Animal Model of Barrett's Esophagus

描述(申请人提供)：本项目的目的是研究胆汁酸在Barrett‘s食道(BE)发展中的作用，并建立BE和食管腺癌(EAC)的动物模型。我们以前的动物模型，食道十二指肠吻合术(EDA)和食管胃十二指肠吻合术(EGDA)，通过在大鼠食道中引入胃和十二指肠内容物的混合反流来模拟EAC的发展。然而，胆汁酸在BE发生发展中的作用仍不清楚。该项目将解决这一问题，具体目标如下： 1.建立含不同胆汁酸反流的大鼠模型，通过饮食补充，模拟BE患者胃食道反流液中胆汁酸的分布。大鼠心脏成形术可诱发返流。这些大鼠将被给予以AIN93M为基础的饲料，其中含有0.25%、0.5%、1%或2%的胆汁酸混合物，模拟人类BE患者胃食道反流中的胆汁酸分布。饮用水中也会加入胰酶(0.4 mg/ml)和溶血磷脂(1 mg/ml)。四周后，将分析组织病理学和食道粘膜中胆汁酸的分布情况。还将分析食道和胃内容物中的pH、胰酶、溶血磷脂和胆汁酸分布。这些结果将有助于我们选择两种治疗条件进行长期研究。 2.探讨胆汁酸在大鼠BE、EAC发育中的作用。心脏成形术大鼠将被给予AIN93M饲料，其中含有胆汁酸混合物(在AIM 1中测定的浓度)以及饮水液中的胰酶和溶血磷脂。分别于术后10、20、40、60周处死大鼠。对BE、BE伴不典型增生的发展，以及可能的EAC的发展进行分析和表征。 这些研究有望确定胆汁酸在BE形成中的作用，并导致一种新的BE和EAC动物模型的发展。该动物模型为今后研究BE和EAC的发病机制、预防和治疗奠定了基础。

DESCRIPTION (provided by applicant): 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.