# Mechanisms of Duox2 variants in the pathogenesis of preclinical IBD

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $657,281

## Abstract

PROJECT SUMMARY/ABSTRACT
Inflammatory Bowel Disease (IBD) is a debilitating gut disorder with significant morbidity and healthcare
resource utilization. Because early diagnosis and treatment may improve the prognosis of IBD, there is an
urgent need to better understand the preclinical incipient disturbance of gut microbe-epithelial homeostasis
in at-risk individuals to identify novel therapeutic targets to halt disease onset, which is our long-term objective.
A crucial host factor in maintaining a homeostatic relationship with the gut microbiota is Dual Oxidase 2
(DUOX2), an epithelial-specific NADPH oxidase releasing H2O2 into the supra-epithelial mucus layer. DUOX2
is highly inducible by abnormal microbial colonization and among the most robustly and consistently
overexpressed genes in mucosal biopsies from patients with preclinical IBD. We previously showed a defect
in DUOX2 leads to activation of compensatory epithelial defense systems in specific-pathogen-free mice and
loss-of-function alleles in human populations are associated with increased susceptibility to IBD. However,
the relevant mechanisms underlying this genetic association remain unclear. The objective here is to
determine how DUOX2 loss-of-function genetic variants render an individual susceptible to dysbiosis and a
loss of mucosal immune homeostasis leading to IBD. We hypothesize that dysregulation of IL-17C
signaling is a critical pathogenic driver of DUOX2-associated IBD. The rationale for the proposed
research is that, once it is known how dysregulation of IL-17C signaling in DUOX2 defective hosts contributes
to pathogenesis of IBD, novel strategies can be developed to identify at-risk individuals and restore
homeostasis to prevent the onset of IBD. We will test our hypothesis and, thereby, accomplish our objective
by pursuing the following specific aims: 1. Determine the mechanisms of how DUOX2 loss-of-function results
in microbe-dependent activation of the IL17C axis. 2. Assess the function of IL17RE-like protein, a hitherto
uncharacterized IBD risk factor. 3. Investigate the role of chronic IL-17C activation in DUOX2 defective hosts
as a driver of IBD pathogenesis. The expected outcome of the proposed work is a mechanistic framework of
how DUOX2 variants cause an increased risk for IBD, namely by sustained activation of IL17C-mediated
immune responses due to abnormal microbe-epithelial interactions. Such results are expected to have an
important positive impact because understanding how DUOX2 variants contribute to IBD pathogenesis is
highly likely to provide new targets for preventative and therapeutic interventions for diseases associated with
dysregulated microbe-intestinal interaction (e.g., IBD, IBS, colon cancer) in addition to fundamentally
advancing the fields of gut mucosal immunity.

## Key facts

- **NIH application ID:** 10896391
- **Project number:** 5R01DK134486-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Helmut F Grasberger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $657,281
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896391

## Citation

> US National Institutes of Health, RePORTER application 10896391, Mechanisms of Duox2 variants in the pathogenesis of preclinical IBD (5R01DK134486-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10896391. Licensed CC0.

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