Aminoglycosides are indispensable antibiotics commonly used worldwide and a primary cause of preventable hearing loss. They have traditional roles against infectious diseases such as tuberculosis and in the prophylactic treatment of cystic fibrosis patients against Pseudomonas, but new applications are emerging with the use of these drugs to correct mutations due to premature stop codons such as those that account for up to 70% of Hurler Syndrome cases and 10-20% of both muscular dystrophy and cystic fibrosis. Given a 10- 20% incidence of cochlear and vestibular disturbances in aminoglycoside treatment, ototoxicity constitutes a major global health problem. Much of what we know about cell death, survival and protection in the cochlea has come from extensive research into aminoglycoside ototoxicity. Previously, this laboratory has delineated mechanisms of and developed protective strategies against ototoxicity that eventually led to a successful clinical trial. The studies proposed now will follow exciting preliminary results that point to as yet uncharted pathways of cell death and survival in the mouse cochlea in vivo and in organotypic culture. Specifically, the uptake of drug into and the release of tumor necrosis factor-? from supporting cells may change our view of the role of the "supporting" cells in cochlear pathologies. The discoveries that aminoglycoside antibiotics interfere with nuclear phosphoinositide signaling and histone acetylation, and that they bind to proteins carrying nucleolar localization signals and impede nuclear translocation processes, will open novel avenues into toxicity research. Results from those studies will give insight into hitherto unexplored regulatory mechanism of gene expression in the cochlea and their involvement in aminoglycoside ototoxicity. Finally, we propose improved approaches to protection based upon interference with TNF-? actions and histone deacetylation in a concerted effort with antioxidant therapy to optimize pharmacological protection against aminoglycoside-induced hearing loss. The results will chart new pathways of cell death in the inner ear that may also be relevant for understanding other cochlear pathologies such as cisplatin-induced hearing loss, noise trauma and age-related hearing impairment. The attenuation or prevention of adverse effects of aminoglycosides will have far reaching implications for the continued, but safe use of this family of drugs whose primary efficacy is undisputed.

Public Health Relevance

Aminoglycoside antibiotics are indispensable as drugs against microbial infections including multi-drug resistant tuberculosis. Novel applications include antibacterial prophylaxis in cystic fibrosis patients and correction of genetic diseases by codon read-through. They do, however, cause hearing loss in 15-20% of patients, and will provide novel insights into the molecular mechanisms of their toxicity and aid in the design of new and effective therapeutic protection. 16

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003685-14
Application #
8287125
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
1998-05-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$312,143
Indirect Cost
$108,500
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
Kendall, Ann; Schacht, Jochen (2014) Disparities in auditory physiology and pathology between C57BL/6J and C57BL/6N substrains. Hear Res 318:18-22
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
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
Bottger, Erik C; Schacht, Jochen (2013) The mitochondrion: a perpetrator of acquired hearing loss. Hear Res 303:12-9
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; 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
Op de Beeck, Ken; Schacht, Jochen; Van Camp, Guy (2011) Apoptosis in acquired and genetic hearing impairment: the programmed death of the hair cell. Hear Res 281:18-27
Oishi, Naoki; Schacht, Jochen (2011) Emerging treatments for noise-induced hearing loss. Expert Opin Emerg Drugs 16:235-45
Chen, Fu-Quan; Schacht, Jochen; Sha, Su-Hua (2009) Aminoglycoside-induced histone deacetylation and hair cell death in the mouse cochlea. J Neurochem 108:1226-36

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