The Role of FOXM1 in Eosinophilic Esophagitis Pathogenesis

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Project Summary Eosinophilic esophagitis (EoE) is a rare, chronic disorder characterized by persistent allergic inflammation that leads to fibrosis and stricture which effects about 150,000 people in the United States. Clinical manifestations include weight loss, vomiting, dysphagia, and food impaction, all of which dramatically impact patients' quality of life. Histologically, it is characterized by mucosal eosinophilic infiltration and esophageal epithelial remodeling events, specifically basal cell hyperplasia (BCH) and dilated intracellular spaces (DIS). These epithelial changes disrupt the mucosal barrier which normally provides protection from acid and food particles during normal swallows. In our preliminary data we have found that Forkhead box (FOX) M1 expression is increased in the esophagus of EoE patients. Further, FOXM1 is induced in the epithelium after stimulation with IL-13, the major effector cytokine in EoE. We have found that inhibition of FOXM1 in esophageal epithelial cell culture reduces epithelial perturbations in the setting of cytokine stimulation and reduces chemoattractant secretion. Based on these findings, we hypothesize that FOXM1 disrupts epithelial homeostasis and contributes to eosinophil chemotaxis in EoE We propose 2 aims in this application. The first aim will determine the mechanism by which FOXM1 disrupts epithelial homeostasis in the esophageal epithelium using 3D epithelial modeling techniques that are well established in the Muir Lab: organoid culture and air-liquid interface culture. We will induce EoE in mice and evaluate the effect of FOXM1 inhibition on disease severity and epithelial damage. We will compliment this with chromatin immunoprecipitation to identify differentially regulated targets of FOXM1. In the second aim we will define the role of FOXM1 in regulation of chemotaxis in the EoE epithelium. We have found that pharmacological inhibition of FOXM1 leads to downregulation of both total and phosphorylated STAT6 protein, as well as CCL26 (the gene encoding Eotaxin-3, the key chemoattractant for eosinophils in EoE). We will test whether FOXM1 inhibition interferes with eosinophil chemotaxis in vitro and in vivo. Thisinnovative and hypothesis-driven study is backed by strong preliminary data generated by the PI. The PI is uniquely poised to accomplish these aims with her previous track record in investigating mechanisms of epithelial inflammation in EoE using 3D epithelial culture and murine models.