[R01] Mechanisms of aryl hydrocarbon receptor control of eosinophilic esophagitis

Ente: National Institute of Diabetes and Digestive and Kidney Diseases

Scadenza: 2029-05-31

Importo max: 611.916 EUR

Paese: US

Descrizione

PROJECT SUMMRAY Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus partially mediated by epithelial barrier breach, resulting in harmless antigens penetrating the underlying tissues, encountering immune cells, and triggering allergic responses. The surge in allergy prevalence is often attributed to shifts in environmental conditions and western life style. The molecular mechanisms involved in how the environment elicits allergic diseases is an area of active research that is yet to be fully understood. The aryl hydrocarbon receptor (AHR) is an intracellular receptor responsive to various external stimuli, including dietary compounds, air toxicants, pharmacologic agents, microbiota metabolites and tryptophan metabolites. Our research has uncovered that AHR acts as a sensor molecule, capable of either maintaining epithelial homeostasis and barrier integrity, or initiating an innate immune response when exposed to diverse AHR ligands from different environmental sources. As a result, AHR can play a dual role in EoE, both protecting against and exacerbating EoE. We have shown that select AHR ligands induced protective transcriptional responses in esophageal epithelial cells. These responses counteract pathways involved in the development of type 2 immunity, including restoring barrier function and the deficiency of SPINK7, a crucial endogenous protease inhibitor, normally essential for averting EoE. These anti-inflammatory reactions rely on the activation of the transcription factor Ovo Like Zinc (OVOL1). Conversely, environmental factors such as enriched tryptophan diets can stimulate AHR, exacerbating esophageal inflammation in mice. In this study we aim to elucidate the mechanism through which AHR mediates its protective and detrimental reactions in response to divergent AHR ligands. We have established experimental platforms including the generation of AHR and OVOL1 deficient esophageal epithelial cell lines, mice with conditional depletion of Ahr and Ovol1 in the esophageal epithelium, experimental EoE murine models and three-dimensional human organotypic esophageal raft cultures to test the hypothesis that AHR drives differential esophageal epithelial responses, and the nature of the AHR ligands dictates the AHR dependent protective (barrier function) and detrimental (innate inflammation) outcomes. Successful completion of this study holds immediate translational significance, as it could pave the way for dietary adjustments, probiotics, and newly-approved AHR agonists which will offer potential avenues for interventions against EoE. Istituzione: CINCINNATI CHILDRENS HOSP MED CTR PI: Nurit P AZOUZ Progetto: 5R01DK140127-03

Settori: National Institute of Diabetes and Digestive and Kidney Diseases

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