Objectives: Sensorineural hearing loss (SNHL) is strongly associated with many aspects of military service including blast injury. The objectives of this proposal are to improve the prevention and treatment of SNHL in veterans. Research Design: To improve our understanding of cellular processes underlying hair cell (HC) damage and loss, the contributions of molecular isoforms within known HC damage and survival pathways will be evaluated by determining their expression, and by evaluating HC loss in gene knockout mice. To improve SNHL prevention, pharmaceutical agents that can protect cochlear HCs from damage will also be identified. To improve treatment for SNHL, transcription factors that enhance the ability of Atoh1 to induce the conversion of mammalian cochlear non-sensory cells into HCs will be identified. In addition, modifications to mechanisms of gene silencing will be studied to identify epigenetic limitations on the ability of nonsensory inner ear cells to adopt features of the HC phenotype. Methodology: Studies will be performed using in vitro cultures of inner ear sensory epithelia, and in vivo studies of noise damage to the cochlea. For identification of HC protectants and transcription factors, innovative high-throughput methods have been developed to permit rapid, but targeted, screening of pharmaceuticals and induced gene expression in mammalian cochlear epithelia. Progress over the past period of funding: Mechanisms of ototoxin entry into HCs have been identified;cellular patterns of reactive oxygen species accumulation into HCs have been determined and antioxidant treatments evaluated;two novel intracellular pathways of HC protection have been defined;three gene mutations that lead to deafness have been identified;a critical period of HC development in which transplantation is possible has been determined;two novel transcription factors that enhance the conversion of nonsensory cochlear cells into HCs have been identified, and epigenetic manipulation of the cochlear sensory epithelium to enhance gene expression induced by a viral vector has been performed. Clinical Relationship: The prevention and treatment of SNHL is of great importance to veterans and to 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 C (NURC)
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VA San Diego Healthcare System
San Diego
United States
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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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