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首页> 美国卫生研究院文献>Frontiers in Cellular Neuroscience >The Inner Ear Heat Shock Transcriptional Signature Identifies Compounds That Protect Against Aminoglycoside Ototoxicity
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The Inner Ear Heat Shock Transcriptional Signature Identifies Compounds That Protect Against Aminoglycoside Ototoxicity

机译：内耳热休克转录特征识别可防止氨基糖苷耳毒性的化合物

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Mechanosensory hair cells of the inner ear transduce auditory and vestibular sensory input. Hair cells are susceptible to death from a variety of stressors, including treatment with therapeutic drugs that have ototoxic side effects. There is a need for co-therapies to mitigate drug-induced ototoxicity, and we showed previously that induction of heat shock proteins (HSPs) protects against hair cell death and hearing loss caused by aminoglycoside antibiotics in mouse. Here, we utilized the library of integrated cellular signatures (LINCS) to identify perturbagens that induce transcriptional profiles similar to that of heat shock. Massively parallel sequencing of RNA (RNA-Seq) of heat shocked and control mouse utricles provided a heat shock gene expression signature that was used in conjunction with LINCS to identify candidate perturbagens, several of which were known to protect the inner ear. Our data indicate that LINCS is a useful tool to screen for compounds that generate specific gene expression signatures in the inner ear. Forty-two LINCS-identified perturbagens were tested for otoprotection in zebrafish, and three of these were protective. These compounds also induced the heat shock gene expression signature in mouse utricles, and one compound protected against aminoglycoside-induced hair cell death in whole organ cultures of utricles from adult mice.
机译：内耳的机械感觉毛细胞转换为听觉和前庭感觉输入。毛细胞容易因各种应激源而死亡，包括使用具有耳毒性副作用的治疗药物进行治疗。需要一种共同疗法来减轻药物引起的耳毒性，并且我们之前已经证明了热休克蛋白（HSP）的诱导可防止小鼠氨基糖苷类抗生素引起的毛细胞死亡和听力丧失。在这里，我们利用集成的细胞签名库（LINCS）来识别引起与热激相似的转录谱的微扰。对热休克小鼠和对照小鼠的尿囊的RNA（RNA-Seq）进行大规模并行测序，可提供热休克基因表达特征，并将其与LINCS结合使用，以鉴定候选微扰蛋白，其中几种已知可以保护内耳。我们的数据表明LINCS是筛选内耳中产生特定基因表达特征的化合物的有用工具。测试了42个LINCS识别的扰动袋对斑马鱼的耳保护作用，其中三个具有保护性。这些化合物还诱导了小鼠尿囊中的热休克基因表达特征，并且一种化合物在成年小鼠的尿囊的全器官培养物中免受氨基糖苷诱导的毛细胞死亡。

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