OHC-TRECK: A Novel System Using a Mouse Model for Investigation of the Molecular Mechanisms Associated with Outer Hair Cell Death in the Inner Ear
OHC-TRECK: A Novel System Using a Mouse Model for Investigation of the Molecular Mechanisms Associated with Outer Hair Cell Death in the Inner Ear
复制标题
OHC-TRECK：使用小鼠模型研究与内耳外毛细胞死亡相关的分子机制的新系统
DOI：
10.1038/s41598-019-41711-2
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发表时间：
2019
影响因子：
4.6
通讯作者：
Kikkawa Yoshiaki
中科院分区：
文献类型：
--
作者：
Matsuoka Kunie;Wada Kenta;Miyasaka Yuki;Yasuda Shumpei P.;Seki Yuta;Nishito Yasumasa;Yonekawa Hiromichi;Taya Choji;Shitara Hiroshi;Kikkawa Yoshiaki
外毛细胞（OHC）负责放大声音，这些细胞的死亡会导致听力损失。尽管声音放大和 OHC 死亡的机制已得到充分研究，但 OHC 死亡后对耳蜗的影响却知之甚少。为了研究 OHC 死亡的后果，我们使用新型小鼠模型 Prestin-hDTR 建立了 OHC 敲除系统，该模型使用 prestin 启动子来表达人白喉毒素 (DT) 受体基因 (hDTR)。给成年 Prestin-hDTR 小鼠施用 DT 会导致几乎所有 OHC 的消耗，而对其他耳蜗和前庭细胞没有显着损害，这表明该系统是分析 OHC 死亡后耳蜗和前庭其他细胞如何受到影响的有效工具。为了评估 OHC 死亡后耳蜗的变化，我们对未处理组和 DT 处理组的野生型和 Prestin-hDTR 小鼠进行了差异基因表达分析。该分析表明，与炎症/免疫反应相关的基因显着上调。此外，我们发现一些与听力损失相关的基因因 OHC 死亡而被强烈下调。总之，这些结果表明，这种 OHC 敲除系统是识别与 OHC 死亡相关的生物标志物的有用工具。
Outer hair cells (OHCs) are responsible for the amplification of sound, and the death of these cells leads to hearing loss. Although the mechanisms for sound amplification and OHC death have been well investigated, the effects on the cochlea after OHC death are poorly understood. To study the consequences of OHC death, we established an OHC knockout system using a novel mouse model,Prestin-hDTR, which uses the prestin promoter to express the human diphtheria toxin (DT) receptor gene (hDTR). Administration of DT to adultPrestin-hDTRmice results in the depletion of almost all OHCs without significant damage to other cochlear and vestibular cells, suggesting that this system is an effective tool for the analysis of how other cells in the cochlea and vestibula are affected after OHC death. To evaluate the changes in the cochlea after OHC death, we performed differential gene expression analysis between the untreated and DT-treated groups of wild-type andPrestin-hDTRmice. This analysis revealed that genes associated with inflammatory/immune responses were significantly upregulated. Moreover, we found that several genes linked to hearing loss were strongly downregulated by OHC death. Together, these results suggest that this OHC knockout system is a useful tool to identify biomarkers associated with OHC death.