Eosinophilic esophagitis (EE) is an emerging worldwide food allergic disorder associated with significant morbidity and polysensitization to multiple food allergens, resulting in chronic gastroesophageal reflux disease (GERD)-like symptoms and greatly restricted diets in many individuals. We have made the observation that the mRNA and protein for desmoglein (Dsg) 1, a major protein involved in forming epithelial junctions through desmosomes, is markedly downregulated in EE, and its expression remains decreased even following treatment-induced disease remission. Furthermore, we have preliminary evidence linking EE susceptibility with SNPs within the Dsg1 gene. It is remarkable that mutations of Dsg genes and autoanfibodies against Dsg proteins have been associated with squamous epithelium disorders that sometimes include esophageal pathology and features commonly seen in EE (e.g. epithelial erosion, dilated intracellular spaces (DIS), and eosinophilic infiltrates). Taken together, we propose the central hypothesis that Dsg1 is specifically involved in EE disease pathogenesis and susceptibility. We are well positioned to answer key questions concerning EE based on a multi-faceted approach including: (1) an extensive databank of samples from well-characterized EE and control patients;(2) newly developed systems for culturing and manipulating esophageal epithelial cells in vitro and ex vivo;and (3) our ability to validate Dsg1 genetic linkage using replication cohorts of EE patients and parent offspring trios, as well as our ability to test genotype/phenotype relationships using our EE sample databank. Accordingly, we will study the following three Aims.
In Aim 1, we will examine Dsg1 expression and regulation in esophageal epithelial cells.
In Aim 2, we will assess the function role of Dsg1 in the context of EE. And in Aim 3, we will examine the association between EE and variants of the Dsg1 gene. These experiments fit into the general theme of the U19 as they examine the role of epithelial cells and their gene products in the pathogenesis of atopic disorders.
Eosinophilic esophagitis (EE) is an emerging disease that is growing in recognition. Despite its association with food allergy and being triggered by oral antigen-induced allergic responses, there is a poor understanding of its cause and relationship to other forms of food allergy. Herein, we pursue the molecular basis of EE based on a new pathway implicating Dsg1 in disease pathogenesis. The proposal will uncover fundamental mechanisms with broad scientific and clinical implications.
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