# Endosomal Signaling of PAR2 in Oral Cancer Pain

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $47,552

## Abstract

Oral cancer pain is a prevalent, debilitating, and chronic condition that disrupts patients’ ability to
eat and speak. Patients develop tolerance from continuous use of opioids to treat cancer pain and require
escalating doses to achieve relief. Opioids also produce severe side effects, including respiratory depression,
addiction, and sedation. Alternative non-opioid strategies are necessary. However, the pathobiology of oral
cancer pain is currently not well understood. My research proposal explores the mechanisms by which G-protein
coupled receptors (GPCRs) and transient receptor potential (TRP) ion channels regulate oral cancer pain. Oral
cancers and immune cells such as macrophages secrete proteases that cleave and activate GPCRs at the cell
surface. GPCR activation and G protein coupling triggers downstream signaling cascades, which can sensitize
TRP channels. Specifically, the GPCR protease-activated receptor-2 (PAR2) mediates oral cancer mechanical
allodynia and leads to transient receptor potential vanilloid 4 (TRPV4) activation and hyperexcitability of
nociceptors. However, GPCR signaling from the plasma membrane is transient. Beta arrestins desensitize
GPCRs and couple the receptors for clathrin-mediated endocytosis, which together terminate plasma membrane
signaling. While endosomes were traditionally thought of as a conduit for receptor recycling and degradation,
recent work from my lab demonstrated that GPCRs in endosomes continue to generate sustained signals that
mediate pain transmission. However, whether PAR2 signals from endosomes to sensitize TRPV4 and evoke
hyperexcitability has not been established. The purpose of this research is to identify the mechanisms of
endosomal PAR2 signaling and its effect on TRPV4 sensitization in oral cancer. pH-stimulus responsive
nanoparticles that deliver PAR2 antagonists to endosomes of pain-sensing trigeminal neurons will be developed
to examine this pathway. Aim 1 will develop pH-stimulus responsive nanoparticles and characterize the
biophysical properties of the nanoparticles loaded with PAR2 antagonist. Aim 2 will explore the mechanisms of
endosomal PAR2 signaling and its role in TRPV4 sensitization via genetically-encoded biosensors and calcium
indicators. Aim 3 seeks to assess mechanisms of PAR2 signaling in pre-clinical mice models of oral cancer.
Investigating endosomal PAR2 signaling via pH-stimulus nanoparticle will elucidate whether endosomal GPCRs
are valid therapeutic targets for oral cancer pain. In completing the aims and training plan outlined in this proposal,
the graduate student, Shavonne Teng, will gain a deep understanding of GPCR signaling relevant to chronic
pain. She will learn bioengineering approaches to develop nanomedicines, learn biophysical and cell biology
approaches to study GPCR and TRP regulation, and learn how to study orofacial pain in mouse models. This
research training will expand on her past experience and also prepare her for a research career as an
ind...

## Key facts

- **NIH application ID:** 10490291
- **Project number:** 5F31DE031178-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Shavonne Teng
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $47,552
- **Award type:** 5
- **Project period:** 2021-09-15 → 2024-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490291

## Citation

> US National Institutes of Health, RePORTER application 10490291, Endosomal Signaling of PAR2 in Oral Cancer Pain (5F31DE031178-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10490291. Licensed CC0.

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