# Molecular mechanisms of cochlear hair bundle mechanics

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $627,637

## Abstract

Project Summary
 Hair cells are auditory mechanoreceptors that use an apically located hair bundle to convert mechanical
vibrations due to sound into electrical activity, a process termed mechanotransduction. The
mechanotransduction process is essential to cochlear amplification, which is responsible for our excellent sound
level sensitivity, large dynamic range, and amazing frequency discrimination. Loss of mechanotransduction leads
to loss of cochlear amplification. Control of the range of sensitivity of the mechanotransduction process is
hypothesized to be a key contributor to augmenting the dynamic range. In this proposal, we will investigate two
mechanisms that can control the range of stimuli to which the hair cell is responsive.
 Mechanotransduction adaptation can adjust the range of sensitivity in the presence of an ongoing stimulus.
One type of adaptation described decades ago is termed slow adaptation due to its kinetics. Slow adaptation
was hypothesized to function via the motor model of adaptation. We recently overturned the motor model of slow
adaptation, and we now propose a new model of slow adaptation requiring the phosphoinositide PIP2. In this
proposal, we build upon our existing data by studying specific mutations in TMC1, the putative
mechanotransduction channel, that we hypothesize to have a role in mediating PIP2 binding to modulate channel
function. These experiments will provide mechanistic insight for slow adaptation.
 The second mechanism of sensitivity control is through cAMP. We recently discovered that cAMP functions
to reduce gating spring stiffness, thereby controlling the sensitivity of the mechanotransduction channel. In this
proposal, we will study the upstream and downstream signaling pathways using knockout mouse models to
identify the molecular contributors to the pathway. These models will allow us to also identify the physiological
role of the cAMP pathway in the cochlea. These experiments will lead us one step closer to understanding the
role of cAMP in normal hearing function and identifying the molecular component(s) of the gating spring, which
is the final downstream target.

## Key facts

- **NIH application ID:** 10809373
- **Project number:** 2R01DC016868-06A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Anthony Wei Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $627,637
- **Award type:** 2
- **Project period:** 2018-06-07 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809373

## Citation

> US National Institutes of Health, RePORTER application 10809373, Molecular mechanisms of cochlear hair bundle mechanics (2R01DC016868-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10809373. Licensed CC0.

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