耳聋是全球性的重大公共卫生问题。线粒体遗传是耳聋发病的重要分子基础之一。线粒体tRNASer(UCN)是一个突变热点区域。而且线粒体突变致病具有组织特异性。通过前期研究，课题组在中国人群中发现了一个携带tRNASer(UCN) T7505C突变的家系，通过永生化淋巴细胞功能研究明确了该突变导致线粒体功能障碍，并且构建了该突变的转线粒体细胞系。因此，本课题拟在这些研究基础上，深入探讨耳聋的分子致病机制。首先，利用转线粒体细胞模型分析tRNASer(UCN) T7505C突变对线粒体功能的影响；其次利用上皮细胞构建该突变的iPSCs，定向分化毛细胞样细胞，研究该突变对特异性iPSCs 及定向分化毛细胞样细胞线粒体功能的影响，揭示该突变导致内耳毛细胞功能缺陷的组织特异性及致聋机制。本课题的实施有利于深入诠释线粒体突变的致聋机制，也为耳聋的预防，早期诊断，遗传咨询，干预和治疗提供科学依据。

Hearing loss is a global public health problem. Mitochondrial genetic is one of the important molecular basis of deafness. Mitochondrial tRNASer(UCN) is one of hot spots associated with hearing loss. Also, mitochondrial disease has tissue specificity. Our previous studies identified a Chinese pedigree carrying mitochondrial tRNASer(UCN) T7505C mutation. Functional studies of immortalized lymphocyte carrying mitochondrial tRNASer(UCN) T7505C mutation demonstrate that this mutation lead to mitochondrial function defect. Therefore, the present study will further investigate the pathophysiology of hearing loss. Firstly, we will analysis mitochondrial functional change of cybrids cell lines carrying mitochondrial tRNASer (UCN) T7505C mutation. Secondly, we will establish, identify and evaluate iPSCs, directional differentiation inner ear hair cells carrying this mutation and analysis mitochondrial functional change of specific iPSCs and directional differentiation inner ear hair cells. We will reveal the tissue specificity and deafness mechanism of mitochondrial tRNASer (UCN) T7505C mutation leading to the function defect of inner ear hair cells associated with hearing loss. The success of the project will deeply reveal the pathophysiology of hearing loss. In addition, it will provide value information for prevention, early diagnosis, genetic counseling, intervention and treatment for hearing loss.