Objectives: Sensorineural hearing loss (SNHL) is strongly associated with many aspects of military service including blast injury. The overall objectives of this proposal are to improve the prevention and treatment of SNHL in veterans. Research Design: During the previous period of funding, using medium-throughput screening of hair cells (HCs) from the mammalian cochlea, we identified a number of novel antioxidants and cell signaling inhibitors that are capable of protecting cochlear HCs from high-dose ototoxic damage. Some of these protectants provided better protection than several previously described oto- protectants. We now propose to evaluate the most effective of these compounds in vivo, using a single, invariant model of noise-induced hearing loss in animals, so that the interventions can be strictly compared. We will also evaluate known HC protectants to provide benchmarks. This will allow us to identify optimal compounds for further development as pharmacological interventions in humans. Methodology: Studies will be performed using in vivo studies of noise damage to the cochlea, with intracochlear delivery of HC protectants beginning immediately after exposure. We will use a well- established mouse model of noise damage, delivery of compounds to cochlear perilymph with osmotic minipumps, serial auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) audiometry, and morphological evaluation of cochlear HCs and afferent nerve endings. Progress over the past period of funding: During the past period of funding, we developed a medium-throughput method for screening libraries of potential oto-protectants using the mammalian organ of Corti, the only tissue containing the damage-sensitive mammalian outer HCs. We identified several antioxidants and several cell-signaling pathway inhibitors that were highly effective, and had not previously been evaluated for HC protection. Using an electroporation model of organ of Corti transfection, we also screened more than 200 transcription factors for the ability to enhance HC regeneration caused by ATOH1 expression in nonsensory cells, discovering several novel factors with this ability. We discovered that gene therapy with espin1 dramatically enhanced stereocilia formation on regenerating HCs. Finally, we discovered a novel protective HC pathway mediated by ATP receptors that reduce activity in HCs at high stimulus levels, protecting them from noise damage. These studies resulted in 20 peer-reviewed publications to date. Clinical Relationship: The prevention and treatment of SNHL is of great importance to veterans and the VA. The effects of SNHL on veterans' quality of life are substantial. SNHL and tinnitus also account for more disability compensation in the VA than any other disorder, and rehabilitation costs are high. The proposed research is targeted at developing new and improved therapies for prevention and treatment of this important health problem.

Public Health Relevance

This project seeks to improve the prevention and treatment of sensorineural hearing loss (SNHL) in veterans. The impacts of hearing loss on quality of life, psychological status and employability are of profound importance to veterans, since military service carries a high risk of SNHL. This risk is increasing rapidly, since the degree and nature of military noise exposure has worsened. In addition, SNHL and tinnitus are a high-probability consequence of blast injury. An unfortunately high percentage of military personnel returning from duty in the Middle East have significant SNHL, with threshold shift and/or tinnitus. There are also profound financial implications for the VA. VA rehabilitation costs for hearing loss and tinnitus are high and rising rapidly. Disability payments for hearing disorders are higher than for any other disability, with costs exceeding $1.6 billion/year and estimated to reach $3 billion/year by 2020. Hearing loss is also the fastest growing disability, currently affecting more than 775,000 veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology F (NURF)
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VA San Diego Healthcare System
San Diego
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Hur, Dong Gu; Kurabi, Arwa; Ryan, Allen F (2018) Screening antioxidants for the protection of cochlear sensory cells. Neural Regen Res 13:62-64
Lim, Hyun Woo; Pak, Kwang; Ryan, Allen F et al. (2018) Screening Mammalian Cochlear Hair Cells to Identify Critical Processes in Aminoglycoside-Mediated Damage. Front Cell Neurosci 12:179
Kurabi, Arwa; Schaerer, Daniel; Chang, Lisa et al. (2018) Optimisation of peptides that actively cross the tympanic membrane by random amino acid extension: a phage display study. J Drug Target 26:127-134
Noack, Volker; Pak, Kwang; Jalota, Rahul et al. (2017) An Antioxidant Screen Identifies Candidates for Protection of Cochlear Hair Cells from Gentamicin Toxicity. Front Cell Neurosci 11:242
Hickox, Ann E; Wong, Ann C Y; Pak, Kwang et al. (2017) Global Analysis of Protein Expression of Inner Ear Hair Cells. J Neurosci 37:1320-1339
Masuda, Masatsugu; Li, Yan; Pak, Kwang et al. (2017) The Promoter and Multiple Enhancers of the pou4f3 Gene Regulate Expression in Inner Ear Hair Cells. Mol Neurobiol 54:5414-5426
Kurabi, Arwa; Keithley, Elizabeth M; Housley, Gary D et al. (2017) Cellular mechanisms of noise-induced hearing loss. Hear Res 349:129-137
Deniffel, Dominik; Nuyen, Brian; Pak, Kwang et al. (2017) Otitis Media and Nasopharyngeal Colonization in ccl3-/- Mice. Infect Immun 85:
Ryals, Matthew; Pak, Kwang; Jalota, Rahul et al. (2017) A kinase inhibitor library screen identifies novel enzymes involved in ototoxic damage to the murine organ of Corti. PLoS One 12:e0186001
Ryan, Allen F; Kujawa, Sharon G; Hammill, Tanisha et al. (2016) Temporary and Permanent Noise-induced Threshold Shifts: A Review of Basic and Clinical Observations. Otol Neurotol 37:e271-5

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