Epithelial-Refluxate Interactions in Barrett's Esophagus

巴雷特食管上皮反流相互作用

• 批准号: 6787772
• 负责人: ANSON W LOWE
• 金额: $ 40万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787772
• 关键词: Epithelial; Refluxate; Interactions; Barrett; Esophagus

DESCRIPTION (provided by applicant): The major objective of our studies is to understand the molecular changes that occur in response to acid and bile exposure in normal and Barrett's esophagus (BE). BE is a metaplastic premalignant condition of the esophagus that is associated with an increased risk of up to 30-fold of developing esophageal adenocarcinoma. Exposure of the esophagus to the duodeno-gastro-esophageal (DGE) refluxate, important constituents of which include acid and bile, is a major risk factor for the development of BE and subsequent esophageal adenocarcinoma. Our overall hypothesis is that identifying acid and bile stimulated up- or down regulated genes in the normal esophagus and Barrett's epithelium, and characterizing the signaling pathways that are involved, should provide potential diagnostic and therapeutic targets and essential clues regarding the mechanisms of esophageal metaplasia and abnormal cell proliferation in BE. Our specific aims and hypotheses are: (i) Use a human microarray approach, ex vivo, to identify the genes that are modified in response to acid or bile in normal esophagus, BE and duodenum. This aim is based on the hypothesis that the DGE refluxate modulates the genetic program of normal esophageal, BE and duodenal epithelia differently, in a refluxate constituent-dependent fashion. (ii) Identify the acid or bile-induced modified genes in squamous esophageal and Barrett's cell lines. This aim is based on the hypothesis that tissue cultured cell lines, due to their ability to provide an unlimited supply of RNA for gene profile analysis, may provide complimentary information to that obtained using ex vivo biopsies. (iii) Study the signaling cascades of protein kinase C, Cox-2, and Src kinase that are involved in acid/bile-induced stimulation, and define their potential interactions. This aim is based on the hypothesis that characterizing the signaling pathways that are involved in acid and bile stimulated cell proliferation complements the microarray gene profiling strategies and may provide potential complimentary targets for decreasing the risk of dysplasia and adenocarcinoma in BE. Overall, our study seeks to define the molecular signals that play a role in developing metaplasia and that regulate the acid- and bile-mediated responses in the esophagus.

描述（由申请人提供）：我们研究的主要目的是了解正常和巴雷特食管（BE）中酸和胆汁暴露后发生的分子变化。BE是食道的一种化生的癌前病变，与发展为食道腺癌的风险增加高达30倍相关。食管暴露于十二指肠-胃-食管（DGE）反流，其重要成分包括酸和胆汁，是发生BE和随后的食管腺癌的主要危险因素。我们的总体假设是，确定正常食管和Barrett上皮中酸和胆汁刺激的上调或下调基因，并描述相关的信号通路，应该为BE食管化生和异常细胞增殖机制提供潜在的诊断和治疗靶点和重要线索。