# Identifying the role of serotonin receptor 4 and trefoil factor 3 in intestinal wound repair

> **NIH NIH K01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $123,648

## Abstract

PROJECT SUMMARY
Background and aims: Serotonin (5-HT) exerts numerous physiological functions in the gastrointestinal tract via
activation of 14 different serotonin receptor subtypes. Elevated serotonin levels are noted in response to tissue
damage, indicating that serotonin release may mediate important repair mechanisms. Serotonin has been shown
to have reparative effects on skin injury and gastric ulcers, and serotonin receptor 4 (5-HTR4) specifically has
been shown to have anti-ulcerogenic action after colon tissue damage. However, the mechanism behind this
phenomenon is unclear. Recently 5-HTR4 has been identified on goblet cells, which are known to produce trefoil
factor 3 (TFF3); a key compound in intestinal repair. Currently the link between 5-HTR4 and TFF3 is unknown.
Preliminary data generated using human intestinal enteroids has demonstrated that exogenous serotonin
stimulates TFF3 release to promote repair in live imaging wound healing assays. This effect was mitigated by
inhibition of the TFF3 receptor CXCR4. In a microbial-centered approach, our lab has also identified a single
commensal bacterium, Bifidobacterium dentium, which in gnotobiotic mice and in mouse and human enteroids
is able to stimulate serotonin release from enterochromaffin cells. Additionally, treatment of human enteroids
with B. dentium metabolites also enhance epithelial restitution in a wound healing assay, similar to exogenous
serotonin. The overall hypothesis of this proposal is that serotonin activates 5-HTR4 on goblet cells to stimulate
TFF3 release, which acts on its receptor CXCR4 to mediate signaling cascades responsible for epithelial repair.
Aim 1 seeks to define the requirement of TFF3 for 5-HTR4 mediated epithelial repair in vivo using mouse models
and colonoscopy-induced colonic wounds. Aim 2 seeks to examine a microbial approach for stimulating
serotonin production and wound healing in vivo. Finally, Aim 3 addresses the signaling cascade required for
TFF3 mediated restitution in intestinal epithelial cells in mouse and human colonic enteroids in vitro. Mucosal
healing is critical for in the treatment of ulcers, surgical anastomoses, enterocutaneous fistulae and inflammatory
bowel disease wounds. Failure to properly heal wounds can result in complications including infection, prolonged
hospitalization, and critical illness. Long-term objective and aims: My long-term goal is to become a productive
independent investigator at research institution. Receiving a K01 Career Development Award would better equip me
to achieve this goal. My research is well suited for the National Institute of Diabetes and Digestive and Kidney
Diseases as it relates to intestinal wound repair. My current institution, Baylor College of Medicine, offers the scientific
resources required to complete this proposal. Additionally, I have assembled a group of renowned scientists to serve
on my mentorship committee and leaders in the fields of microbiology and wound repair to serve a...

## Key facts

- **NIH application ID:** 9871379
- **Project number:** 1K01DK123195-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Melinda Anne Engevik
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $123,648
- **Award type:** 1
- **Project period:** 2020-01-13 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9871379

## Citation

> US National Institutes of Health, RePORTER application 9871379, Identifying the role of serotonin receptor 4 and trefoil factor 3 in intestinal wound repair (1K01DK123195-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9871379. Licensed CC0.

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