Project Summary EoE is a newly recognized chronic, antigen driven allergic disease that causes tissue remodeling. Esophageal remodeling includes fibrosis and smooth muscle hypertrophy/dysfunction that leads to esophageal rigidity and dysmotility. Clinical symptoms include vomiting, poor growth, dysphagia, food impactions, and strictures. My patient oriented research (POR) program focuses on elucidating the mechanisms and clinical impacts of esophageal remodeling in children. Herein I propose to become an outstanding POR mentor to a diverse group of undergraduate/graduate students, postdoctoral fellows, and junior faculty trainees from multiple disciplines and to continue and extend my research to understanding EoE as a disease of both inflammation and “mechanotransduction”. In the Research Plan, I test 3 hypotheses on the fundamental mechanisms of EoE. The first is a potentially paradigm shifting central hypothesis that a rigid matrix alters the function of esophageal fibroblasts and smooth muscle cells to propagate EoE together with, and independently of, inflammation. This has the clinical implication that there is a pressing, unmet clinical need for therapies that target inflammation- independent remodeling. The second hypothesis, an extension of my current POR, is that the adherens junction protein, E-cadherin, is pivotal in the loss of esophageal epithelial cell barrier function and that super resolution microscopy is a cutting-edge tool that will aid our understanding of the interaction between barrier function and E-cadherin localization at the nanometer level. The third aim is to evaluate gender differences in EoE severity with the hypothesis that male fibroblasts are intrinsically more biased to esophageal inflammation and remodeling. Together with my collaborators and our co-mentees, I have developed and utilized innovative primary human models that transition from single cells and intact multicellular and functional ex vivo human mucosal platforms to an in vivo analyses of esophageal rigidity and motility in children. With our large, well- phenotyped EoE population, we are able to continuously translate our findings back to the patient. I have involved mentees in each of my aims, developed a formal plan to train junior investigators in the lab, clinic and career path, created a formal mentoring plan and team for my mentees and myself, and integrated the unique resources at UCSD including the CTSA funded Clinical and Translational Research Institute. I have a strong record of funded POR and training mentees but require the protected time and further education to become the inspiring mentor I envision. This is an important goal for sustaining research and creating a legacy of investigators in eosinophilic gastrointestinal disorders (EGIDs). My past and current group of mentees are from Allergy/Immunology, Gastroenterology, and Bioengineering, all of whom are dedicated to, and united by, the singular goal of unraveling mechanisms of EGIDs...