# Molecular Mechanisms of Epithelial Contribution to Esophageal Inflammation and Tissue Repair

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $355,500

## Abstract

PROJECT SUMMARY
The overarching goal of this proposal is to understand the contribution of the epithelium to esophageal
inflammation and tissue injury through mechanistic studies of the key inflammatory mediator inhibitor of nuclear
factor kappa-B kinase subunit beta (IKKβ). The significance of this proposal lies in 1) the prevalence of
esophageal disorders, which are a significant burden in the U.S. and throughout the world and 2) the central
role of epithelial IKKβ signaling in the regulation of diverse biological processes, such as inflammation,
immunity, cell survival, and cell growth in numerous tissues and cell types. The PI is an early-stage investigator
who is an expert in epithelial inflammation and injury, inflammatory mediators, animal models of disease, and
epithelial biology, and is supported by a superb research team, complemented by expert collaborators. Here,
we will take advantage of new mouse models and complementary in vitro systems utilizing 3D culture system
to test the hypothesis that activation of epithelial IKKβ signaling produces a pro-inflammatory, pro-
proliferative, pro-angiogenic milieu that tips the balance towards the development esophageal diseases such
as squamous cell dysplasia and cancer. To explore these processes, we will undertake three interrelated
Specific Aims. In Aim 1, we will determine the functional interplay of STAT3 activation and IKKβ signaling in
the proliferative response of esophageal epithelial cells. This will be undertaken using mice with both active
IKKb and STAT3 deletion, and three-dimensional (3D) mouse esophageal organoids. In Aim 2, we will define
the role of epithelial IKKβ signaling in epithelial-endothelial cell interactions during the transition from a normal
state to esophageal dysplasia. Here, we will utilize a novel transgenic mouse model with esophageal epithelial
IKKβ deletion treated with 4-Nitroquinoline 1-oxide (4-NQO), and 3D vascular network formation assay. In Aim
3, we will investigate the role of epithelial IKKβ signaling in the inflammatory response of esophageal epithelial
cells during the transition from a normal state to esophageal dysplasia. This will be undertaken new transgenic
mouse model of esophageal epithelial IKKβ deletion that is treated with 4-NQO. These complementary
approaches will confirm and extend the findings from our Preliminary Data and from our recent publication in
Gastroenterology. Moreover, the proposed research will be supported by the superb and collegial intellectual
environment and the exceptional resources and facilities available to the PI. We anticipate that these studies
will provide insight into the factors that regulate normal esophageal epithelial homeostasis, the
microenvironment, and the pathways that are disrupted in esophageal diseases, both benign and malignant.

## Key facts

- **NIH application ID:** 10359705
- **Project number:** 5R01DK116988-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** MARIE-PIER TETREAULT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $355,500
- **Award type:** 5
- **Project period:** 2018-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359705

## Citation

> US National Institutes of Health, RePORTER application 10359705, Molecular Mechanisms of Epithelial Contribution to Esophageal Inflammation and Tissue Repair (5R01DK116988-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10359705. Licensed CC0.

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