Pathways of Injury and Repair in Barrett's Carcinogenesis

PROGRAM SUMMARY The central hypothesis of this program project is that “Altered squamous epithelial integrity (Prj 1) and inflammatory injury (Prj 2) activate signaling pathways including EPHB2 (Prj 3) that affect precursor cells at the squamocolumnar junction (SCj) transition, esophageal submucosal gland (ESMG), and basal squamous niches, resulting in the alteration of regulatory factors that include Notch, Myc, p63, and SOX9, leading to acinar ductal metaplasia (ADM), multi-layered epithelium (MLE), Barrett's esophagus (BE), and ultimately esophageal adenocarcinoma (EAC).” The Specific Aims of our program are: 1) To elucidate signaling pathways by which mutated VSIG10L alters epithelial integrity leading to MLE and BE like metaplasia on novel mouse models. 2) To define the spatial and temporal pattern of CXCL8 (IL-8) in ESMG following esophageal injury and phenotype the inflammatory infiltrate that leads to the development of acinar ductal metaplasia (ADM) in ESMG associated with BE/EAC. 3)To identify mediators of EPHB2 signaling that lead to c-MYC activation and metaplastic cellular differentiation after injury in the development of BE and its progression to EAC. 4) To define how altered epithelial integrity, inflammatory cells, and alteration of signaling molecules that control differentiation (EPHB2) lead to metaplasia by altering transcription factors. 5) Integrate projects by providing investigators effective support through Core resources with state-of-the-art Biorepository, Bioinformatics, and Administrative Services. These objectives build and synergize on the considerable clinical, basic science, and translational expertise available at our institutions, 1) to focus laboratory research on understanding the genetic susceptibility and molecular changes that influence the development of BE and EAC; and 2) to then translate laboratory discoveries into clinical applications for effective detection, molecular risk stratification, and prevention of progression from BE to EAC.