Taukulis Ian A, Olszewski Rafal T, Korrapati Soumya, Fernandez Katharine A, Boger Erich T, Fitzgerald Tracy S, Morell Robert J, Cunningham Lisa L, Hoa Michael
Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, United States.
Laboratory of Hearing Biology and Therapeutics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, United States.
Front Mol Neurosci. 2021 Sep 9;14:718241. doi: 10.3389/fnmol.2021.718241. eCollection 2021.
The endocochlear potential (EP) generated by the stria vascularis (SV) is necessary for hair cell mechanotransduction in the mammalian cochlea. We sought to create a model of EP dysfunction for the purposes of transcriptional analysis and treatment testing. By administering a single dose of cisplatin, a commonly prescribed cancer treatment drug with ototoxic side effects, to the adult mouse, we acutely disrupt EP generation. By combining these data with single cell RNA-sequencing findings, we identify transcriptional changes induced by cisplatin exposure, and by extension transcriptional changes accompanying EP reduction, in the major cell types of the SV. We use these data to identify gene regulatory networks unique to cisplatin treated SV, as well as the differentially expressed and druggable gene targets within those networks. Our results reconstruct transcriptional responses that occur in gene expression on the cellular level while identifying possible targets for interventions not only in cisplatin ototoxicity but also in EP dysfunction.
血管纹（SV）产生的内淋巴电位（EP）对于哺乳动物耳蜗中的毛细胞机械转导至关重要。为了进行转录分析和治疗测试，我们试图创建一个EP功能障碍模型。通过给成年小鼠单次注射顺铂（一种常用的具有耳毒性副作用的癌症治疗药物），我们急性破坏了EP的产生。通过将这些数据与单细胞RNA测序结果相结合，我们确定了顺铂暴露诱导的转录变化，以及SV主要细胞类型中伴随EP降低的转录变化。我们利用这些数据来识别顺铂处理的SV特有的基因调控网络，以及这些网络中差异表达且可成药的基因靶点。我们的结果重建了细胞水平上基因表达中发生的转录反应，同时确定了不仅针对顺铂耳毒性而且针对EP功能障碍的可能干预靶点。
