# Novel mechanisms protecting the gut from TNF

> **NIH NIH R37** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $651,105

## Abstract

PROJECT ABSTRACT
Tumor necrosis factor (TNF) is a pleiotropic cytokine that promotes host defense, cell survival and tissue
regeneration under homeostatic condition However, if dysregulated and overexpressed, TNF is a major driver
of chronic inflammation. Excessive TNF production in the gastrointestinal tract targets the epithelium, drives
increased cell death, and is sufficient to elicit substantial tissue inflammation and chronic disease. Blockade of
TNF is a widely utilized biologic that provides therapeutic benefit in a subset of inflammatory bowel disease
(IBD) patients. Despite this knowledge, the mechanisms that control the beneficial versus detrimental roles of
TNF in the intestine are poorly defined. The fundamental focus of this proposal is to mechanistically
define a novel pathway that protects the intestine from TNF-driven damage and inflammation. In
recently published and new preliminary data, we have determined that group 3 innate lymphoid cells (ILC3s)
are essential to protect the intestinal epithelium from TNF-driven damage and inflammation. Surprisingly, this
did not occur via traditional effector pathways, and rather involved production of prostaglandins and growth
factors. These data provoke a fundamental hypothesis that ILC3s are essential to shape the protective versus
pathologic roles of TNF in the intestine, and this balance is disrupted in human IBD where ILC3s are known to
become dysregulated. We will mechanistically test this hypothesis by asking the following specific questions:
(1) How does ILC3 production of sensing of prostaglandins impact intestinal health and inflammation? And (2)
What are the cellular and molecular mechanisms by which ILC3-derived HB-EGF augments intestinal immunity
and protects the gut from TNF? Finally, we will directly translate our findings from basic mouse models into
samples from IBD patients. Results from these experiments will pave the way for a greater understanding of
TNF-driven intestinal damage and inflammation, which could provoke novel preventative, therapeutic or
curative strategies for multiple chronic inflammatory diseases.

## Key facts

- **NIH application ID:** 10890196
- **Project number:** 5R37AI174468-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Gregory F Sonnenberg
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $651,105
- **Award type:** 5
- **Project period:** 2023-07-18 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890196

## Citation

> US National Institutes of Health, RePORTER application 10890196, Novel mechanisms protecting the gut from TNF (5R37AI174468-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10890196. Licensed CC0.

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