# Epigenetic Pathways in Chronic Stress-associated Visceral Hyperalgesia

> **NIH NIH R56** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $390,000

## Abstract

Project Abstract
Chronic stress is commonly associated with enhanced abdominal pain (visceral hyperalgesia) and altered
bowel habits in humans with Irritable Bowel Syndrome (IBS) and validated animal models via activation of the
HPA-axis and the glucocorticoid receptor (GR) transcription factor. The cellular and molecular mechanisms
underlying chronic stressed-associated visceral hyperalgesia are poorly understood; however, emerging
evidence indicates that the visceral hyperalgesia is linked to decreased expression of colon epithelial cell tight
junction proteins and increased paracellular permeability. Our lab and others have reported a potentially
significant role for epigenetic mechanisms in nociceptive neural pathways in chronic stress-induced visceral
hyperalgesia. It is unknown whether epigenetic mechanisms are directly involved in the decreased expression
in intestinal epithelial tight junction proteins, increased paracellular permeability and visceral hyperalgesia. In
this proposal, we provide compelling preliminary data supporting the novel hypothesis that methylation of
repressive histone H3K9 plays a pivotal role in chronic stress- and pro-inflammatory cytokine-mediated visceral
hyperalgesia via down-regulation in colon epithelial tight junction proteins and increased paracellular
permeability using two validated rat models (males and females) and patients with diarrhea-prone IBS (males
and females), differentiated human Caco-2 cells, human-derived colonoids and human-derived colon epithelial
cell monolayers. We will examine the following vertically-integrated specific aims to confirm the role of
H3K9me2/me3 in the pathophysiology of chronic stress-associated visceral hyperalgesia: Specific Aim 1: Test
the global hypothesis that methylation of the repressive histone H3K9 plays a key role in chronic stress-
induced intestinal barrier dysfunction and visceral hyperalgesia using two validated male animal models;
Specific Aim 2: Examine how H3K9 methylation regulates intestinal epithelial tight junction gene transcription
and protein expression, paracellular permeability and visceral hyperalgesia in response to chronic stress,
corticosterone and pro-inflammatory cytokines; and Specific Aim 3: Assess the translatability of the animal
studies to the human and potential differences based on biological sex. The application is highly significant
because of the clinical importance of chronic stress to enhance visceral pain and the novel global hypothesis,
innovative because of the use of state-of-art methods to study the global hypothesis in a systematic manner
and high impact because of the potential to influence current thinking in the field.

## Key facts

- **NIH application ID:** 10248001
- **Project number:** 1R56DK126675-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SHUANGSONG HONG
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248001

## Citation

> US National Institutes of Health, RePORTER application 10248001, Epigenetic Pathways in Chronic Stress-associated Visceral Hyperalgesia (1R56DK126675-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10248001. Licensed CC0.

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