# Mouse and human vestibular regeneration and function

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $666,002

## Abstract

Abstract:
Sensory hair cells are required for balance function. Vestibular hair cell degeneration causes balance
dysfunction/hypofunction manifested as dizziness and vertigo. While the mammalian cochlea lacks the ability
to regenerate lost hair cells, a limited degree of spontaneous regeneration occurs in the utricle, a vestibular
organ detecting linear acceleration. Prior studies have shown that ATOH1 overexpression can enhance the
extent of hair cell regeneration, but these regenerated hair cells fail to fully mature. In preliminary experiments,
we have characterized hair cell degeneration and regeneration in the mature mouse utricle in vivo, and found
that transient, rather than constitutive, overexpression of ATOH1 promotes both hair cell regeneration and
maturation. The first aim of this proposal is to determine if transient ATOH1 overexpression increases hair cell
regeneration and maturation. Specifically, regenerated hair cells labeled via fate-mapping are probed via
histology and electrophysiology to assess bundle morphology, expression of bundle proteins,
mechanosensitvity, basolateral currents, and synaptic properties including vesicle release. To gain an
unbiased insight into the genetic signature of regenerated hair cells, we will use single cell RNA sequencing
technologies and bioinformatic approaches to delineate the transcriptomes of ATOH1-enhanced regenerated
hair cells and validate them histologically. In the second aim, we will test whether transient overexpression of
ATOH1 enhances regeneration and maturation of hair cells in human utricles in vitro. We will leverage our
established pipeline of human utricles from organ donors and vestibular schwannoma patients, where the latter
cohort shows hair cell degeneration, a low level of spontaneous hair cell regeneration and incomplete
maturation. Regenerated hair cells will be assessed histologically for bundle morphology, expression of bundle
and synaptic proteins and via single cell RNA sequencing to probe transcriptomes of ATOH1-enhanced
regenerated human hair cells. In summary, we will apply state-of-the art technologies (gene therapy, hair cell
physiology, single cell RNA-seq, bioinformatic strategies) to study vestibular hair cell regeneration in transgenic
mouse models and human utricles. We have assembled a team of experts who have worked together to collect
promising preliminary data. At the end of this 5-year proposal, we will have determined whether transient
ATOH1 overexpression can promote regeneration and maturation of mouse and human hair cells at the
histological, electrophysiological, and transcriptomic levels.

## Key facts

- **NIH application ID:** 10803599
- **Project number:** 2R01DC016919-06
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Alan Gi-Lun Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $666,002
- **Award type:** 2
- **Project period:** 2018-12-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803599

## Citation

> US National Institutes of Health, RePORTER application 10803599, Mouse and human vestibular regeneration and function (2R01DC016919-06). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10803599. Licensed CC0.

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