# Investigating the role of tip link biophysics on MET function

> **NIH NIH F32** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2024 · $73,828

## Abstract

Project Summary: Broad Impact: Hair cells (HCs) are the sensory transduction cells of the auditory and
vestibular systems. When a mechanical stimulus such as sound or linear, gravitational, or angular accelerations
are applied to these hair cells, small microvillus-like, actin-filled protrusions called stereocilia from the apical pole
of the HCs are deflected. This causes filamentous tip link protein complexes at the tips of hair cell called
stereocilia to pull upon and lead to the opening of mechanoelectrical transduction (MET) channel complex. The
opening of MET channels causes an influx of positively charged ions that depolarize the HCs, resulting in a
variety of physiological processes from synaptic transmission to nerve fibers to physical changes in HC length
by a phenomenon known as electromotility.
However, there is a reigning question of the roles of the protein constituent of the tip links and the MET channel
complex is unclear. For example, whether tip links modulate the mechanical stimuli in HCs by acting as dampers,
extra masses, or springs is yet to be discovered. These tip links are composed of four large extracellular peptide
chains – two of protocadherin 15 (PCDH15) and two of cadherin 23 (CDH23). Due to limitations in heterologous
expression of MET channel complex proteins, MET must be studied in animal models. Recent gene therapy
developments provide a great tool to study one component of tip links: PCDH15. Here, this project seeks to
exploit this novel protein manipulation technique to study the biophysical properties of tip links and the influence
of these properties on the MET channel function. Aim 1: To uncover whether the length of the tip links is important
for MET, MET function of miniaturized PCDH15s with shortened lengths will be compared to that of wild-type-
like tip links. Aim 2: To reveal the role of Ca2+-binding site-mediated flexibility on the hair-cell MET function, tip
links formed by mutant PCDH15s will be compared against wild-type-like tip links using single-cell
electrophysiology. Aim 2.1: Computational simulations that are used to predict protein dynamics will be used to
estimate the flexibility of the tip links when specific Ca2+ binding sites are perturbed. Aim 2.2: MET currents of
different Ca2+-binding-site-perturbed mutant PCDH15s will be measured to reveal the effect of Ca2+-binding at
specific sites on MET. Training: This project aims to forge the applicant into well-rounded auditory neuroscientist.
In pursuit of this goal, the project will teach the applicant inner ear whole-cell hair-cell electrophysiology,
stereocilia bundle deflection, confocal microscopy imaging, animal handling, and in silico methods. Additional
training will provide dedicated time to allow the applicant to grow his network with collaborations across many
different laboratories. Together, this project seeks not only to develop a strong scientist, but also to increase our
collective knowledge on the biophysics underlying the hai...

## Key facts

- **NIH application ID:** 11070464
- **Project number:** 1F32DC022491-01
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Frank Yeh
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $73,828
- **Award type:** 1
- **Project period:** 2024-08-29 → 2027-08-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11070464

## Citation

> US National Institutes of Health, RePORTER application 11070464, Investigating the role of tip link biophysics on MET function (1F32DC022491-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11070464. Licensed CC0.

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