The aim of this project is to investigate the role of bile acids in the development of Barrett's esophagus (BE), and to develop an animal model for BE and esophageal adenocarcinoma (EAC). Our previous animal models, esophagoduodenal anastomosis (EDA) and esophagogastroduodenal anastomosis (EGDA), mimicked the development of EAC by introducing mixed reflux of gastric and duodenal contents into the rat esophagus. Nevertheless, the role of bile acids in the development of BE is still not clear. This project will address this issue with the following specific aims: 1. To generate rats with reflux containing different levels of bile acids, through dietary supplementation, mimicking the bile acids profile in the gastroesophageal refluxate of human BE patients. Reflux will be induced by cardioplasty in rats. These rats will be given AIN93Mbased diets containing 0.25%, 0.5%, 1% or 2% bile acids mixture that mimics the bile acids profile in the gastroesophageal refluxate of human BE patients. Trypsin (0.4 mg/ml) and lysolecithin (1 mg/ml) will also be given in drinking fluid. Four weeks later, histopathology and the bile acids profile in the esophageal mucosa will be analyzed. The pH, trypsin, lysolecithin and the bile acids profile in the esophageal and gastric contents will also be analyzed. These results will help us select two treatment conditions for the long-term study. 2. To determine the role of bile acids in the development of rat BE, and possibly EAC. Cardioplasty rats will be given AIN93M diets containing bile acids mixtures (concentrations determined in Aim 1) plus trypsin and lysolecithin in drinking fluid. The rats will be sacrificed at 10, 20, 40 and 60 weeks after surgery. The development of BE, BE with dysplasia, and possibly EAC will be analyzed and characterized. These studies are expected to determine the effect of bile acids on the formation of BE, and lead to the development of a novel animal model of BE and EAC. Such an animal model would provide a basis for future studies on the mechanism, prevention, and therapy of BE and EAC.
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| Liu, Tong; Zhang, Xinyan; So, Chi-Kwong et al. (2007) Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis 28:488-96 |
| Chen, Xiaoxin; Wang, Su; Wu, Nan et al. (2004) Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis. Clin Cancer Res 10:6703-9 |
| Su, Yinghao; Chen, Xiaoxin; Klein, Michael et al. (2004) Phenotype of columnar-lined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett's esophagus. Lab Invest 84:753-65 |
