Aminoglycoside antibiotics are essential for treating life-threatening bacterial sepsis, yet induce acute nephrotoxicity and permanent deafness/balance disorders. These noxious side-effects affect as many as 120,000 individuals each year in the US. The goal of this proposal is to identify the molecular mechanisms that traffic aminoglycosides across the blood-labyrinth barrier into the cochlear fluids and sensory hair cells to induce cytotoxicity and hearing loss. The long-term goal is to protect the cochlear sensory hair cells from drug-induced ototoxicity, and maintain life-long hearing function. Our published data indicate that systemically-delivered gentamicin is trafficked from the strial vasculature, across the stria vascularis, into endolymph prior to hair-cell uptake. We have identified a candidate aminoglycoside transporter, and inhibition of this transporter reduces cochlear uptake of fluorescently-tagged aminoglycosides. Aminoglycoside uptake by hair cells is also potentiated by prior noise trauma, implicating the involvement of additional gentamicin-permeant cation channels besides the mechanoelectrical transduction channel.
The specific aims of this project are: First, to determine if the candidate aminoglycoside transporter is required for gentamicin uptake, cochlear trafficking and induction of ototoxicity in vivo (Aim 1). Second, to test if other non-selective cation channels (besides the MET channel) expressed by hair cells are gentamicin-permeant and induce cytotoxicity (Aim 2). And, third, since noise trauma and aminoglycosides trigger oxidative stress in hair cells, we will determine if oxidative stress activates gentamicin-permeant cation channels and enhances hair cell uptake of gentamicin in vivo (Aim 3). Identifying the molecular mechanisms of aminoglycoside trafficking across the BLB and entry into hair cells is crucial to rational development of new clinical strategies that protect cochlear function during life-saving aminoglycoside therapy. For example, the genes involved in these mechanisms can then be screened for single nuclear polymorphisms (SNP) that induce gain-of-function activity in identified gentamicin-permeant channels and transporters. This will allow clinicians to use aminoglycosides more judiciously and personalize gentamicin therapy for individual cases prior to treatment for life-threatening bacterial sepsis, tuberculosis and for prophylaxis in premature babies, and casualties with severe burns and blast injuries.

Public Health Relevance

This project will test if: (i) a candidate transporter is required for trafficking ototoxic gentamicin into endolymph and cochlear hair cells;(ii) other cation channels are also gentamicin-permeant and contribute to cytotoxicity;and (iii) whether noise or drug-induced oxidative stress increases hair cell uptake of gentamicin. The proposed experiments will test specific mechanisms for systemic gentamicin trafficking to hair cells during (a) drug therapy and (b) noise-induced threshold shifts that synergistically potentiate aminoglycoside ototoxicity. Understanding these pathophysiological molecular mechanisms is crucial to developing new pharmacological or genetic strategies to prevent gentamicin-induced ototoxicity during treatment for bacterial sepsis, tuberculosis and endocarditis, among many others indications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC012588-02
Application #
8489279
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$390,907
Indirect Cost
$137,071
Name
Oregon Health and Science University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Garinis, Angela C; Kemph, Alison; Tharpe, Anne Marie et al. (2017) Monitoring neonates for ototoxicity. Int J Audiol :1-8
Jiang, Meiyan; Karasawa, Takatoshi; Steyger, Peter S (2017) Aminoglycoside-Induced Cochleotoxicity: A Review. Front Cell Neurosci 11:308
Jiang, Meiyan; Taghizadeh, Farshid; Steyger, Peter S (2017) Potential Mechanisms Underlying Inflammation-Enhanced Aminoglycoside-Induced Cochleotoxicity. Front Cell Neurosci 11:362
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Garinis, Angela C; Cross, Campbell P; Srikanth, Priya et al. (2017) The cumulative effects of intravenous antibiotic treatments on hearing in patients with cystic fibrosis. J Cyst Fibros 16:401-409
Chu, Yu-Hsuan; Escobedo, Jorge O; Jiang, Meiyan et al. (2016) Rhodamine analogues for molecular ruler applications. Dyes Pigm 126:46-53
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Koo, Ja-Won; Quintanilla-Dieck, Lourdes; Jiang, Meiyan et al. (2015) Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity. Sci Transl Med 7:298ra118
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