# Lysyl oxidase induced esophageal remodeling in eosinophilic esophagitis

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $396,000

## Abstract

Project Summary
 Eosinophilic esophagitis (EoE) is a chronic, debilitating disorder characterized by persistent allergic
inflammation that over time leads to fibrosis and stricture. While it is characterized by intense eosinophil and
mast cell infiltration, pathologic tissue remodeling events lead to irreversible fibrosis and significant clinical
symptoms. These remodeling events include epithelial basal cell hyperplasia and subepithelial fibrosis. Our
previous work has implicated lysyl oxidase (LOX), an enzyme known to cross-link collagen and potentiate tissue
stiffness, as a key mediator of pathologic esophageal remodeling. LOX is robustly expressed in the esophageal
mucosa of patients with active EoE inflammation, particularly in those with fibrosis. Robust in vitro and in vivo
data suggest that TGF signaling in esophageal epithelium enhances LOX production, which in turn, promotes
remodeling in both the epithelial (basal cell hyperplasia) and fibroblast compartments. We therefore seek to
define the mechanisms whereby epithelial TGF and LOX promote remodeling in the esophagus and further
exploit these mechanisms for clinical application. We hypothesize that the epithelial TGF-LOX axis drives basal
cell hyperplasia and fibrostenosis in EoE. In Aim 1, we will evaluate the cell autonomous effects of epithelial
LOX, evaluating how epithelial TGF drives LOX-induced basal cell hyperplasia in 3D epithelial culture and
chromatin immunoprecipitation assays. In Aim 2, we will evaluate the non-cell autonomous effects of epithelial
TGF and LOX by evaluating their effects on fibroblast activation and tissue stiffness. And finally, in Aim 3 we
will evaluate the therapeutic and prognostic potential of this pathway by performing pre-clinical proof of purpose
studies, treating mice with EoE inflammation with anti-TGF antibody and validating LOX expression in EoE
patient tissue. Data from this study will inform future therapies targeting tissue remodeling as well as work
towards identifying patients with fibrotic disease prior to the onset of disability.
 This innovative and hypothesis-driven study is backed by strong preliminary data generated by the PI
while she was supported by an NIH career K08 award. The PI is uniquely poised to accomplish these aims with
her previous track record in investigating mechanisms of epithelial-fibroblast crosstalk, LOX in EoE, and 3D
epithelial culture and co-culture models.

## Key facts

- **NIH application ID:** 9943366
- **Project number:** 1R01DK124266-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Amanda Brooke Muir
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,000
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9943366

## Citation

> US National Institutes of Health, RePORTER application 9943366, Lysyl oxidase induced esophageal remodeling in eosinophilic esophagitis (1R01DK124266-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9943366. Licensed CC0.

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