# Epidermal keratinocytes mediate mechanical pain following neuropathic injury

> **NIH NIH F31** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $46,752

## Abstract

Project Summary
Keratinocytes, the most abundant cell type in the epidermis, mediate normal touch sensation by detecting and
encoding tactile information to sensory neurons. However, it is unknown if keratinocyte mechanotransduction
contributes to chronic mechanical pain following tissue injury. My preliminary data suggest that keratinocytes
isolated from nerve injured animals are sensitized to mechanical stimulation. Considering this finding, I propose
to investigate if injury induced sensitization of keratinocyte mechanotransduction contributes to the development
of touch evoked neuropathic pain. I will specifically examine if this sensitization is mediated by the mechanically
gated ion channel PIEZO1, which my preliminary data suggests is a major keratinocyte mechanotransducer.
Here in Aim 1, I hypothesize that sensitization of keratinocyte PIEZO1 contributes to the development of chronic
mechanical pain in a mouse model chemotherapy-induced peripheral neuropathy (CIPN). I will utilize epidermal
specific PIEZO1 knockout mice and mechanical behavioral assays to determine if loss of PIEZO1 protects
against CIPN mechanical pain (Aim 1A). Additionally, I will utilize ex vivo skin nerve (Aim 1B) and whole-cell
patch clamp (Aim 1C) recordings to determine if loss of keratinocyte PIEZO1 reduces CIPN sensory nerve and
keratinocyte mechanical hypersensitivity. In Aim 2, I hypothesize that PIEZO1 mediates human keratinocyte
mechanotransduction. I will utilize whole-cell patch electrophysiology and PIEZO1 targeted siRNA to determine
if knockdown of PIEZO1 reduces human keratinocyte mechanical sensitivity (Aim 2A). Next, I will determine if
incubation with the chemotherapeutic paclitaxel sensitizes human keratinocytes to mechanical stimulation and if
PIEZO1 knockdown reduces this hypersensitivity (Aim 2B). Finally, I will use mass spectrometry to investigate
signaling factors released from human keratinocytes by PIEZO1 activation under naïve conditions and following
paclitaxel treatment (Aim 2C). Together these aims will determine if keratinocytes enhance evoked mechanical
pain following neuropathic injury and if epidermal PIEZO1 may be potentially targeted to relieve neuropathic
pain.

## Key facts

- **NIH application ID:** 10387370
- **Project number:** 1F31NS125941-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Alexander R Mikesell
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387370

## Citation

> US National Institutes of Health, RePORTER application 10387370, Epidermal keratinocytes mediate mechanical pain following neuropathic injury (1F31NS125941-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10387370. Licensed CC0.

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