Spag6基因缺陷致小鼠前庭功能异常的机制研究

Gene defects in inner ear, the sense organ responsible for hearing and balance, can lead to hearing loss, and /or vestibular dysfunction. Vestibular dysfunction can be caused by genetic mutation and other factors. As vestibular anomaly is closely related to genetic factors, it is of great importance to find out the key genes that may regulate vestibular development as well as to reveal the influence of gene defects on this disorder. Previously, we have shown that Sperm-associated antigen (Spag6) gene is expressed both in the cochlea and the vestibule. Spag6-deficient mice exhibit hearing loss, whether spag6 deficiency affects vestibular function, however, remains unknown. Based on our previous studies, this project will utilize spag6 knockout mice and HEI-OC1 cell lines as experimental materials to further explore :1) whether spag6 knockout affects the vestibular function of mice; 2) the spatio-temporal expression of spag6 in mouse vestibule; 3) the abnormalities in vestibular structure appeared in spag6 knockout mice; and 4) the possible signaling pathways are involved due to spag6 defects. The implementation of this project will reveal the vestibular dysfunction attributable to spag6 defects and its potential mechanism(s), which might, in turn, provide a new target for the treatment of hereditary vestibular disorders.

内耳作为负责听觉和平衡的感觉器官，其基因缺陷可导致听力损失和（或）前庭功能障碍。前庭功能异常与遗传因素密切相关，因此，发现可能调控前庭发育的关键基因并揭示基因缺陷对前庭功能的影响，具有极其重要价值。我们前期发现人类精子相关抗原6（Sperm-associated antigen，Spag6）基因在小鼠耳蜗和外周前庭均表达，缺陷小鼠出现听功能障碍，但spag6对前庭功能的影响尚不明确。本课题拟在前期研究的基础上，利用spag6敲基因小鼠和HEI-OC1细胞系，通过前庭功能评估、组织学分析和分子生物学技术，进一步研究：1)spag6缺失对前庭功能是否有影响；2）spag6在小鼠前庭的时空表达；3）spag6缺陷小鼠前庭形态结构的异常；4）spag6致前庭异常的可能机制。本项目的实施将初步揭示spag6缺陷导致的前庭功能异常和其机制，为治疗遗传性前庭源性平衡障碍提供新靶点。

内耳作为负责听觉和平衡的感觉器官，其基因缺陷可导致听力损失和（或）前庭功能障碍。前庭功能异常与遗传因素密切相关，因此，发现可能调控前庭发育的关键基因并揭示基因缺陷对前庭功能的影响，具有极其重要价值。本项目发现人类精子相关抗原6（Sperm-associated antigen，Spag6）基因在小鼠耳蜗和外周前庭均表达，缺陷小鼠出现听功能和前庭功能障碍，本课题在前期研究的基础上，利用spag6敲基因小鼠，通过前庭功能评估、组织学分析和分子生物学技术，揭示了：1)spag6缺失对前庭-听功能的影响；2）spag6在小鼠前庭和耳蜗的时空表达；3）spag6缺陷小鼠前庭形态和耳蜗基底膜结构的异常；4）spag6致前庭-听功能异常的分子机制是通过影响平面极性和caspase依赖的凋亡途径。本项目揭示了spag6缺陷导致的听-前庭功能异常和其机制，为治疗遗传性内耳疾病提供新靶点和理论依据。