耳聋是全球性重大公共卫生问题，线粒体12S rRNA A1555G是母系遗传性聋病的主要易感突变。研究发现携带该突变的家系及个体存在听力损伤程度、发病年龄和耳聋外显率的明细差异，环境因素（如氨基糖苷类抗生素等）与核基因（如YARS2等）能影响聋病表型表达，但核基因如何调控聋病表型的机制尚不明确。本项目拟在我们前期研究基础上，探讨母系遗传性耳聋的分子致病机制及听觉功能重建策略。首先，利用携带12S rRNA和YARS2基因突变的细胞模型，研究线粒体和核修饰基因互作导致耳聋发病的机制；其次，构建患者特异性iPS细胞，探讨遗传缺陷对iPS细胞分化毛细胞的影响；最后，通过CRISPR-Cas9技术对突变的核修饰基因进行基因校正，尝试修复患者来源iPS细胞的功能缺陷，实现内耳毛细胞功能重建。本项目的实施将有利于进一步诠释耳聋的致病机制，为聋病及其他母系遗传性疾病细胞干预治疗提供新的思路和理论依据。

Deafness is a major public health problem worldwide, affecting nearly 30 million people in China. Mitochondrial 12S rRNA A1555G is a major susceptibility mutation of matrilineal hereditary deafness. Studies showed that those families and individuals carrying 12S rRNA A1555G mutation exhibits different onset ages、various degrees of hearing loss and also distinct disease penetrance. Environmental factors (such as exposure of aminoglycoside antibiotics, etc.) and nuclear genes (such as YARS2) have expressed the regulation effect of hearing loss morbidity; however, the specific mechanism of how nuclear modify gene regulating a deaf disease phenotype is still unclear. This project is designed to further study the molecular pathogenesis mechanism of matrilineal hereditary deafness and explore hearing function recovery strategy base on our previous research results. First, we will assess the effects of the YARS2 mutation on mitochondrial dysfunction associated with the A1555G mutation. The second aim is to investigate the effects of genetic defects on hair cell differentiation from patients-derived iPS cells. Finally, we aim to rescue the mitochondrial dysfunction in patients-derived iPS cells by CRISPR - Cas9 mediated genome editing. The implementation of this project will be conducive to a deepen understanding the mechanism of the interaction between nuclear and mitochondrial genome. In addition, the success of this study will provide valuable information and technology for the development of intervention and therapeutic approaches for deafness in China and worldwide, as well as other maternally transmitted diseases.