Eosinophilic esophagitis (EoE) is an emerging antigen-mediated chronic inflammatory disease, characterized by mucosal eosinophilia and tissue remodeling events, leading to basal cell hyperplasia (BCH) and subepithelial fibrosis. While immune cell-mediated mechanisms regulating EoE disease activity are rapidly emerging, our understanding of the relationship between esophageal epithelial biology and EoE pathogenesis is presently limited. Autophagy is a cellular adaptive response to physiologic stressors that is activated in esophageal epithelia upon exposure to EoE inflammation to limit oxidative stress. Pharmacological autophagy inhibition aggravates disease-associated oxidative stress, basal cell hyperplasia (BCH) and eosinophil infiltrates in a robust murine model of EoE, suggesting that autophagy supports esophageal homeostasis via cell autonomous and non-cell autonomous mechanisms in the context of EoE inflammation. The present proposal utilizes murine models with squamous epithelia-specific autophagy impairment coupled with ex vivo esophageal 3D organoids, reconstitute the epithelial-stromal structure in the organotypic 3D culture and EoE patient specimens with associated clinical data as a comprehensive platform to define the mechanistic and functional role of autophagy in EoE pathogenesis. The central hypothesis is that epithelial autophagy is a fundamental mucosal defense mechanism activated to suppress reactive oxygen species-mediated esophageal tissue remodeling in EoE. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicant's laboratory and will be tested by pursuing the following three interrelated Specific Aims: (1) To determine how autophagy influences epithelial cell fate in the EoE inflammatory milieu; (2) To determine the effect of epithelial autophagy on lamina propria remodeling; (3) To evaluate the therapeutic utility of autophagy activation in EoE. These innovative studies will reveal novel insight into the role of autophagy in regulation of epithelial integrity and epithelial-stromal crosstalk in the context of EoE, thereby fundamentally advance the fields of epithelial biology and mucosal defense. By evaluating the therapeutic utility of pharmacological autophagy enhancement in EoE, these studies have the potential for direct translational impact in this disease for which dietary elimination and/or swallowed corticosteroids therapy remain the current standard of care due to a lack of viable targeted therapeutic strategies. Furthermore, this novel therapeutic strategy may serve as a platform for similar approaches in the treatment of esophageal disorders beyond EoE in which BCH and inflammation have been implicated as well as additional human pathologies involving autophagy dysregulation. Thus, this innovative and translational research will have substantial positive impact by integrating basic science and preclinical experimental approaches to define the direct molecular mechanisms underlying esophageal epithelial homeostasis and utilizing this knowledge to direct the development of novel translational applications related to EoE diagnosis, monitoring and therapy.
The proposed research is relevant to public health because a detailed understanding of the role of autophagy in esophageal epithelial homeostasis will fundamentally advance the fields of epithelial biology and mucosal defense. These findings will provide a platform for new avenues of translational applications for therapy in eosinophilic esophagitis. Thus, the proposed research is relevant to the NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burden of human diseases.
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| Kasagi, Yuta; Chandramouleeswaran, Prasanna M; Whelan, Kelly A et al. (2018) The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes. Cell Mol Gastroenterol Hepatol 5:333-352 |
| Natsuizaka, Mitsuteru; Whelan, Kelly A; Kagawa, Shingo et al. (2017) Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat Commun 8:1758 |
