Esophageal diseases, including Barrett's esophagus (BE), adenocarcinoma and squamous cancers are serious health problems in industrial societies. However, relatively little is known about the molecular mechanisms underlying these disorders. My previous studies using mouse models demonstrated that the transcription factor, Sox2, is essential for the normal development of the esophagus. In the adult esophagus Sox2 is expressed at high levels in basal progenitor cells, but its function at this stage remains unknown. Interestingly, in humans decreased SOX2 protein levels in the esophagus have been associated with the development of BE. My hypothesis is that Sox2 regulates the homeostasis of the adult esophagus, and that precise levels of Sox2 are required for normal proliferation and differentiation of the esophageal epithelium. Moreover, I hypothesize that disruption of the Sox2 regulatory network is a major component of the progression of multifactorial diseases such as BE and cancer. To test this hypothesis, I will first delete and overexpress Sox2 specifically in the epithelial cells of the mouse esophagus. I will then examine phenotypic changes and study the underlying mechanisms leading to the abnormalities. In addition, my previous work suggested that bone morphogenetic protein (Bmp) signaling pathway suppresses Sox2 expression in foregut. Recently, upregulation of this signaling pathway has been implicated in the development of BE.
My second aim therefore is to test the hypothesis that defects in Bmp signaling upstream of Sox2 contribute to esophageal disorders. I will start by examining the effect of increased Bmp signaling on cultured basal cells isolated from the adult mouse esophagus. I will then ectopically activate Bmp signaling in the basal cells of the mouse esophagus in vivo, and analyze the phenotypic changes, including potential effects on Sox2 expression. Taken together these studies will provide critical information on the requirements of Sox2 and Bmp signaling for the homeostasis of the adult esophagus. They may have implications for devising therapeutic strategies for esophageal diseases.
This proposal has direct relevance to esophageal diseases. The incidence of Barrett's esophagus, esophageal adenocarcinoma has increased significantly in recent two decades. Studying the molecular mechanisms underlying the homeostasis of the adult esophagus using mouse model systems will facilitate the development of strategic therapies for treating esophageal disease.
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