# Genetic and Immunological Dissection of Eosinophilic Esophagitis

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $658,567

## Abstract

Project Summary
This study's long-term goal is to elucidate the genetic and immunologic features of Eosinophilic Esophagitis
(EoE). EoE is an emerging chronic disease that often starts in childhood and continues into adulthood and is
associated with substantial morbidity, yet there are currently no FDA-approved therapies. Understanding this
subject has significant implications as elucidating the fundamental genetic and immunologic features of the
disease has potential to yield improved diagnostics and therapies. The central hypothesis of this proposal is that
genome-wide association study (GWAS) interrogation, followed by genetic and biological validation, will uncover
key processes involved in disease pathoetiology with a focus on the interface of adaptive and innate immunity.
The rationale for this hypothesis is based on our prior studies, including initial GWAS that have identified disease
susceptibility at chromosomes 2p23 and 5q22. Evidence is accumulating that the causal genes at these 2 loci
are CAPN14 (calpain 14) and TSLP (thymic stromal lymphopoietin), respectively. These findings shift the focus
from primary eosinophil defects to epithelial responses as being causal of EoE pathogenesis. Mechanistic
studies have established that CAPN14 contributes to impaired epithelial barrier function and that TSLP promotes
adaptive type 2 T cell immunity associated with overproduction of IL-5 and IL-13. CAPN14 sits at the interface
of innate and adaptive immunity, as it is constitutively expressed by esophageal epithelium; however, it is also
markedly induced by IL-13, likely derived from food antigen–activated Th2 cells. In addition to these 2 genetic
loci (2p23, 5q22), GWAS have implicated numerous other suggestive loci, of which 11 have been recently
preliminarily implicated using a custom-designed Illumina SNP array approach followed by preliminary functional
analyses. Despite these advances, the causal gene variants and/or genomic pathways for EoE pathogenesis
remain largely unclear. Herein, we will test the relevant and key hypothesis that GWAS interrogation, followed
by genetic and biological validation, will uncover disease pathoetiology. We will test this central hypothesis via 3
complimentary aims using innovative approaches that combine genetic and biological studies. In Aim 1, we will
focus on a primary GWAS lead, CAPN14. We will test the hypothesis that CAPN14 is an essential regulator of
cellular junctions and barrier integrity and contributes to IL-13–induced, EoE-related epithelial responses. We
will identify its binding partners and potential substrates and the consequences of CAPN14 deficiency in
esophageal epithelial cells and CAPN14 transgenic overexpression in mice. In Aim 2, we will test the hypothesis
that meta-analysis of additional EoE cohorts analyzed by GWAS will refine the involvement of implicated
loci/genes and identify new variants. In Aim 3, we will interrogate disease-associated single-nucloeotide
polymorphisms (SNPs)...

## Key facts

- **NIH application ID:** 10364802
- **Project number:** 2R01AI124355-06A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Marc E. Rothenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $658,567
- **Award type:** 2
- **Project period:** 2015-09-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364802

## Citation

> US National Institutes of Health, RePORTER application 10364802, Genetic and Immunological Dissection of Eosinophilic Esophagitis (2R01AI124355-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10364802. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*