555A>G突变人群的听力损失风险；分析中国非综合征耳聋人群中MARVELD2的突变位点及频率，发现显著不同于以往报到的巴基斯坦、斯洛伐克、匈牙利和罗马人群，我们的工作还首次筛选到新致聋候选突变MARVELD2 c.730G>A；分析了中国非综合征性听力损失人群中的耳聋相关基因GJB2突变谱和基因型，数据显示约21.18%汉族非综合症耳聋是由于GJB2基因突变导致；最后课题成功构建了斑马鱼基因沉默、基因敲除模型，研究结果证明了gtpbp3基因缺陷、mtu1基因缺陷影响毛细胞功能进而导致听力损失。以上研究结果在线发表于《Nucleic Acids Research》、《Protein Cell》、《The International Journal of Biochemistry & Cell Biology》等国际知名学术期刊，收到同行专家高度评价，其中mtu1的工作得到了《人民日报》、《新华网》、《浙江日报》等媒体专题报道。