Mitochondria in eosinophilic esophagitis pathogenesis

Project Summary Eosinophilic esophagitis (EoE) is a chronic food allergen- and immune-mediated disease that exerts a significant clinical and financial burden worldwide. Interleukin (IL)-13 is an essential mediator of EoE due its pleotropic effects on esophageal inflammation and tissue remodeling. We have identified IL-13 as a critical mediator of

increased mitochondrial mass and mitochondrial DNA (mtDNA) release in esophageal epithelial cells. Our preliminary data indicate that IL-13-mediated alterations in mitochondrial mass and mtDNA release are dependent upon JAK/STAT signaling. We further provide preliminary data suggesting that depletion of

mitochondria limits EoE-associated epithelial remodeling and inflammation. These findings support our overarching hypothesis that IL-13 in the EoE inflammatory milieu activates STAT signaling in esophageal epithelium to drive alterations in mitochondrial biology that promote EoE pathogenesis and may serve as novel

biomarkers in EoE patients. To test this hypothesis, we will define the direct molecular mechanisms through which IL-13 signaling regulates mitochondrial biology (Aim 1) and the functional significance of these findings with regard to EoE-associated tissue remodeling and inflammation (Aim 2). Furthermore, we will elucidate the

clinical significance of EoE-associated alterations in mitochondria by exploring their biomarker potential in EoE patients (Aim 3). The proposed studies will illuminate the IL-13/STAT/mitochondria axis as a novel player in EoE pathobiology and have great potential to improve clinical care in this disease that remains a major cause of upper

GI morbidity.