# Project 3: Functional genomics of hearing loss genes in zebrafish

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2020 · $331,482

## Abstract

Abstract. About 1 child for every 500 to 1000 newborns is affected by sensorineural hearing loss, making it one
of the most common birth defects. Genetic factors underlie most cases of hearing loss in young people. Low-
cost genomic sequencing technologies continually identify new mutations associated with human hearing loss,
but their functional validation is unacceptably slow. Even in the case of genes with well-established links to
hearing loss, there is often a lack of knowledge regarding underlying mechanisms of pathogenesis. There is an
urgent need to fill this knowledge gap. Thus, our long-term goal is to illuminate the pathologies responsible for
hearing loss and to develop novel treatment strategies. To accomplish this goal, we used CRISPR/Cas9
technology to generate a library of 50 zebrafish lines with mutations in established human hearing loss genes.
Most (94%) human hearing loss genes have an orthologue in zebrafish, suggesting high functional conservation.
Zebrafish are an ideal model organism to study hearing loss, given their external embryonic development,
transparent body, accessible inner ear and the presence of lateral line neuromasts, which are functionally
analogous to mechanoreceptors of the mammalian inner ear. We hypothesize that our mutant zebrafish lines
will reveal distinct phenotypes and mechanisms corresponding to disrupted structure and function of the inner
ear. The inner ear contains two complex sensory systems (auditory and vestibular) necessary for hearing and
balance. These two systems are directly dependent on functional sensory epithelia, which are composed
primarily of two cell types, the hair cells and the supporting cells. Sound waves are transduced into electrical
signals by the hair bundles present in sensory hair cells in the inner ear. This process requires a specific ionic
environment in the endolymph surrounding the hair cell stereocilia and the perilymph covering the hair cell body.
This ionic homeostasis is maintained by ion channels and ion transporters. It is likely that many cases of hearing
loss are caused by abnormalities in the hair cells themselves or in their environment. We will initially focus on
two hearing loss genes, slc26a4 and stereocillin, as a “training set” to elucidate their hearing loss phenotypes
and mechanisms in zebrafish. Additionally, we will investigate 16 select mutants from our library for their roles
in inner ear function. We will test our hypothesis by pursuing the following Specific Aims: 1) Elucidate the
mechanisms and phenotypes underlying hearing loss in slc26a4 mutant zebrafish. 2) Determine the role of
stereocillin in hair cell development and function in zebrafish. 3) Large-scale functional validation of candidate
genes associated with non-syndromic hearing loss. Our research will provide novel insights into the cellular and
molecular phenotypes of slc26A4 and stereocillin hearing loss mutants (Aims 1 & 2) and will enable us to expand
our efforts by identifying ...

## Key facts

- **NIH application ID:** 9997969
- **Project number:** 5P20GM103636-08
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Gaurav K Varshney
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,482
- **Award type:** 5
- **Project period:** 2013-03-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997969

## Citation

> US National Institutes of Health, RePORTER application 9997969, Project 3: Functional genomics of hearing loss genes in zebrafish (5P20GM103636-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997969. Licensed CC0.

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