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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001205-06
Application #
9378699
Study Section
Neurobiology F (NURF)
Project Start
2012-10-01
Project End
2020-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161
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
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
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
Deniffel, Dominik; Nuyen, Brian; Pak, Kwang et al. (2017) Otitis Media and Nasopharyngeal Colonization in ccl3-/- Mice. Infect Immun 85:
Cho, Chang Gun; Pak, Kwang; Webster, Nicholas et al. (2016) Both canonical and non-canonical NF-?B activation contribute to the proliferative response of the middle ear mucosa during bacterial infection. Innate Immun 22:626-634
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
Hernandez, Michelle; Leichtle, Anke; Pak, Kwang et al. (2015) The transcriptome of a complete episode of acute otitis media. BMC Genomics 16:259
Ryan, Allen F; Ikeda, Ryoukichi; Masuda, Masatsugu (2015) The regulation of gene expression in hair cells. Hear Res 329:33-40
Froud, Kristina E; Wong, Ann Chi Yan; Cederholm, Jennie M E et al. (2015) Type II spiral ganglion afferent neurons drive medial olivocochlear reflex suppression of the cochlear amplifier. Nat Commun 6:7115
Morton-Jones, Rachel T; Vlajkovic, Srdjan M; Thorne, Peter R et al. (2015) Properties of ATP-gated ion channels assembled from P2X2 subunits in mouse cochlear Reissner's membrane epithelial cells. Purinergic Signal 11:551-60

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