# Molecular Mechanisms of Hair Bundle Development and Maintenance

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $408,427

## Abstract

Project Summary
The detection of sound in the cochlea requires hair cells and their mechano-sensitive organelles, called
stereocilia. The long-term goal of this laboratory is to study how stereocilia grow and how their integrity is
maintained over a lifetime. These are critical processes and are commonly disrupted in hereditary forms of
human hearing loss. In this proposal, we investigate a molecular motor called myosin 15 (MYO15A) that sets
the size of the actin filament core that is the structural foundation within each stereocilium. Mutations in the
MYO15A gene cause human hereditary hearing loss, DFNB3. Our initial experiments have revealed a novel
mechanism that allows MYO15A to control the actin core, and we hypothesize that the hair cell regulates
stereocilia architecture using different MYO15A isoforms. To test this, we will investigate the molecular properties
of MYO15A to understand how it influences growth of the actin core, reveal how these activities are regulated
within the hair cell, and examine how mutations cause hearing loss in a mouse model. In Aim 1, we use purified
proteins and spectroscopy / single-molecule assays to extensively characterize how MYO15A accelerates actin
polymerization. As part of this, we will introduce mutations to explore candidate regions within MYO15A that
underlie this activity. In Aim 2, we expand our study to different isoforms of MYO15A and use biochemical assays
and cryo-electron microscopy to investigate key differences in their enzymatic activity and how these are
regulated. In Aim 3, we characterize a mutant mouse where a novel MYO15A isoform has been removed using
CRISPR genetic engineering, and study how these animals lose their hearing using a combination of high-
resolution electron and light microscopy. Overall, our proposal will provide critical new information into basic
mechanisms of stereocilia plasticity, in addition to revealing the distinct pathologies that cause deafness in
patients suffering with DFNB3.

## Key facts

- **NIH application ID:** 10029316
- **Project number:** 1R01DC018827-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Jonathan Edward Bird
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,427
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029316

## Citation

> US National Institutes of Health, RePORTER application 10029316, Molecular Mechanisms of Hair Bundle Development and Maintenance (1R01DC018827-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10029316. Licensed CC0.

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