Structural and molecular markers for detection and monitoring of pediatric fibrostenotic Eosinophilic Esophagitis

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PROJECT SUMMARY This K23 proposal describes a 5-year career development and research program for Dr. Calies Menard-Katcher, an Assistant Professor at the University of Colorado School of Medicine (CU SOM) and a subspecialist within the Gastrointestinal Eosinophilic Diseases Program at Children's Hospital Colorado. This K23 will provide the candidate necessary support to launch a successful career in patient-oriented research in eosinophilic gastrointestinal diseases. Building on prior research experience and preliminary data, she is investigating the fibrostenotic phenotype of pediatric Eosinophilic Esophagitis (EoE) by means of complimentary and advanced assessment tools including functional luminal impedance (FLIP) and gene analyses. This K23 application includes the following components: Research: EoE, a chronic, allergen triggered esophageal disease has emerged as one of the most common causes of swallowing problems in children and adults. Esophageal stricture, also termed fibrostenotic EoE (FS-EoE), has emerged as the major complication of EoE. This phenotype has worse clinical outcomes and may be more resistant to current treatments. Evidence suggests that clinically meaningful assessment of the FS esophagus is unlikely to be captured by current clinical assessment tools. Alternative strategies are needed to assess esophageal function and the impact of remodeling beyond the mucosa to advance understanding of disease mechanism and improve targeted therapies. Endoscopic assessment with FLIP and endoscopic ultrasound (EUS) can provide this approach. Paired with RNA sequencing to identify novel FS-EoE associated genes, this proposal will provide critical advancement in the study of the FS-EoE phenotype. We hypothesize structural measurements of the esophagus and molecular markers of tissue remodeling will distinguish FS-EoE from non-FS EoE in pediatric subjects. We will determine distensibility of the esophagus in pediatric FS-EoE compared to inflammatory non-FS-EoE in relation to other clinical features of EoE (Aim 1), identify a gene signature defining pediatric FS-EoE (Aim 2) and assess changes in structural and molecular features in response to medical treatment (Aim 3). Results from this novel research will provide significant impact by identifying never before reported structural, functional and molecular signatures of pediatric FS-EoE. Career Development: Dr. Menard-Katcher's short-term goal is to obtain the training required to become an independent investigator with R01 funding to address important questions that will lead to better understanding of the pathogenesis and management of EoE. This training award will allow for development of expertise in endoscopic assessment of EoE phenotypes, next generation sequence interpretation and early assessment of potential biomarkers. Glenn T. Furuta, MD, the primary mentor for this proposal, is a nationally recognized investigator and clinical expert in the field of eosinophilic GI diseases (EGIDs). An advisory committee of co-mentors will provide additional key guidance for the success of the proposed research and the candidate's transition to independence. In addition Dr. Menard-Katcher will continue didactic training, including completion of a Master's in Clinical Sciences, to support her goals.