Towards Multi-modal Biomarker and Personalized Medicine: Integrating Esophageal Biochemical, Structural, and Molecular Alterations in Pediatric Eosinophilic Esophagitis

About This Grant

Project Summary: Eosinophilic esophagitis (EoE) is a chronic, allergen-mediated, clinicopathologic disease, and a leading cause of upper gastrointestinal morbidity among children in the United States. It is characterized by esophageal eosinophilic infiltration and progressive fibrotic remodeling leading to debilitating dysfunction, dysphagia, and esophageal food impactions. Advances in understanding EoE pathophysiology have led to the development of clinical, endoscopic, histological, and molecular indices. While these metrics have enhanced our ability to identify EoE, essential gaps remain. Specifically, their limited accuracy in classifying disease activity status, stratifying severity and risk of fibrotic complications, and informing personalized therapy continues to constrain progress in optimizing patient care. The increasing prevalence of pediatric EoE reiterates the urgency to address these translational gaps through innovative approaches. To this end, during his K23 award, the Principal Investigator (PI), an Early Stage Investigator, identified distinct biochemical and architectural features that distinguished non- EoE controls from EoE, and active EoE (aEoE) from inactive EoE (iEoE) by using Raman spectroscopy (RS), stimulated Raman spectroscopy (SRS), and second-harmonic generation (SHG) microscopy. In this proposal, he will leverage the emerging paradigm shift toward integrative, multimodal markers — an approach yet to be applied in EoE, and build on his previous work to develop more comprehensive metrics of disease processes. He has preliminarily demonstrated that (a) Raman-RNA (biochemical-molecular) biomarker signature [area under the curve (AUC) = 0.937] outperforms Raman alone (AUC = 0.875) and RNA alone (AUC = 0.875) in differentiating aEoE from iEoE, (b) epithelial biochemical and structural changes correlate with subepithelial ECM and LPF, and (c) baseline esophageal glycogen, protein, and lipid content can classify responders from non- responders to non-biologic EoE therapies such as proton-pump inhibitors and topical corticosteroids. Advancing these innovations further, he will develop Raman-RNA biomarker signatures that stratify aEoE and iEoE and compare their diagnostic performance against existing activity indices (Aim 1), identify Raman-SRS-SHG signatures for fibrotic transformation by investigating how the epithelial biochemical changes relate to and predict subepithelial ECM and LFP (Aim 2), and in a prospective cohort, evaluate if the baseline esophageal biochemical, clinical, endoscopic, and histologic features predict response to dupilumab (Aim 3). The investigative team's expertise, proven track record, exciting preliminary data, established protocols, state-of-the- art resources, institutional support, and a motivated patient population position this project for success within the funding period. This innovative and interdisciplinary research will address critical translational gaps in EoE and improve clinical outcomes for children with EoE. It will also catalyze new avenues of investigation and technological innovations, establishing the PI as an independent investigator at the intersection of pediatric gastroenterology and translational research.