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.