# Understanding Mechanisms and Sex-Differences in Visceral Pain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $822,501

## Abstract

Project Summary/Abstract
Our current understanding of mechanisms underlying visceral hypersensitivity, such as that associated with
irritable bowel syndrome (IBS), remains rudimentary. Importantly, treating this and other functional gut disorders
is limited, with a clear need for alternative treatment options. For the growing population afflicted by IBS, GI
hypersensitivity and pain persist long after signs of tissue injury have resolved. Unlike other intestinal disorders,
patients with IBS are hypersensitive with a lower pain threshold following colonic rectal distention (CRD) testing.
Identifying the molecular and cellular components that mediate both the acute and persistent phases of visceral
pain is a critical first step in understanding how environmental and endogenous factors produce long-term
changes in the nervous system or associated tissues to engender chronic pain syndromes. In this new multi-PI
application, we have taken a team-science approach and a multifaceted strategy designed to maximize the
relevance of our pre-clinical basic research discoveries.
Enterochromaffin (EC) cells are key sensory cells in the intestinal epithelium that release serotonin onto primary
sensory nerve fibers, thereby evoking a sensation of discomfort and pain in response to luminal irritants, such
as bacterial metabolites, inflammatory agents, or ingested chemicals. Our group recently established that EC
cell-mucosal afferent signaling is a major mediator of visceral pain. We also show that the strength of this signal
differs in males versus females. We will leverage our new colitis-free chemogenetic model of visceral
hypersensitivity to zero in on the contribution of EC cells to visceral pain and identify molecular mechanisms
through which these cells modulate the activity of nearby sensory nerve fibers. We will also ask how estrogen
signaling contributes to the strong female bias that is characteristic of human IBS.
Our team brings expertise in neurophysiology, pharmacology, visceral tissue anatomy, sex differences, and
hormone signaling in female physiology and an unusually wide-ranging set of innovative approaches to tackle a
prevalent gut-brain disorder.

## Key facts

- **NIH application ID:** 10917054
- **Project number:** 5R01DK135714-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** HOLLY A. INGRAHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $822,501
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917054

## Citation

> US National Institutes of Health, RePORTER application 10917054, Understanding Mechanisms and Sex-Differences in Visceral Pain (5R01DK135714-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10917054. Licensed CC0.

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