# Mechanotransduction and calcium regulation in cochlear hair cells

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $336,813

## Abstract

ABSTRACT
 Noise can irreversibly damage the sensory receptors of the inner ear, the hair cells, and lead to
permanent hearing loss. Hair cells respond to sound-induced mechanical vibrations with inward current,
passing through mechanotransduction channels at the tips of stereocilia. In response to stereocilia
deflections, calcium ions enter the cell, bind to fixed and mobile buffers and are extruded by cell membrane
calcium pumps. The basal, high frequency outer hair cells have relatively few calcium pumps. Thus,
mitochondria, which are concentrated in a belt beneath the cuticular plate, a support structure for
stereocilia, may play a major role in calcium removal during mechanical stimulation in these cells. The goal
of this study is to understand how mechanical overstimulation impairs mechanotransduction, perturbs
calcium balance, and disrupts redox homeostasis in cochlear hair cells. This will aid in understanding why
basal, high frequency outer hair cells are more susceptible to noise exposure than apical, low frequency
ones. In addition we will test a novel strategy to increase hair cell viability by protecting their mitochondria
from calcium overload and oxidative damage. The first aim of our proposal is to determine changes in hair
cell mechanotransduction function following mechanical overstimulation. Our preliminary data show
significant calcium increases in the basal, high frequency outer hair cells during mechanical stimulation.
Calcium was promptly removed from the cytosol following stimulation, while mitochondrial calcium overload
was sustained. Because an increase in mitochondrial calcium is commonly reported in cell death pathways,
a study of hair cells' mitochondrial calcium balance following overstimulation is necessary. Within the
second aim, we will use a knockout mouse model with impaired mitochondrial calcium uptake to determine
whether mitochondrial calcium overload is required for oxidative stress in hair cells following
overstimulation. When overloaded with Ca, mitochondria undergo oxidative damage; this will further
increase oxidative stress, initiating a feed-forward cycle to further damage mitochondria. We will test the
hypothesis that mitochondrial calcium overload and dysfunction in outer hair cells contribute to the
vulnerability of these sensory cells to overstimulation. To complement our genetic studies, we will also
examine whether protecting mitochondria against calcium overload and oxidative stress will increase hair
cell viability by using a pharmacological approach: we will use novel Szeto-Schiller peptides that
concentrate to the inner mitochondrial membrane to protect mitochondria from oxidative damage and
improve mitochondrial bioenergetics. In summary, our study will reveal how mechanical overstimulation can
damage the stereociliary bundle and impair its function. In addition, this study will establish the role of
mitochondrial Ca2+ overload in hair cell dysfunction and death, providing not only a mechanis...

## Key facts

- **NIH application ID:** 9939511
- **Project number:** 5R01DC015016-05
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Ruben Stepanyan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,813
- **Award type:** 5
- **Project period:** 2016-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939511

## Citation

> US National Institutes of Health, RePORTER application 9939511, Mechanotransduction and calcium regulation in cochlear hair cells (5R01DC015016-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9939511. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*