# Nociceptor neuron regulation of gastrointestinal barrier protection and host defense

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2022 · $555,093

## Abstract

PROJECT SUMMARY
Nociceptor neurons are peripheral sensory neurons that densely innervate the gastrointestinal tract, detecting
noxious/harmful stimuli to mediate protective neural reflexes including pain. However, the role of nociceptor
neurons or their molecular mediators in regulating gut physiology, barrier protection, and host defense is not
well understood. Here we hypothesize that specific gut-innervating nociceptors signal to epithelial cells to
modulate gut barrier defenses at homeostasis and during bacterial invasion. Our preliminary data show that
nociceptor neurons and the nociceptor neuropeptide calcitonin gene-related peptide (CGRP) signal to intestinal
goblet cells and microfold (M) cells, two types of gut epithelial cells that mediate barrier protection and host
defenses. Recent molecular phenotyping of DRG neurons show that multiple types of nociceptors innervate
the gut. In this project, we will utilize targeted genetic and molecular approaches to: 1) Determine whether
Nav1.8+ nociceptor neurons or their specific subsets (CGRP+, MRGPRD+) are necessary for maintenance of
gut epithelial cell function during homeostasis, and barrier protection against the enteric pathogens Salmonella
Typhimurium or Citrobacter rodentium; 2) Determine whether chemogenetic (DREADD) or dietary ligand
activation of nociceptor neurons is sufficient to induce changes in gut epithelial cells and barrier function; 3)
Define the role of the nociceptor neuropeptide CGRP-RAMP1 axis in regulating barrier epithelial (goblet cells,
M cells) and immune cells in modulating barrier host defenses. We aim to use innovative and interdisciplinary
approaches from neurobiology, gastroenterology, and immunology to interrogate the role of nociceptor neurons
in gut barrier function and enteric host defense. The team includes experts in nociceptor neurons and
neuroimmunology (Chiu lab), and gut microbial and immune responses (Huh lab). A role for the nervous
system in regulating gastrointestinal barrier defenses could lead to novel approaches to treat autoimmune and
inflammatory diseases. A greater understanding of how neurons signal to epithelial cells and immune cells the
gastrointestinal tract could lead to novel insights in tissue barrier homeostasis. Our findings could also have
relevance to disease conditions where gut barrier dysfunction occur such as autoimmune or inflammatory
diseases. Targeting neurons or CGRP signaling could therefore lead to novel approaches to enhance barrier
integrity to treat gastrointestinal diseases.

## Key facts

- **NIH application ID:** 10322730
- **Project number:** 5R01DK127257-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Isaac Ming-Cheng Chiu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $555,093
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322730

## Citation

> US National Institutes of Health, RePORTER application 10322730, Nociceptor neuron regulation of gastrointestinal barrier protection and host defense (5R01DK127257-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10322730. Licensed CC0.

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