# Mechanosensor Proteins in Hair Cell Repair

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $465,409

## Abstract

Abstract
Sensory hair cells of the inner ear experience continuous mechanical and metabolic stress. The maintenance of
hair cells is further challenged by damage from a variety of other ototoxic factors, including loud noise, aging,
genetic defects, and ototoxic drugs. Because mammalian auditory hair cells do not regenerate, the repair of hair
cell damage is important for continued auditory function. Our research program is especially interested in
molecular processes involved in the maintenance of the stereocilia filamentous (F)-actin core. Recent studies
have concluded that the stereocilia actin core is stable over months, implying that any structural damage must
be actively repaired. The stereocilia F-actin core can sustain damage, most notably by noise exposure, which
was shown to cause “gaps” in phalloidin labeling of F-actin in stereocilia. In preliminary studies, we found that
these gaps are repaired in days. We therefore propose to investigate the molecular mechanisms by which
the F-actin lesions are sensed and repaired. The proposed study was inspired by an emerging concept in
mechanobiology, according to which F-actin possesses intrinsic mechanosensory properties. In this model,
mechanical strain modulates the interaction of actin filaments with effector proteins. For a variety of actin binding
proteins, their constitutive binding to F-actin is merely tuned by force. A subset of LIM domain proteins however
are unique in that mechanical strain reveals previously hidden binding sites on F-actin, providing an on/off switch
for downstream processes. These processes were implicated in the recruitment of actin repair substrates and in
the prevention of F-actin fiber breakage. We reasoned that hair cells might employ a similar strategy to repair its
F-actin-based stereocilia. In our search for molecules involved in this process, we focused on proteins that are
enriched in the hair cell bundle, contain potential mechanosensor domains, and cause progressive hearing loss
in human or mice with loss of function. We identified two proteins, XIRP2 (Xin Actin Binding Repeat Containing
2) and CRIP3 (cysteine rich protein 3) that fulfill these criteria. We hypothesize that XIRP2 and CRIP3 are
mechanosensor proteins capable of sensing F-actin damage and recruiting additional repair factors,
thus playing essential roles in hair cell stereocilia repair and maintenance. To test this, in SA1, we propose
to test the hypothesized mechanosensor function of XIRP2 in fibroblasts. In preliminary studies, we discovered
a novel mechanosensor domain in the C-terminus of XIRP2. We will use live cell laser ablation and cell stretch
experiments to define the mechanosensor region, and investigate the mechanisms by which XIRP2’s
mechanosensor function is regulated. In SA2, we propose to test the mechanosensor and repair function of
XIRP2 in vivo, using a mouse model that lacks the mechanosensor domain. We will also perform ex vivo
experiments to test whether fluorescently...

## Key facts

- **NIH application ID:** 10873323
- **Project number:** 5R01DC021176-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Jung-Bum Shin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $465,409
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873323

## Citation

> US National Institutes of Health, RePORTER application 10873323, Mechanosensor Proteins in Hair Cell Repair (5R01DC021176-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873323. Licensed CC0.

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