Principal Investigator: Anil K. Rustgi

Institution: University of Pennsylvania

Year Awarded: 2013

Project Title: Mouse Model of Barrett’s Esophagus


Barrett’s esophagus is characterized by the change of the normal stratified squamous esophagus epithelium to a simple columnar small intestinal-like epithelium, which is termed incomplete intestinal metaplasia. Under normal conditions, exposure to acid and bile salts causes the esophageal squamous epithelium to undergo tissue renewal and regeneration. However, chronic exposure to acid and bile salts can accelerate a change of the stratified esophageal epithelium to that of a small intestinal-like epithelium. These morphological changes may be characterized by the presence of columnar enterocytes and secretory goblet cells. There is emerging evidence that only a columnar-lined esophagus (CLE) is present without the presence of goblet cells. The molecular mechanisms underlying the metaplasia in Barrett's esophagus are not clearly understood. Previous studies from our lab have implicated two genes, c-myc, and the intestinal specific transcription factor, Cdx1. Overexpression of both genes in esophageal epithelial cells promotes an initial metaplasia, which involves changes in expression of keratin genes and appearance of mucin expressing cells in organotypic 3D cultures. Although these changes underlying a switch in cell fates were observed, there was an absence of a complete transition to Barrett’s esophagus, thereby suggesting additional alterations may be necessary. To that end, previous genetic studies have demonstrated that loss of Notch signaling is required for the differentiation of the small intestine into the goblet cell lineage. Furthermore, microarray data from our human Barrett’s esophagus samples reveal that there is a decrease in expression of Notch receptors and its ligands. We hypothesize that resident esophageal basal cells have the capacity to undergo transdifferentiation to a BE cell type. We wish to test this hypothesis by undertaking the generation and characterization of a novel genetic mouse model (L2-Tet-Myc;K14-Cdx2;L2-dnMAML) to determine if BE can be recapitulated. Such a model would then serve as a platform for novel chemopreventive, diagnostic and therapeutic strategies by the BETRNet.