Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux disease (GERD) and chronic esophagitis (CE) and can lead to esophageal narrowing and stricture. EE is differentiated from GERD/CE by the lack of response to acid suppression, and the magnitude of mucosal eosinophilia and epithelial thickening, yet the exact values for the latter two features and molecular markers diagnostic for disease have not been established. Recent attention has been drawn to understanding the etiology and treatment of EE since there has been a surge of newly recognized cases. Employing genome wide microarray expression profile analysis, we recently discovered that the eosinophil chemoattractant and activating factor eotaxin-3 was the single most dysregulated gene in the esophagus of EE patients. Notably, levels of eotaxin-3 strongly correlated with disease severity and a single nucleotide polymorphism (SNP) in the eotaxin-3 gene conferred disease susceptibility. Furthermore, mice harboring a genetic deletion in the eotaxin receptor (CCR3) were protected from the development of experimental EE. These and other findings have led us to hypothesize that a primary event in EE pathogenesis involves overproduction of eotaxin-3 by esophageal (epithelioid-like) cells.
In Aim I, we hypothesize that eotaxin-3 will be over-produced in a full spectrum of patients with EE compared with normal individuals. Furthermore, we will test several related sub-hypotheses concerning the cell type(s) that produce eotaxin-3, the relative level of eotaxin-3 compared with other eosinophil chemoattractants, and the activity of recombinant eotaxin-3 on eosinophils from EE patients.
In Aim 2, we will test the hypothesis that topical glucocorticoid therapy mediates its effects by reducing eotaxin-3 expression. Furthermore, we will determine the genetic transcript signature associated with eotaxin-3 down-regulation and aim to identify a set of gene expression levels that may predict therapeutic responsiveness.
In Aim 3, we will test the hypothesis that specific SNPs in the eotaxin-3 confer EE disease susceptibility and influence disease phenotype. These studies are aimed to provide mechanistic and diagnostic breakthroughs concerning the pathogenesis of a poorly understood disorder. These studies are timely given the recent attention that EE is receiving in the medical community and the emergence of anti-eotaxin-3/CCR3 therapeutics that may have potential to provide targeted therapy for EE.
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