# Endosomal Platforms for Signaling Pain

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2024 · $647,474

## Abstract

PROJECT SUMMARY/ABSTRACT
G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) are mediators of and
therapeutic targets for diverse disorders, including chronic pain. This proposal challenges the
dogmas that these receptors signal primarily from the plasma membrane and that cell surface
receptors are the optimal therapeutic targets. Completed studies revealed that GPCR endosomal
signaling controls pain and that endosomally-targeted antagonists provide more effective
analgesia than conventional drugs. The renewal application extends these concepts to
tropomyosin receptor kinase A (TrkA), a RTK for nerve growth factor (NGF). Although successful
for the treatment of pain, NGF monoclonal antibodies have not been approved due to adverse
outcomes of systemic antagonism. A deeper understanding of how NGF and TrkA signal pain is
required. Anatomical and electrophysiological studies with mouse and human nociceptors,
behavioral studies in mice, biophysical assays using recombinant proteins, model cells and
nociceptors, and nanoparticle-encapsulated antagonists will be used to study NGF pain. Aim 1
hypothesizes that neuropilin 1 (NRP1) is required for NGF-induced sensitization of nociceptors
and NGF-evoked nociception. Preliminary studies suggest that NRP1 and the scaffolding protein
GAIP/RGS19-interacting protein (GIPC1) are necessary for NGF-induced nociception. Co-
expression of TrkA, NRP1 and GIPC1 protein and mRNA in mouse and human nociceptors will
be studied. Inhibitors of NRP1 and GIPC1 will be used to ascertain their contributions to NGF-
induced sensitization of nociceptors and nociception. Aim 2 hypothesizes that NRP1 acts as an
NGF coreceptor and TrkA chaperone to enhance NGF signaling of pain in nociceptors.
Biophysical approaches will be used to study NGF association with NRP1, assembly of
TrkA/NRP1 heteromers, TrkA surface expression, and NGF signaling in subcellular
compartments of nociceptors. The role of GIPC1 as a scaffold for TrkA and NRP1 association will
be studied. Aim 3 hypothesizes that endocytosis and endosomal NGF/TrkA/NRP1 signaling in
nociceptors mediates sustained sensitization and nociception. The contribution of endocytosis to
NGF-induced nociception will be studied using inhibitors of endocytosis and NGF/TrkA/NRP1
antagonists encapsulated into nanoparticles designed to deliver cargo to endosomes of
nociceptors. NGF-induced endocytosis of TrkA/NRP1, compartmentalized signaling, nociceptor
sensitization and nociception will be studied. A deep understanding of TrkA trafficking-dependent
signaling will provide insights into the mechanisms and treatment of chronic pain, with implications
for other RTK-mediated pathologies (e.g., cancer).

## Key facts

- **NIH application ID:** 10801229
- **Project number:** 2R01NS102722-07
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** NIGEL W BUNNETT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $647,474
- **Award type:** 2
- **Project period:** 2017-08-15 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801229

## Citation

> US National Institutes of Health, RePORTER application 10801229, Endosomal Platforms for Signaling Pain (2R01NS102722-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801229. Licensed CC0.

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