# Nanomechanics of inner-ear hair-cell transduction

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $373,136

## Abstract

PROJECT SUMMARY
Vibrations from sound and mechanical stimuli from head movements are transformed into electrochemical
signals for brain processing by inner-ear hair-cell mechanoreceptors mediating our senses of hearing and
balance. Essential to hair-cell function are the proteins that form its mechanotransduction apparatus comprised
of a fine tip-link filament that pulls on an ion channel complex to trigger sensory perception. The tip-link
filament is formed by cadherin-23 (CDH23) and protocadherin-15 (PCDH15) proteins while the ion channel
complex is thought to be formed by members of the transmembrane channel-like protein family TMC1 and
TMC2, the transmembrane inner ear protein TMIE, and the tetraspan membrane protein of hair-cell stereocilia
TMHS (also known as LHFPL5). In addition, the calcium and integrin binding protein CIB2 binds to TMC
channels to regulate mechanotransduction. All these proteins are important for hearing and balance and are
involved in inherited deafness, yet their molecular structures and the functional architecture of the transduction
complex they form are poorly understood. The overall long-term goal of this project is to reveal the
structural determinants of function for the proteins forming the inner-ear tip link and transduction ion
channel complex. In Aim 1, we will use cryo-electron microscopy, high-speed atomic force microscopy, and
molecular dynamics simulations to study the full-length extracellular domains of CDH23 and PCDH15 and
thereby establish the structural determinants of tip-link function in inner ear mechanotransduction. In Aim 2, we
will generate testable predictions using microsecond-long molecular dynamics simulations with biasing
membrane potentials to characterize permeation of ions and ototoxic aminoglycosides through experimentally
validated structural models of TMC protein pores. In Aim 3, we will use various computational and biophysical
techniques, including nuclear magnetic resonance and native mass spectrometry, to explore regulatory
mechanisms of transduction by CIB proteins. Results obtained from the proposed experiments and simulations
will provide an initial and dynamic molecular view of the protein components of the inner ear
mechanotransduction apparatus as we advance to understand its architecture and function in normal and
impaired hearing and balance.

## Key facts

- **NIH application ID:** 11142233
- **Project number:** 7R01DC015271-08
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Marcos Sotomayor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $373,136
- **Award type:** 7
- **Project period:** 2024-07-22 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11142233

## Citation

> US National Institutes of Health, RePORTER application 11142233, Nanomechanics of inner-ear hair-cell transduction (7R01DC015271-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11142233. Licensed CC0.

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