# Esophageal tissue aging under homeostatic and inflammatory conditions

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $447,760

## Abstract

Project Summary
Esophageal dysfunction and pathology represent significant health burdens in the United States and worldwide.
While patient age is an established risk factor for dysphagia, esophageal cancer and Eosinophilic Esophagitis
(EoE)-associated subepithelial fibrosis, our understanding of the biology of aging in the esophagus remains
elusive. Under homeostatic conditions, esophageal squamous epithelium comprises a basal compartment of
proliferative cells that undergo differentiation in suprabasal layers and luminal desquamation, facilitating tissue
renewal. Perturbation of this defined proliferation/differentiation gradient in esophageal epithelium is a feature of
esophageal pathologies, including EoE. While the prevalence of BCH is nearly identical in pediatric and adult
patients with active EoE, preliminary data indicate that BCH is present in ~20% of normal esophageal epithelial
specimens from adults while remaining undetectable in normal pediatric specimens. We have recently
demonstrated that autophagy (‘self-eating’) is activated in esophageal epithelium in response to EoE
inflammation, serving to limit BCH and eosinophilia. Preliminary data indicate that autophagy flux is stalled in
aged esophageal epithelium under normal conditions. Moreover, EoE induction in aged mice results in
diminished eosinophilia and subepithelial fibrosis. The overarching hypothesis is that age-associated decline in
esophageal epithelial autophagy flux impairs tissue homeostasis and contributes to age-associated alterations
in EoE phenotype. To test this hypothesis, we will define the functional relationship between mTORC1/autophagy
signaling and age-associated esophageal basal cell hyperplasia (Aim 1); elucidate the functional role of epithelial
autophagy in age-associated EoE fibrosis (Aim 2); and investigate the role of epithelial autophagy in the EoE
inflammatory response in the context of aging (Am 3). The biology of aging in the esophagus represents a
significant knowledge gap as understanding mechanisms of tissue aging has the potential to improve strategies
for diagnosis, monitoring and therapy of widely prevalent esophageal diseases, including EoE and cancer. Here,
we investigate epithelial autophagy as a novel regulator of aging in the esophagus under conditions of homeostasis
and EoE inflammation using an innovative approach coupling functional evaluation of human endoscopic biopsies,
3D esophageal organoids and a murine model of EoE featuring age-associated fibrosis. These studies have great
potential to provide novel insight into age-relevant mechanisms/cellular phenotypes in the esophagus and unveil
new biomarkers and therapeutic targets for EoE and other age-associated disorders affecting the esophagus.

## Key facts

- **NIH application ID:** 9942410
- **Project number:** 5R01DK121159-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Kelly A Whelan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $447,760
- **Award type:** 5
- **Project period:** 2019-06-04 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942410

## Citation

> US National Institutes of Health, RePORTER application 9942410, Esophageal tissue aging under homeostatic and inflammatory conditions (5R01DK121159-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9942410. Licensed CC0.

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