# Elucidating mechanisms of fibrosis associated with the Crohns disease-associated pathogenic variant in the metal transporter ZIP8

> **NIH NIH R03** · JOHNS HOPKINS UNIVERSITY · 2024 · $117,900

## Abstract

PROJECT ABSTRACT
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis, affect 1 in 200
Americans. Anti-tumor necrosis factor (TNF)-alpha therapies remain the cornerstone of therapy for patients
with IBD, but approximately 40% of patients will experience primary or secondary loss of response, and “anti-
TNF-experienced” patients are less likely to respond to all subsequent therapies in current clinical practice.
Single-cell RNA sequencing has uncovered key cellular signatures associated with anti-TNF refractoriness that
strongly implicate signaling between inflammatory macrophages and activated fibroblasts. There remains a
major gap in our understanding of the patient-specific factors that predispose to this aberrant macrophage-
fibroblast activation, how it links to anti-TNF unresponsiveness, and the potential to modulate it to change to
disease course and treatment response. Our work has focused on the functional implications of a pathogenic
variant in a metal transporter, ZIP8 A391T, that dysregulates manganese homeostasis and is associated with
complicated (stricturing and penetrating) Crohn’s disease. In studying ZIP8 391-Thr in a mouse model (Zip8
393T-knock-in (KI)), we have shown increased susceptibility to colitis, but even more interestingly, we have
observed enhanced fibrosis. These mice also exhibit marked induction of Il-11, a pro-inflammatory and pro-
fibrotic cytokine that is a hallmark of aberrant signaling between inflammatory macrophages and activated
fibroblasts in patients with Crohn’s disease – particularly anti-TNF refractory disease. We therefore
hypothesize that study of aberrant macrophage-fibroblast signaling is a key feature of disease pathogenesis in
the Zip8 393T-KI mice. Establishing the underlying disease mechanisms are important because (1) up to 25%
of patients with Crohn’s disease carry ZIP8 391-Thr in some populations and (2) the Zip8 393T-KI could serve
as a novel translational model for mechanistic studies, particularly related to anti-TNF non-response. We will
study this hypothesis in two aims: In Aim 1, we will determine if Zip8 393T-KI perturbs macrophage innate
immune responses; in Aim 2, we will compare fibroblast activation induced by Zip8 393T-KI vs. WT Zip8
macrophages. The long-term goal is to establish if ZIP8 391-Thr genotype has clinical implications for the
prevention of and treatment of patients with Crohn’s disease and use study of ZIP8 391-Thr-related pathology
as key opportunity to elucidate the role of Mn homeostasis in human disease. This R03 application builds from
a K08 that established the altered Mn homeostasis and fibroinflammatory phenotype in colitis in Zip8 393T-KI
mice. This application with strong translational relevance will provide critical mechanistic insight of the ZIP8
genotypic effect on macrophage-fibroblast signaling and the interaction with Mn homeostasis to prioritize
therapeutic targets, including STAT3 or IL-11 inhibition, and patient ...

## Key facts

- **NIH application ID:** 10758267
- **Project number:** 5R03DK134595-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Joanna Miller Peloquin Melia
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $117,900
- **Award type:** 5
- **Project period:** 2023-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758267

## Citation

> US National Institutes of Health, RePORTER application 10758267, Elucidating mechanisms of fibrosis associated with the Crohns disease-associated pathogenic variant in the metal transporter ZIP8 (5R03DK134595-02). Retrieved via MORVS 2026-11-02 from https://api.morvs.ai/grant/nih/10758267. Licensed CC0.

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