# Role of Gas2 in cytoskeletal architecture, support cell stiffness, and cochlear function

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $445,957

## Abstract

The identification of gene mutations associated with hearing loss in humans and animal models
has contributed greatly to our understanding of cell type specific functions in the inner ear.
Despite this progress, the cause of inherited forms of hearing loss still remains unknown in
many cases, suggesting that the discovery of new genes associated with sensorineural hearing
loss (SNHL) is far from saturated. To fill this gap, we performed a screen for novel regulators of
cochlear development and identified several genes that are predicted to play important roles in
cochlear function. We generated a mouse knockout for one of these genes, Growth arrest
specific 2 (Gas2), encoding a putative cytoskeletal regulatory protein. Gas2 knockout mice
display severe hearing loss with no alterations in inner ear development at embryonic stages.
Instead, we propose that the cause of hearing loss is due to a progressive destabilization of the
microtubule cytoskeleton in pillar and Deiters’ cells, two specialized support cells in the organ of
Corti that are thought to provide tensile strength and a structural framework for transferring
mechanical forces during sound-evoked vibrations. The experiments in this grant proposal are
designed to transform our understanding of the role that support cells play in cochlear function.
Firstly, we will test the hypothesis that Gas2 dependent stabilization of microtubule bundles in
pillar and Deiters’ cells is required for hearing. Secondly, we will determine the influence of
Gas2 and a-tubulin detyrosination on cell surface mechanical properties and microtubule
dynamics. Finally, we will pursue the exciting possibility that viral delivery of Gas2 to support
cells might prevent hearing loss when administered prior to the onset of symptoms in neonatal
Gas2 knockout mice, and even more provocatively, might repair the cytoskeletal defects and
restore hearing when administered to adults. Taken together, these experiments will clarify the
proposed role of Gas2 as a microtubule and actin cross-linking protein that is required to
stabilize microtubule bundles in cochlear support cells and that this activity is necessary for
auditory function.

## Key facts

- **NIH application ID:** 10407601
- **Project number:** 5R01DC006254-19
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DOUGLAS J EPSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $445,957
- **Award type:** 5
- **Project period:** 2003-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407601

## Citation

> US National Institutes of Health, RePORTER application 10407601, Role of Gas2 in cytoskeletal architecture, support cell stiffness, and cochlear function (5R01DC006254-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10407601. Licensed CC0.

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