# The role of a lysosomal mechano-sensitive ion channel in pain

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $435,875

## Abstract

Project Summary/Abstract:
Chronic pain reduces quality of life and work capability in millions of Americans. Currently, understanding of
the underlying mechanisms and treatments for chronic pain are still limited. The long-term goal of this research
is to identify major ion channel mechanisms and pharmacological targets for the treatment of neuropathic pain.
The goal of the proposed research is to explore the role of a lysosomal ion channel (Tmem63A) in mediating
functional currents in DRG neurons, and neuropathic pain associated with peripheral nerve injury. The central
hypothesis of this proposal is that Tmem63A mediates a mechano-sensitive ion current in lysosomes of non-
peptidergic nociceptive DRG neurons and positively contributes to neuropathic pain associated with peripheral
nerve injury. Two specific aims are proposed in the current project: 1) Test that Tmem63A mediates a
mechano-sensitive ion current in lysosomes, and facilitates lysosomal peripheral trafficking in non-peptidergic
nociceptive DRG neurons; and 2) Test that functional up-regulation of Tmem63A contributes to neuropathic
pain associated with peripheral nerve injury. In Aim 1, mouse DRG neurons will be dissociated. Dissociated
DRG neurons will be subjected to virus-mediated knockdown or overexpression of Tmem63A. The cell type-
specific, and subcellular-specific expression and mechano-sensitive currents of Tmem63A will be studied in
four groups of DRG neurons using single-cell PCR, immunocytochemistry, and whole-lysosome patch clamp.
Additional, lysosome positioning in these DRG neuron groups will also be studied by immunocytochemistry. In
Aim 2, an in vivo repeated oxaliplatin treatment model (or chronic oxaliplatin treatment) of mouse will be used,
and sensory behaviors (mechanical, heat and cold) will be assessed. A virus-mediated in vivo knockdown of
Tmem63A in peripheral neurons will be conducted. The expression of Tmem63A will be detected in multiple
sensory tissues using qPCR, Western blot, and immunohistochemistry methods. Lysosomal positioning will be
examined by immunohistochemistry. The functional currents of Tmem63A will be measured in dissociated
DRG neurons. The effects of oxaliplatin on expression and function of Tmem63A, lysosomal positioning will be
studied. Moreover, the effects of Tmem63A knockdown on the oxaliplatin-induced neuropathic pain behaviors
will be studied. To our knowledge, the roles of lysosomal-specific ion channels, or lysosomal mechano-
sensitive ion channels in pain have not been reported. Therefore, the current study has the potential to
establish lysosomal ion channels as potential targets for the treatment of multiple pain conditions.

## Key facts

- **NIH application ID:** 10580905
- **Project number:** 1R21NS130417-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** JILL C FEHRENBACHER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $435,875
- **Award type:** 1
- **Project period:** 2022-09-28 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10580905

## Citation

> US National Institutes of Health, RePORTER application 10580905, The role of a lysosomal mechano-sensitive ion channel in pain (1R21NS130417-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10580905. Licensed CC0.

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