Molecular Mechanisms of Reactive Epithelial Changes in Pediatric Eosinophilic Esophagitis

PROJECT SUMMARY
Eosinophilic esophagitis (EoE) is a newly described immune-mediated disease and a leading cause of
esophageal morbidity in children and young adults. Histologically, pediatric EoE is characterized by esophageal
basal cell hyperplasia (BCH) and extensive Th2-associated inflammation. Despite many advances in our
understanding of the pathophysiology of EoE, the molecular mechanisms leading to the development of BCH in
pediatric EoE remain to be elucidated. The proposed training in this mentored career development award
outlines a five-year integrated program of mentored research and career development activities to support Dr.
Dominique Bailey's development into an independent physician-scientist. This comprehensive program will build
on Dr. Bailey's experience as pediatric gastroenterologist and her background in developmental biology by
enabling her to develop new skills and advanced expertise in 3D organoid culture systems, flow cytometry,
epithelial stem cell biology, and immunology through formal coursework and implementation of a thoughtfully
designed research plan. Specifically, her research proposal aims to utilize innovative approaches to explore the
molecular mechanisms underlying BCH in pediatric EoE.
Using a novel conditional IL-13 overexpression mouse model of early onset EoE, we have been able to study
Th2-driven BCH. Our preliminary data demonstrate increased levels of yes-associated protein 1 (YAP) in the
nuclei of hyperplasic esophageal basal cells in these mice and pediatric EoE patient biopsies. However, the role
of YAP in EoE pathogenesis has not been clearly investigated. Based on these findings, the overall hypothesis
is that YAP mediates IL-13-induced BCH during the pathogenesis of EoE. In Aim 1, we will use YAP loss- and
gain-of function mouse models to test the hypothesis that YAP activation promotes BCH. In Aim 2, using in vivo
and in vitro assays, we will elucidate the signaling pathway through which IL-13 directly modulates the
transcription of YAP, thereby resulting in BCH. In Aim 3, we will begin to translate findings to pediatric EoE
patients to directly assess the YAP expression in pediatric EoE biopsies and test whether YAP inhibition blocks
BCH in organoids. Overall, findings from the proposed studies will significantly advance our understanding of
the pathophysiology of pediatric EoE and provide new insights into potential biomarkers and novel therapeutic
targets for pediatric EoE. Dr. Bailey's mentors and Advisory Committee, comprised of a multidisciplinary team of
experts in field of GI epithelial biology, immunology and eosinophilic diseases, will guide her through the research
and training goals outlined in her proposal and establish the foundation for a future R01 application. Collectively,
Dr. Bailey's program proposal, mentorship and Advisory Team and Columbia University's supportive research
environment will help to achieve her long-term goal of developing an independent academic research career
focused on the role of epithelial barrier dysfunction during the EoE pathogenesis.

Grant Number: 5K08DK128603-05
NIH Institute/Center: NIH
Principal Investigator: Dominique Bailey