内质网应激介导细胞凋亡信号通路导致人工耳蜗植入术后前庭功能减退的分子机制及保护措施

眩晕、平衡障碍是人工耳蜗植入（CI）术后常见不良反应，随着患者年龄增大，姿势不稳和跌倒的风险也将增加。我们前期研究发现：CI术后前庭诱发肌源性电位（VEMPs）引出率降低、平衡功能受损；建立动物模型可以进行不同刺激方式的VEMPs检测；内质网应激参与遗传性耳聋小鼠耳蜗外毛细胞损伤。我们推测CI造成内耳微环境改变，激活内质网应激细胞凋亡信号通路，最终导致外周前庭系统结构和功能受损。本课题拟建立豚鼠CI模型，观察CI术后前庭功能和结构变化，并从基因及蛋白质水平检测前庭组织中内质网应激介导细胞凋亡的关键标志物的表达水平，同时试行经内耳给予内质网应激信号通路抑制剂，验证其对前庭功能保护效应。本研究不仅有助于阐明CI手术后前庭功能减退的分子机制，也可以为保护CI植入者前庭功能提供新的思路及理论基础。

The symptom of vertigo or imbalance is one of the major side effect of cochlear implant (CI). With the age increase, patients underwent CI surgery might be evidence for high risk of postural instability and accidental falls caused by vestibular dysfunction. However, the leading cause underlying vestibular dysfunction after CI remains unclear. We performed several primary studies aimed to reveal the potential mechanisms. Firstly, we found that children with CI showed lower response rate of ocular and cervical vestibular-evoked myogenic potentials (oVEMP and cVEMP). Moreover, CI might disturb equilibrium function within one week post-surgery revealed by static posturography. Secondly, we succeed a guinea pig model to perform air and bone-conductive VEMP tests. Thirdly, we revealed that endoplasmic reticulum stress (ER stress) is the earliest molecular event leading to hair cell apoptosis and hearing loss in a mouse model of human inherited deafness. In the current project, we propose that the perturbation of ER homeostasis caused by CI triggers vestibular cell apoptosis, resulting in abnormal bone turnover and new bone formation which finally leads to vestibular dysfunction. We will detect this hypothesis by perform CI surgery in guinea pigs and then test the vestibular function, vestibular cell morphology and the cellular markers involving the signaling pathway of ER stress-induced apoptosis in vestibule. The goal of the proposed project is to determine the underlying cellular mechanism of vestibular dysfunction after CI and provide a novel strategy for improvement of the vestibular function in CI patients.