# Measurement and Molecular Mechanisms of Altered Esophageal Distensibility

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2022 · $377,215

## Abstract

PROJECT SUMMARY
A common element mediating the morbidity of esophageal disorders is altered distensibility of the esophageal
wall, potentially resulting in impaired food transit, episodic choking, esophageal retention, and aspiration. In
this proposal we will develop novel methodologies to quantify esophageal wall distensibility in disease states
characterized by either increased or decreased distensibility, phenotype patients accordingly, obtain mucosal
biopsies, and investigate the corresponding molecular mechanisms. Patients with eosinophilic esophagitis
(EoE), scleroderma (SSc), and achalasia will be studied using functional luminal imaging probe (FLIP)
topography and 4D impedance manometry (4D-IM) before and after standard of care (SOC) treatment (or in
conjunction with SOC care and Bravo pH-metry in the case of SSc). Our overarching goal is to understand the
molecular mechanisms leading to altered esophageal luminal distensibility through mechanistic studies of key
mediators of inflammation: inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) and signal transducer
and activator of transcription 3 (STAT3). The significance of this proposal lies in: 1) expanding our
understanding of esophageal disease pathogenesis from a one-dimensional focus on neuromuscular function
to a comprehensive study of esophageal wall mechanics as the determinant of function and dysfunction; and
2) the central roles of epithelial IKKβ and epithelial STAT3 signaling in the regulation of diverse biological
processes, such as inflammation, immunity, cell survival, and cell growth. The projects leaders have expertise
in esophageal pathophysiology, translational research, animal models of esophageal disease, cell signaling,
and epithelial cell biology. Here, we will test the hypothesis that altered esophageal distensibility is mediated
through differential IKKβ activation in the esophageal mucosa triggered by either eosinophilic inflammation in
EoE or abnormal luminal pressurization in achalasia and that STAT3 signaling promotes esophageal smooth
muscle atrophy in SSc. To explore these processes, we will undertake three interrelated Specific Aims. In
Aim 1, we will investigate epithelial IKKβ/NFκB and STAT3 signaling as modulators of altered esophageal
luminal distensibility in EoE, SSc, and achalasia using mucosal biopsies in patients phenotyped using FLIP
topography and 4D-IM as well as Bravo pH-metry in the case of SSc. In Aim 2, we will determine the role of
epithelial IKKβ signaling in promoting fibrosis in EoE. Here, we will utilize a novel transgenic mouse model
with esophageal epithelial IKKβ deletion treated with egg ovalbumin, and 3D organotypic culture. In Aim 3, we
will determine the requirement for epithelial STAT3 signaling in promoting esophageal smooth muscle cell loss
in SSc esophageal disease. This will be undertaken with a new transgenic mouse model of SSc (esophageal
epithelial STAT3 deletion treated with bleomycin). We anticipate that thes...

## Key facts

- **NIH application ID:** 10439751
- **Project number:** 5P01DK117824-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** MARIE-PIER TETREAULT
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $377,215
- **Award type:** 5
- **Project period:** 2018-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439751

## Citation

> US National Institutes of Health, RePORTER application 10439751, Measurement and Molecular Mechanisms of Altered Esophageal Distensibility (5P01DK117824-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10439751. Licensed CC0.

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