# Roles of the Synapse in Hair-Cell Pathology

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $324,063

## Abstract

Project Summary: Loud or extended noise exposure damages cochlear hair cells often
resulting in either loss of synaptic connections with auditory nerve fibers or hair-cell death. One
mechanism for this damage occurs through overstimulation of hair cells, which leads to a surge
of Ca2+ at hair-cell synapses, metabolic stress on the hair cell, and excessive release of the
neurotransmitter glutamate. The overall goal of this proposal is to understand how pathological
changes at the hair-cell synapse stemming from excessive noise exposure ultimately contribute
to noise-induced damage. Our objectives are to 1) test the hypothesis that hair-cell
overstimulation triggers synaptic-ribbon loss, 2) determine the role of glutamate signaling in
hair-cell pathology and repair of acoustic overexposure, and 3) identify the downstream
effectors of glutamate-receptor mediated hair-cell death.
Current gaps in our understanding of how hair-cell synapse overstimulation contributes to hair-
cell damage are in large part due our inability to follow the time course of dynamic intracellular
processes in noise-exposed hair cells and to separate glutamate induced damage to hair-cells
versus innervating nerve terminals in mammalian cochlea. This project will circumvent these
issues by investigating noise-induced hair-cell damage using live-cell imaging, tissue-specific
genetic ablation, and pharmacological tools in the zebrafish lateral line— a mechanosensory
organ which is made up of clusters of innervated hair cells. Zebrafish lateral-line hair cells are
similar to mammalian hair cells at the molecular and cellular level, but are pharmacologically
and optically accessible within the whole larvae. This feature allows for direct environmental
manipulation and phenotypic observations in a live, intact preparation, which is currently not
feasible in the mammalian cochlea. The results of each of our objectives will reveal how specific
pathological changes at hair-cell synapses contribute to multiple pathologies resulting from
excess noise exposure, thereby furthering our understanding of the underlying causes of
sensorineural hearing loss.

## Key facts

- **NIH application ID:** 10187542
- **Project number:** 5R01DC016066-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Lavinia Sheets
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $324,063
- **Award type:** 5
- **Project period:** 2017-07-17 → 2023-09-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187542

## Citation

> US National Institutes of Health, RePORTER application 10187542, Roles of the Synapse in Hair-Cell Pathology (5R01DC016066-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10187542. Licensed CC0.

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