# Basic Mechanisms on Hearing Loss of Cochlear Origin

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

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: We previously used in vitro screening to identify novel compounds that can protect
hair cells (HCs) from ototoxic damage. We tested them in vivo against noise-induced hearing loss
(NIHL) and found partial protection. We also used high-resolution proteomics to identify additional
processes involved in NIHL. Overall, our results suggest that many cellular processes contribute to HC
damage. In this application we propose to screen compound combinations targeting diverse HC
damage and survival processes, to identify the most effective combinations. This will allow us to
identify optimal strategies for further development as pharmacological interventions in humans, using
compound combinations and/or multi-acting compounds.
Methodology: Studies will be performed in vitro using aminoglycoside damage or in vivo using noise
damage to the cochlea. For in vivo studies, intracochlear or intratympanic delivery of HC protectants
will begin immediately after exposure. We will use a well-established mouse model of noise damage,
chronic delivery of compounds to cochlear perilymph or the round window 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, using the mammalian
organ of Corti, the only tissue containing the damage-sensitive mammalian outer HCs, we screened
several compound libraries. We identified a broad range of compounds targeting different cellular
processes, that were effective in protecting HCs. We then transferred selected compounds to an in
vivo model of noise-induced hearing loss (NIHL), where we also noted protection. We also
completed the first-ever high-resolution proteomics study of NIHL, which identified many proteins
and processes not previously known to be involved in noise damage, and which are potential targets
for pharmacotherapy. We also performed the first high-resolution proteomic study of isolated HCs.
In addition, we completed studies of gene regulation relevant to HC regeneration, and found that
gene therapy with espin1 dramatically enhanced stereocilia formation on regenerating HCs. 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. Our studies resulted in 18 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 d...

## Key facts

- **NIH application ID:** 10554258
- **Project number:** 5I01BX001205-11
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Allen F. Ryan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10554258

## Citation

> US National Institutes of Health, RePORTER application 10554258, Basic Mechanisms on Hearing Loss of Cochlear Origin (5I01BX001205-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10554258. Licensed CC0.

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