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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00445

The inner ear heat shock transcriptional signature identifies compounds that protect against aminoglycoside ototoxicity

 Lisa L. Cunningham1*,  Matthew Ryals1, Robert J. Morell1,  Daniel Martin1,  Erich T. Boger1, Patricia Wu2 and David W. Raible2, 3
  • 1National Institute on Deafness and Other Communication Disorders (NIDCD), United States
  • 2Virginia Merrill Bloedel Hearing Research Center, University of Washington, United States
  • 3Department of Biological Structure, School of Medicine, University of Washington, United States

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 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. 42 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.

Keywords: Library of Integrated Cellular Signatures (LINCS) , Drug Screening and Discovery, Hearing Loss, Ototoxicity,, RNA-Seq

Received: 28 Aug 2018; Accepted: 06 Nov 2018.

Edited by:

Michael E. Smith, Western Kentucky University, United States

Reviewed by:

Agnieszka J. Szczepek, Charité Universitätsmedizin Berlin, Germany
Alan G. Cheng, Stanford University, United States
Andrew Forge, University College London, United Kingdom  

Copyright: © 2018 Cunningham, Ryals, Morell, Martin, Boger, Wu and Raible. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Lisa L. Cunningham, National Institute on Deafness and Other Communication Disorders (NIDCD), Bethesda, MSC 2320, Maryland, United States, lisa.cunningham@nih.gov