# The Role of Lysyl Oxidase in Epithelial Differentiation in Eosinophilic Esophagitis

> **NIH NIH R03** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $132,000

## Abstract

PROJECT SUMMARY
 This R03 proposal stems directly from studies and career development activities outlined in Dr. Muir’s
K08. This award represents a new research direction that will enhance Dr. Muir’s advancement towards
independence. This award will allow Dr. Muir to obtain additional skills in combining genetically altered cells with
three-dimensional culture systems in order to define novel mechanisms of esophageal epithelial differentiation
with direct relevance to eosinophilic esophagitis (EoE). This will be achieved with the guidance of research
mentors, Drs. Rustgi and Nakagawa and my K08 interdisciplinary advisory committee of Drs. Herlyn (Chair),
Tong, and Heuckeroth.
 Eosinophilic esophagitis (EoE) is an allergic disease characterized by esophageal infiltration of
eosinophils. In addition to inflammatory cell invasion, this disease is characterized histologically by epithelial
changes, specifically failure of epithelial differentiation leading to basal cell hyperplasia. Under homeostatic
conditions, esophageal epithelial differentiation is known to be regulated by the Notch family of receptors,
however, little is known about Notch regulation in the context of EoE. Through the work of the ongoing K08, Dr.
Muir has investigated the role of collagen cross linking enzyme, lysyl oxidase (LOX) in promoting fibrosis in EoE.
In the work presented in this proposal, she now seeks to determine the effects of this enzyme on esophageal
epithelial differentiation. Dr. Muir’s preliminary data demonstrate that LOX affects the epithelial proliferation-
differentiation gradient in the esophagus. In LOX over-expressing esophageal epithelial cells (EPC-LOX) there
is loss of epithelial differentiation in 3D organoid culture and Notch signaling is suppressed. Based on these
findings the overall hypothesis is that LOX-mediated suppression of Notch signaling contributes to EoE
pathobiology by limiting squamous differentiation and promoting barrier defects. Guided by strong
preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine the relationship
between LOX and EoE-associated impairment of epithelial differentiation and integrity and 2) Determine the how
LOX-mediated modulation of Notch signaling influences squamous differentiation. Under the first aim, she will
evaluate the effects of LOX overexpression on proliferation-differentiation and barrier integrity utilizing functional
assays of cell proliferation and barrier integrity. In the second aim, she will define how Notch signaling
contributes to impaired squamous differentiation in the context of LOX over-expression. The approach in this
proposal is innovative because it utilizes a novel esophageal 3D organoid culture system which recapitulates
esophageal histology and epithelial differentiation observed in vivo. The proposed research is significant as it
seeks to elucidate the role of LOX in esophageal epithelial differentiation and provide the basis for future studies
w...

## Key facts

- **NIH application ID:** 9902422
- **Project number:** 5R03DK118310-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Amanda Brooke Muir
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $132,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902422

## Citation

> US National Institutes of Health, RePORTER application 9902422, The Role of Lysyl Oxidase in Epithelial Differentiation in Eosinophilic Esophagitis (5R03DK118310-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9902422. Licensed CC0.

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