Eosinophilic Esophagitis (EoE) is a chronic esophageal disease that affects up to 4 in 10,000 children and adults in the US. To date, no cure or FDA approved medications exists. Histopathologically, the esophageal mucosa in EoE is characterized by dense eosinophilia, dilated intraepithelial spaces and basal cell hyperplasia. Based on preliminary data, this proposal seeks to determine the mechanisms by which specifically identified molecules involved in epithelial proliferation, stratification, differentiaion and barrier function contribute to the pathogenesis of EoE. In this regard the transcription factor Hypoxia-inducible factor (HIF-1?) and its epithelial target molecules are down regulated in this chronic disease. We hypothesize that signaling thru HIF-1? mediates a critical link between epithelial sensing of its inflammatory microenvironment and regeneration of the epithelium in EoE. In the first experimental aim, the applicant will employ in vitro techniques to identify mechanisms that experimental and eosinophilic inflammatory hypoxia impacts physiologic and regenerative processes of proliferation and stratification. Cells stably expressing genetically altered HIF-1? (stabilization, transcriptional mutant and knockdown), as well as functional analysis including 3-Dimensional air-liquid interface (ALI) and organotypic cultures (OTC) will be used. In the second aim hypoxia mediated dysregulation of proliferation and stratification in epithelial cell differentiation and barrier function will be examined in vitro and in vivo. To addrss the biological significance and therapeutic implications of our findings, we will genetically stabilize esophageal epithelial specific HIF-1? pathways in our L2-IL5OXA mouse EoE model.
The third aim will employ pharmacological stabilization of HIF-1? signaling in cells, mice and ex vivo patient specimens. Based on preliminary data presented in this application, it is expected that dysregulated HIF-1? signaling in EoE will result in aberrant regenerative responses in the epithelium. Data also suggests the consequence of dysregulated HIF-1? may include dysfunctional differentiation and barrier formation. These findings will serve to highlight the potential for therapeutic targeting of the HIF-1? signaling pathway in EoE. The applicant has a strong background in epithelial cell differentiation and proliferation processes in acute and chronic disease. This expertise is now being applied to understand the functional consequences of eosinophil induced chronic hypoxia on epithelial cells of the stratified esophageal epithelium. In this proposal, she will extend these findings towards the role of HIF-1? signaling in mediating normal epithelial regeneration, pinpointing the HIF-1? signaling pathway as a viable therapeutic target in EoE. The applicant has chosen a rich environment in which to perform their studies. The combined mentorship of PhD and physician-scientist in an academically rich environment will allow the candidate to determine mechanistic insights and utilize clinical specimens to determine clinical relevance of the proposed studies. The mentoring/advisory committee convened is a dynamic mixture of PhD and physician-scientist researchers, all extremely successful and respected within their fields. Their previous scientific and translational research and mentoring achievements will undoubtedly contribute to the ultimate success of this proposal and to the applicant's career development towards eventual independence.
Eosinophilic esophagitis (EoE) is a chronic clinicopathologic allergic gastrointestinal disorder, currently affecting ~4 in 10,000 individuals. Although immense efforts have been invested in understanding the clinical course and natural history of this emerging disease, to date there is a paucity of therapeutic modalities and no cure for EoE. Understanding the molecular mechanisms of how hypoxia, and the novel and directly translatable target HIF-1? (hypoxia-inducible factor), drives protective transcriptional machinery in the epithelium is an attractive avenue to target therapeutically. Upon completion, this project would lead to a paradigm-shift in our current concepts about the failure to resolve maladaptive epithelial responses in EoE.
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