Aminoglycoside antibiotics remain the most commonly used antibiotics and the primary cause of preventable hearing loss worldwide. The impact of aminoglycoside ototoxicity has recently been aggravated by the global resurgence of tuberculosis and the increased occurrence of resistant bacteria necessitating multidrug regimens including aminoglycoside. Given the ten to 20% incidence of cochlear and vestibular disturbances associated with aminoglycoside treatment, this constitutes a major global health problem. The last decade has brought major advances in understanding the mechanisms of aminoglycoside action and designing interventions to prevent the ototoxic side effects. The proposed research is founded on past and recent discoveries from this laboratory that have led to the hypothesis of metal chelation and free radical formation by amino glycosides, and spurred by a first successful human trial demonstrating protection from gentamicin-induced hearing loss. The anticipated studies will follow new leads from preliminary experiments to delineate further the molecular mechanism of ototoxic action including the pathways of cell death and protection. Since we have recently established the adult mouse as a model for aminoglycoside ototoxicity we can combine biochemical and physiological investigations with the tools of molecular biology and the availability of mutant animals. In particular, our studies will 1. Characterize the potential contribution of lysosomal pathways to drug-induced hair cell death; 2. test the contribution of NF-kappaB mediated gene activation to cell survival; 3. analyze the regulation of the NF-kappaB pathway by signaling through phosphoinositide 3-kinase and Akt; 4. identify improved pharmacological protection based on an improved understanding of the mechanism of drug action. The results will define biochemical and molecular events involved in cell death and survival in aminoglycoside ototoxicity. The data may also help to understand other pathologies that are associated with oxidant stress, such as cisplatin ototoxicity, noise trauma and perhaps presbycusis. Optimized interventions to prevent aminoglycoside ototoxicity may serve as a basis for the translation of laboratory findings to the clinic. The attenuation or prevention of adverse effects of aminoglycosides will have far reaching implications for the continued but safe use of a family of drugs whose primary efficacy is unquestioned.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003685-08
Application #
6891880
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (06))
Program Officer
Freeman, Nancy
Project Start
1998-05-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
8
Fiscal Year
2005
Total Cost
$346,937
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Yang, Chao-Hui; Schrepfer, Thomas; Schacht, Jochen (2015) Age-related hearing impairment and the triad of acquired hearing loss. Front Cell Neurosci 9:276
Oishi, N; Duscha, S; Boukari, H et al. (2015) XBP1 mitigates aminoglycoside-induced endoplasmic reticulum stress and neuronal cell death. Cell Death Dis 6:e1763
Duscha, Stefan; Boukari, Heithem; Shcherbakov, Dimitri et al. (2014) Identification and evaluation of improved 4'-O-(alkyl) 4,5-disubstituted 2-deoxystreptamines as next-generation aminoglycoside antibiotics. MBio 5:e01827-14
Oishi, Naoki; Kendall, Ann; Schacht, Jochen (2014) Metformin protects against gentamicin-induced hair cell death in vitro but not ototoxicity in vivo. Neurosci Lett 583:65-9
Kendall, Ann; Schacht, Jochen (2014) Disparities in auditory physiology and pathology between C57BL/6J and C57BL/6N substrains. Hear Res 318:18-22
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Oishi, Naoki; Chen, Jun; Zheng, Hong-Wei et al. (2013) Tumor necrosis factor-alpha-mutant mice exhibit high frequency hearing loss. J Assoc Res Otolaryngol 14:801-11
Chen, Fu-Quan; Zheng, Hong-Wei; Schacht, Jochen et al. (2013) Mitochondrial peroxiredoxin 3 regulates sensory cell survival in the cochlea. PLoS One 8:e61999
Chen, Fu-Quan; Hill, Kayla; Guan, Ya-Jun et al. (2012) Activation of apoptotic pathways in the absence of cell death in an inner-ear immortomouse cell line. Hear Res 284:33-41
Oishi, Naoki; Talaska, Andra E; Schacht, Jochen (2012) Ototoxicity in dogs and cats. Vet Clin North Am Small Anim Pract 42:1259-71

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