# SLC9A3 regulation of esophageal dilated intercellular spaces in EoE Subtypes

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $563,200

## Abstract

Project Summary
Eosinophilic esophagitis (EoE) is an increasingly prevalent chronic inflammatory disease of the esophagus,
mediated by dietary food antigens and clinically characterized by upper gastrointestinal (GI) symptoms including
dysphagia and food impaction. Recently, a confounding esophageal disorder, termed proton-pump inhibitor
(PPI)–responsive esophageal eosinophilia (PPI-REE), has emerged; PPI-REE is indistinguishable from EoE by
clinical, endoscopic or histologic features or by gene profiles. The current clinical conundrums are whether PPI-
REE represents a GERD-related phenomenon, a subtype of EoE or a completely new entity and why PPI-REE
and EoE respond differently to PPI. RNA sequencing (RNA-Seq) analyses of esophageal biopsy samples from
patients with active EoE disease revealed dysregulation of gene networks associated with regulating intracellular
[pH]i and acid protection and that the most upregulated transmembrane transporter activity gene was SLC9A3,
which encodes for the sodium-hydrogen exchanger family member 3 (NHE3). Recently, we have demonstrated
1) increased expression of SLC9A3 within the basal layer of ESSE biopsies from patients with EoE and that
expression positively correlated with disease severity (eosinophils/HPF) and DIS; 2) IL-13 induced SLC9A3
expression and function in ESSE cells and that SLC9A3 activity positively correlating with DIS formation and 3)
SLC9A3-mediated Na+-dependent proton secretion is the primary intracellular acid protective mechanism within
IL-13–stimulated ESSE cells and blockade of this pathway abrogated DIS formation45. In new preliminary studies
we have made several transformative observations: 1) IL-13 induced expression of the transcription factor aryl
hydrocarbon receptor (AhR) and AhR-responsive genes in ESSE cells and EoE biopsies; 2) stimulating ESSE
cells with AhR ligands, suppressed AhR-responsive gene expression including SLC9A3 and 3) a divergent effect
of PPI therapy on SLC9A3 expression in ESSE biopsy samples from individuals with EoE and PPI-REE,
suggesting an opposing impact of PPI on SLC9A3 transcriptional regulation between EoE and PPI-REE.
Collectively, these observations underlie our central hypothesis that SLC9A3 activity promotes DIS formation
in EoE subtypes and that this pathway is divergently responsive to PPI therapy via AhR-dependent signaling.
The specific Aims outlined in this proposal will 1) Aim 1. Determine the relationship between SLC9A3 expression
and function, disease severity and DIS formation in EE subtypes; 2) Define the requirement of SLC9A3 in ESSE
DIS formation and 3) Define the involvement of PPI-induced AhR signaling in Type-2 cytokine-induced SLC9A3
expression and function in ESSE cells. With respect to the expected outcomes, the studies proposed in Aim I
are expected to establish the contribution of SLC9A3 to histopathologic features of EoE and PPI-REE and
responsiveness of this pathway to PPI trial; Aim II are expected to determine the neces...

## Key facts

- **NIH application ID:** 10371034
- **Project number:** 5R01AI140133-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SIMON Patrick HOGAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $563,200
- **Award type:** 5
- **Project period:** 2019-04-22 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371034

## Citation

> US National Institutes of Health, RePORTER application 10371034, SLC9A3 regulation of esophageal dilated intercellular spaces in EoE Subtypes (5R01AI140133-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10371034. Licensed CC0.

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