Early transcriptional response to aminoglycoside antibiotic suggests alternate pathways leading to apoptosis in sensory hair cells in the mouse inner ear.
Early transcriptional response to aminoglycoside antibiotic suggests alternate pathways leading to apoptosis in sensory hair cells in the mouse inner ear.
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DOI：
10.3389/fncel.2015.00190
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发表时间：
2015
影响因子：
5.3
通讯作者：
Segil N
中科院分区：
文献类型：
--
作者：
Tao L;Segil N
氨基糖苷类抗生素是治疗许多细菌感染的“首选药物”，但它们的使用导致多达四分之一的患者听力丧失。几种生化途径与氨基糖苷类抗生素耳毒性有关；然而，关于毛细胞如何在转录组水平上对氨基糖苷类抗生素作出反应，我们知之甚少。在这里，我们研究了全基因组对氨基糖苷类抗生素庆大霉素的反应。利用Corti围产期器官的器官型培养，我们使用从facs纯化的毛细胞中获得的cDNA文库进行RNA测序。在庆大霉素治疗的3小时内，毛细胞中3000多个基因的信使RNA水平发生了显著变化。这些变化的生物信息学分析强调了几种已知的信号转导途径，包括JNK途径和NF-κB途径，以及参与应激反应、细胞凋亡、细胞周期控制和DNA损伤修复的基因。相比之下，只有698个主要参与细胞周期和代谢物生物合成过程的基因在非毛细胞群体中受到显著影响。毛细胞对庆大霉素反应的基因表达谱与先前在庆大霉素引起的肾毒性中观察到的基因表达谱有相当大的相似性。我们的研究结果表明，先前观察到的毛细胞对庆大霉素在特定信号通路中的早期反应反映在基因表达的变化中。此外，观察到的细胞周期调控基因表达的变化表明有丝分裂后状态的破坏，这可能表明有另一种途径调节庆大霉素诱导的凋亡性毛细胞死亡。这项工作为氨基糖苷类抗生素的耳毒性提供了更全面的视角，从而有助于确定潜在的途径或治疗靶点，以减轻氨基糖苷类抗生素的这一重要副作用。
Aminoglycoside antibiotics are “the drug of choice” for treating many bacterial infections, but their administration results in hearing loss in up to one fourth of the patients who receive them. Several biochemical pathways have been implicated in aminoglycoside antibiotic ototoxicity; however, little is known about how hair cells respond to aminoglycoside antibiotics at the transcriptome level. Here we have investigated the genome-wide response to the aminoglycoside antibiotic gentamicin. Using organotypic cultures of the perinatal organ of Corti, we performed RNA sequencing using cDNA libraries obtained from FACS-purified hair cells. Within 3 h of gentamicin treatment, the messenger RNA level of more than three thousand genes in hair cells changed significantly. Bioinformatic analysis of these changes highlighted several known signal transduction pathways, including the JNK pathway and the NF-κB pathway, in addition to genes involved in the stress response, apoptosis, cell cycle control, and DNA damage repair. In contrast, only 698 genes, mainly involved in cell cycle and metabolite biosynthetic processes, were significantly affected in the non-hair cell population. The gene expression profiles of hair cells in response to gentamicin share a considerable similarity with those previously observed in gentamicin-induced nephrotoxicity. Our findings suggest that previously observed early responses to gentamicin in hair cells in specific signaling pathways are reflected in changes in gene expression. Additionally, the observed changes in gene expression of cell cycle regulatory genes indicate a disruption of the postmitotic state, which may suggest an alternate pathway regulating gentamicin-induced apoptotic hair cell death. This work provides a more comprehensive view of aminoglycoside antibiotic ototoxicity, and thus contributes to identifying potential pathways or therapeutic targets to alleviate this important side effect of aminoglycoside antibiotics.
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影响因子：
5.3
作者：
Matsui, JI;Ogilvie, JM;Warchol, ME
通讯作者：
Warchol, ME
DOI：
10.1002/neu.20054
发表时间：
2004-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
Matsui, JI;Gale, JE;Warchol, ME
通讯作者：
Warchol, ME
影响因子：
4.4
作者：
Jamesdaniel, Samson;Ding, Dalian;Coling, Donald E.
通讯作者：
Coling, Donald E.
影响因子：
4.2
作者：
Jiang, HY;Sha, SH;Schacht, J
通讯作者：
Schacht, J
影响因子：
64.5
作者：
ANGEL, P;HATTORI, K;KARIN, M
通讯作者：
KARIN, M