Investigation of epithelial cell biology in preclinical mouse models of early-onset EoE

About This Grant

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 and subsequent epithelial barrier dysfunction in pediatric EoE remain to be elucidated. We previously demonstrated that yes-associated protein 1 (YAP), a key transcriptional regulator in the Hippo signaling pathway, is required for the proliferation and differentiation of basal cells in the developing murine and human esophagus. Using novel pre-weaning mouse models of early-onset EoE and 3D organoid culture systems we have been able to study Th2-driven BCH. Our preliminary data demonstrate nuclear enrichment of YAP in the hyperplastic basal cells of a pre-weaning transgenic mouse model of EoE and esophageal biopsy samples from a pilot study of an EoE patient cohort. In parallel an exploratory untargeted proteomics approach, using human esophageal basal cells (EPC2) cells treated with IL-13 demonstrated that Tenascin-C (TNC), a matrix protein enriched in the basement membrane underlying the hyperplastic basal cells, was among the top-enriched proteins in EPC2 cells upon IL-13 treatment. Moreover, we demonstrated TNC/YAP double-positive cells in our preclinical EoE mouse models as well as increased expression of CD74 in a subpopulation of hyperplastic esophageal basal cells of EoE patients. Based on these findings, the overarching hypothesis is that YAP mediates IL-13-induced CD74 expression, which promotes chronic inflammation characterized by BCH and epithelial barrier dysfunction in pediatric EoE. In Aim 1, we will use YAP loss-of-function mouse models and CD74 inhibitors to test the hypothesis that CD74 activation promotes BCH. In Aim 2, using in vivo and in vitro assays, we will elucidate how CD74 affects the epithelial barrier integrity in the pathogenesis of pediatric EoE. 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.