# Mechanisms Mediating Repair of Stereocilia F-actin in Sensory Hair Cells

> **NIH NIH F31** · UNIVERSITY OF VIRGINIA · 2021 · $8,664

## Abstract

Project Summary/Abstract
Insult to the auditory system often results in irreparable hearing loss due to the inability of mature mammalian
hair cells to regenerate (Burns, J.C. and Corwin, J.T. 2013; Groves, A.K. 2010). However, evidence suggests
that minor damage to mechanotransductive hair bundles can be repaired in some cases. For example, gaps in
phalloidin labeling of the F-actin in stereocilia are found after mechanical damage and appear to indicate
filament breaks. Factors important for the nucleation, elongation, and crosslinking of F-actin assembly,
including γ-actin, cofilin, and espin, are enriched in these sites (Belyantseva, I.A. et al. 2009). My proposal
aims to investigate the mechanisms mediating this F-actin repair process. In Specific Aim 1, I will test the
hypothesis that damage of stereociliar F-actin leads to the incorporation of newly synthesized F-actin in
stereocilia. In order to accomplish this, I will develop mouse models for the visualization of the response of
newly synthesized actin to mechanical damage, using the FLEx-Cre switch system.
Repair of the F-actin core is expected to depend on proteins that mediate the nucleation, polymerization,
stabilization and/or crosslinking of actin filaments. My preliminary studies suggest that XIRP2 (Xin Actin
Binding Repeat Containing 2) may be involved in the stereocilia F-actin repair process, as well. We previously
described XIRP2 as a novel hair cell protein enriched in the hair bundle, where it colocalizes with F-actin.
Knockout of Xirp2 causes progressive hearing loss in mice (Francis, S.P. et al. 2015); moreover, heterozygous
mutations in XIRP2 were identified in humans with age related hearing loss. While less severe than the hearing
loss in the total Xirp2 knockout mice, heterozygous Xirp2 mice also develop progressive hearing loss.
Additionally, immunostaining shows the XIRP2 is enriched in gaps in phalloidin staining, similar to those
described above. In Specific Aim 2, I will test the hypothesis that XIRP2 is recruited to these gaps in as a direct
response of mechanical damage. At these sites, XIRP2 may facilitate the maintenance or repair of the F-actin
stereocilia core and I expect that the dysfunctional repair process in Xirp2-null mice leads to the observed
progressive decline in hearing function. In order to visualize the response of XIRP2 to hair bundle damage, I
will knock in a fluorescent tag at the endogenous Xirp2 locus to enable live imaging. I will determine whether
XIRP2 is recruited to damaged sites in F-actin stereocilia cores using both a mechanical and genetic model of
damage.

## Key facts

- **NIH application ID:** 10366129
- **Project number:** 3F31DC017370-03S1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Elizabeth Lee Wagner
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $8,664
- **Award type:** 3
- **Project period:** 2018-07-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366129

## Citation

> US National Institutes of Health, RePORTER application 10366129, Mechanisms Mediating Repair of Stereocilia F-actin in Sensory Hair Cells (3F31DC017370-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10366129. Licensed CC0.

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