# Cytokines and Inflammatory Bowel Disease

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $163,657

## Abstract

PROJECT SUMMARY
Inflammatory bowel disease (IBD) affects approximately 3.2 million individuals in the US and several million
worldwide. One of the major discoveries in the last 20 years in IBD research has been the key role cytokines
play in intestinal inflammation and the development of anti-cytokine treatments for IBD patients, including anti-
TNFα and anti-IL23 therapies. In spite of these important advances, much more needs to be learned concerning
the basic mechanisms by which cytokines regulate normal gut homeostasis and mediate chronic intestinal
inflammation and IBD. The present competitive renewal application will focus on the TNF superfamily member
TL1A and its receptor DR3, for which strong evidence suggests a major role in the pathogenesis of human and
experimental IBD. The central hypothesis of this proposal is that TL1A/DR3 is a master regulator of
chronic intestinal inflammation in IBD. Based on this concept, targeted manipulation of TL1A/DR3 may
provide a new therapeutic approach for the treatment of this devastating disease. The following three specific
aims are designed to continue our ongoing efforts to understand the role of cytokines in mediating intestinal
inflammation with a particular focus on TL1A. 1) Determine the cellular mechanisms of TL1A/DR3 signaling in
experimental CD-like ileitis. We will test the hypothesis that TL1A/DR3 signaling regulates the balance between
effector and regulatory T cells by using models of DR3 deletion and DR3 activation (SAMP×DR3-/- and SAMP
treated with a DR3 stimulating antibody, i.e. αDR3-SAMP) and we will determine how TL1A/DR3 regulates the
frequency and function of Th1, Th2, Th9, and Tregs in these models. 2) Evaluate the role of TL1A/DR3 in
regulating the balance between pathogenic and protective ILCs in experimental CD-like ileitis. We will determine
the effects of DR3 stimulation or deletion on lamina propria (LP) ILCs in SAMP mice, as well as characterize
ILCs in GF-SAMP×DR3-/-. We will also evaluate the functional effects of ILC3s by performing reconstitution of
specific ILC3 subsets and determine whether their effects on ileitis and epithelial barrier function in SAMP mice.
3) Investigate the effects of TL1A/DR3 signaling on the composition and function of the gut microbiome in
experimental CD-like ileitis. We will first determine the composition of stool content and intestinal mucosa of
SAMP×DR3-/- and αDR3-SAMP littermates by state-of-the-art 16S rRNA and multi-kingdom metagenomics, and
determine differences with control mice. We will then perform a series of in vivo experiments using fecal material
transplantation (FMT) from these mice into SAMP and AKR control germ-free (GF) recipients. Finally, we will
perform FMT from CD patients carrying TL1A mutations into GF SAMP recipients to determine whether the same
effects observed using mouse flora are also present with human flora. The overall objective of this proposal is to
understand basic mechanisms of TL1A/DR3-driven intestin...

## Key facts

- **NIH application ID:** 10671267
- **Project number:** 3R01DK042191-30S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Fabio Cominelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $163,657
- **Award type:** 3
- **Project period:** 1990-07-03 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10671267

## Citation

> US National Institutes of Health, RePORTER application 10671267, Cytokines and Inflammatory Bowel Disease (3R01DK042191-30S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10671267. Licensed CC0.

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