# Molecular mechanisms of cochlear hair bundle mechanics

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $444,812

## Abstract

Project Summary
Cochlear amplification is the process by which our auditory system amplifies and tunes responses to
incoming sounds, bestowing us with our excellent sound level sensitivity, large dynamic range, and fine
frequency discrimination. Auditory sensory cells have two processes hypothesized to contribute to cochlear
amplification: somatic motility that occurs in the cell soma and active hair bundle mechanics that occurs in the
apical stereocilia hair bundle. To assay the contribution of active hair bundle mechanics to cochlear amplification
requires further understanding of the processes related to it. Hair cell mechanotransduction (MET), the process
of converting sound stimuli into electrical signals in the hair bundle, is the driver of active hair bundle mechanics.
MET adaptation is one key mechanism that is hypothesized to contribute to active hair bundle mechanics.
Previous work in non-mammalian models show that adaptation is separated into fast and slow processes, both
of which rely on the influx of calcium to drive the process. Data in the mammalian cochlea indicate that adaptation
also consists of fast and slow components, but our work shows that the underlying biology driving the fast and
slow processes in the cochlea is fundamentally different from what has been previously reported in non-
mammalian hair cells. Thus, new investigations are needed to understand the molecular machinery responsible
for both fast and slow adaptation, and their contributions to mammalian auditory processing.
 From new data about properties of cochlear MET, we hypothesize that tension is essential for adaptation
mechanisms. In Aim 1 of this study, we will investigate the contribution of myosin motors to adaptation and hair
bundle mechanics. We assay this using new, faster stimulation and high-speed imaging to monitor mechanical
changes in the hair bundle coupled with hair cell electrophysiology and pharmacological manipulation. With
numerous myosin motors known to be important for auditory function, in Aim 2 we will explore the contributions
of specific myosin motors to adaptation and hair bundle mechanics using existing mouse models. For Aim 3, we
developed a new mouse model using CRISPR/Cas9 technology to acutely inactivate myosin VIIa motor function,
and we will assess the role of myosin VIIa in tension generation. 
The experiments in this proposal will further our understanding of the molecular mechanisms of mammalian
cochlear adaptation and hair bundle mechanics to develop a new model of the mammalian auditory MET
process. We are uniquely positioned to accomplish this with the new technologies that we have and continue to
develop. Basic mechanistic knowledge of auditory MET will lead to experiments where we can interrogate the
system in vivo to determine specific molecular contributions to cochlear amplification. Understanding cochlear
amplification can lead to better prevention and/or restoration of hearing.

## Key facts

- **NIH application ID:** 9920119
- **Project number:** 5R01DC016868-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Anthony Wei Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $444,812
- **Award type:** 5
- **Project period:** 2018-06-07 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920119

## Citation

> US National Institutes of Health, RePORTER application 9920119, Molecular mechanisms of cochlear hair bundle mechanics (5R01DC016868-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9920119. Licensed CC0.

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