Lysyl oxidase induced esophageal remodeling in eosinophilic esophagitis

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Project Summary Eosinophilic esophagitis (EoE) is a chronic, debilitating disorder characterized by persistent allergic inflammation that over time leads to fibrosis and stricture. While it is characterized by intense eosinophil and mast cell infiltration, pathologic tissue remodeling events lead to irreversible fibrosis and significant clinical symptoms. These remodeling events include epithelial basal cell hyperplasia and subepithelial fibrosis. Our previous work has implicated lysyl oxidase (LOX), an enzyme known to cross-link collagen and potentiate tissue stiffness, as a key mediator of pathologic esophageal remodeling. LOX is robustly expressed in the esophageal mucosa of patients with active EoE inflammation, particularly in those with fibrosis. Robust in vitro and in vivo data suggest that TGF signaling in esophageal epithelium enhances LOX production, which in turn, promotes remodeling in both the epithelial (basal cell hyperplasia) and fibroblast compartments. We therefore seek to define the mechanisms whereby epithelial TGF and LOX promote remodeling in the esophagus and further exploit these mechanisms for clinical application. We hypothesize that the epithelial TGF-LOX axis drives basal cell hyperplasia and fibrostenosis in EoE. In Aim 1, we will evaluate the cell autonomous effects of epithelial LOX, evaluating how epithelial TGF drives LOX-induced basal cell hyperplasia in 3D epithelial culture and chromatin immunoprecipitation assays. In Aim 2, we will evaluate the non-cell autonomous effects of epithelial TGF and LOX by evaluating their effects on fibroblast activation and tissue stiffness. And finally, in Aim 3 we will evaluate the therapeutic and prognostic potential of this pathway by performing pre-clinical proof of purpose studies, treating mice with EoE inflammation with anti-TGF antibody and validating LOX expression in EoE patient tissue. Data from this study will inform future therapies targeting tissue remodeling as well as work towards identifying patients with fibrotic disease prior to the onset of disability. This innovative and hypothesis-driven study is backed by strong preliminary data generated by the PI while she was supported by an NIH career K08 award. The PI is uniquely poised to accomplish these aims with her previous track record in investigating mechanisms of epithelial-fibroblast crosstalk, LOX in EoE, and 3D epithelial culture and co-culture models.