# Validation of Fibroblast-Derived PI16 as a Novel Target for pain Treatment

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $2,908,421

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic pain and the addictive effects of opioids used to control pain are major health problems affecting
millions of Americans. Validation of novel targets for the safe treatment of chronic pain is urgently needed. We
identified peptidase inhibitor 16 (PI16) as a novel regulator of chronic pain in an unbiased RNA seq screen.
PI16 is a putative peptidase inhibitor that has not been studied in the context of pain. We showed that male and
female Pi16-/- mice are protected against mechanical allodynia in the spared nerve injury (SNI) and paclitaxel
models of neuropathic pain. Along the neuraxis, PI16 is only detectable in fibroblasts around peripheral nerves
(perineurium), and in the meninges of dorsal root ganglia (DRG), spinal cord, and brain, but not in neurons,
glia or leukocytes. . PI16 levels in perineurial and DRG meningeal fibroblasts increase during neuropathic pain.
The overall objective of this project is to validate PI16 as a novel target for the treatment of chronic pain
using mouse models and human tissues of neuropathy patients and controls and to identify the underlying
mechanisms. Our central hypothesis is that increased PI16 secretion by DRG meningeal and perineurial
fibroblasts promotes chronic pain by increasing blood nerve barrier (BNB) permeability and leukocyte
trafficking into nerve and DRG. The significance is in the validation of PI16 as a novel, potentially
druggable, regulator of chronic pain and the discovery of fibroblasts as key regulators of chronic pain.
We propose the following three specific aims: 1. Validate the key role of PI16 in chronic pain. In two
independent laboratories, we will test the hypothesis that genetic deletion of Pi16 in male and female mice
protects against chronic pain in well-established models of chronic pain. 2. Investigate expression and
regulation of PI16 in fibroblasts around mouse DRG and mouse and human peripheral nerves.
The hypothesis is that PI16 production by fibroblasts in DRG meninges and perineurium is increased via a
TGFβ− and Epac1-mediated pathway to promote chronic pain. We will use tissues from the neuraxis in mouse
pain model and nerves from humans with neuropathic pain. 3. Determine the contribution of PI16 to
blood nerve barrier integrity in mouse pain models and in a human in vitro model. Using a model
of the human BNB, we will test the hypothesis that PI16 increases BNB permeability and leukocyte
transmigration. Using co-immuno-precipitation and mass spectrometry we will identify novel PI16 targets.
This proposal is conceptually innovative because successful completion will validate PI16 as a novel key
regulator of neuropathic and inflammatory pain and establish a novel role of perineurial fibroblasts in
regulating BNB function with major consequences for chronic pain. The expected findings are significant
because they will advance our fundamental understanding of cellular and molecular mechanisms that
contribute to chronic pain and will identif...

## Key facts

- **NIH application ID:** 9974863
- **Project number:** 1R01NS116704-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Andrew John Shepherd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,908,421
- **Award type:** 1
- **Project period:** 2020-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974863

## Citation

> US National Institutes of Health, RePORTER application 9974863, Validation of Fibroblast-Derived PI16 as a Novel Target for pain Treatment (1R01NS116704-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974863. Licensed CC0.

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