# Regulation of Intestinal Immunity and Repair by Integrins

> **NIH NIH R01** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2024 · $750,588

## Abstract

PROJECT SUMMARY
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of the colon that affects roughly one million
Americans. UC is generally nonfatal and often occurs in the prime of life, potentially resulting in decades of
suffering, disability and lost productivity. The underlying mechanisms that lead to disease are poorly understood,
and there are no current medications that can ‘cure’ UC. Recently almost all patients with UC (but almost none
with Crohn’s disease or no IBD) have been found to make high titer antibodies to the integrin αvβ6. Furthermore,
anti-αvβ6 autoantibodies preceded clinical diagnosis of UC by upto 10 years, and were associated with increased
adverse outcomes, suggesting they may represent a fundamental prerequisite or cause of the pathogenesis of
UC. A major role for αvβ6 is the activation of the cytokine TGF-β, a major regulator of intestinal barrier function
and mucosal immune responses. We have spent many years investigating the role of αv integrins in activating
TGF-β to promote intestinal immunity and maintain homeostasis, and we have found that mice in which αvβ6 is
selectively deleted in the intestinal epithelium develop more severe intestinal inflammation in a colitis model, and
this is associated with changes in epithelial cell gene expression similar to those seen in UC. Based on these
data we hypothesize that intestinal epithelial αvβ6 activates TGF-β for autocrine and paracrine signaling to
promote intestinal immune homeostasis, and that disruption of αvβ6 function results in ‘pre-clinical’ UC in mice
and humans. In this project, we will make use of unique mouse models, human epithelial cell and organoid
cultures, and UC patient samples to test these hypotheses and determine the role of αvβ6 autoantibodies in IBD.
Successful completion of these experiments will define a role for epithelial cells as a nexus for regulation of TGF-
β activation in the intestine, and provide a critical understanding of the regulation of this cytokine in health and
disease.

## Key facts

- **NIH application ID:** 10890412
- **Project number:** 1R01DK136071-01A1
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Adam Lacy-Hulbert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $750,588
- **Award type:** 1
- **Project period:** 2024-06-17 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890412

## Citation

> US National Institutes of Health, RePORTER application 10890412, Regulation of Intestinal Immunity and Repair by Integrins (1R01DK136071-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10890412. Licensed CC0.

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