# Trefoil factor proteins regulate inflammation and immunity

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $422,380

## Abstract

&RQWDFW 3'3, +HUEHUW 'HEURVNL 5
PROJECT SUMMARY
Under normal circumstances, mucosal tissue damage caused by abrasions, chemicals, or biological agents is
quickly resolved, lest persistent inflammatory responses drive chronic disease. However, the basic
understanding of the immunoregulatory and regenerative mechanisms operating at the mucosal interface
remains fragmented and unclear. The central goal of this UO1 project is to uncover how Trefoil factor family
(TFF) proteins protect the gastrointestinal (GI) tract from injurious inflammatory responses and drive host
protection against metazoan parasites and pathogenic bacteria. Preliminary data shows that we have
discovered a previously unknown class of receptors for TFF2 and TFF3, a finding that stands to radically
impact the cellular and molecular understanding of how Trefoil factor responsiveness in immune cells could
govern the balance between tolerance and inflammation. Indeed, we demonstrate that therapeutic
administration of TFF3 resolves colitic inflammation and that TFF3 exposure promotes interleukin 10 family
cytokine secretion from both human and mouse immune cells. Taken together, the over-arching goal of this
project is to bring forth a conceptual and technological advance to the field of Trefoil factor biology. Our two
main questions are: (1) whether Trefoil factors function through cognate receptor-ligand interactions with
members of the Leucine rich repeat and Ig domain containing, Nogo receptor interacting protein (LINGO)
family and (2) whether Trefoil factors critically influence mucosal immune responses in the context of colitis or
pathogen infection through regulation of interleukin 10 family cytokine production. Our central hypothesis is
that Trefoil factor 3 regulates mucosal IL-10 and IL-22 production through LINGO receptor-dependent
mechanisms. Experiments in specific aim 1 will establish whether TFF3 suppresses colitis via LINGO2 and/or
LINGO3-dependent mechanisms, those in specific aim 2 will define the pathway(s) and biological importance
for TFF3-dependent IL-10 production and experiments in specific aim 3 will define the cellular and molecular
mechanism(s) for TFF3-mediated regulation of IL-22. Through successful completion of our project goals, we
intend to stimulate broad interest and collaborative investigation of Trefoil factors as an important part of the
mechanisms that shape immunity, inflammation, and repair at the mucosal interface.
3URMHFW 6XPPDU\$EVWUDFW 3DJH

## Key facts

- **NIH application ID:** 10179207
- **Project number:** 3U01AI125940-05S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** De'Broski R Herbert
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $422,380
- **Award type:** 3
- **Project period:** 2020-11-25 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179207

## Citation

> US National Institutes of Health, RePORTER application 10179207, Trefoil factor proteins regulate inflammation and immunity (3U01AI125940-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10179207. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*