Epithelial-Refluxate Interactions in Barrett's Esophagus

巴雷特食管上皮反流相互作用

• 批准号: 6577393
• 负责人: GEORGE TRIADAFILOPOULOS
• 金额: $ 39.21万
• 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/6577393
• 关键词: Barretts esophagus; bile; biopsy; cancer risk; cell line; clinical research; differential display technique; enzyme activity; gastric acid; gastrointestinal epithelium; human subject; microarray technology; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; patient oriented research; preneoplastic state; prostaglandin endoperoxide synthase; protein kinase C; protein tyrosine kinase; reflux esophagitis

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（由申请方提供）：我们研究的主要目的是了解正常食管和Barrett食管（BE）中酸和胆汁暴露后发生的分子变化。BE是一种食管化生性癌前病变，与食管腺癌发生风险增加高达30倍相关。食管暴露于十二指肠胃食管（DGE）反流液（其重要成分包括酸和胆汁）是BE和后续食管腺癌发展的主要风险因素。我们的总体假设是，确定酸和胆汁刺激的上调或下调基因在正常食管和巴雷特上皮，并表征所涉及的信号通路，应提供潜在的诊断和治疗目标和基本线索的食管化生和异常细胞增殖的BE的机制。 我们的具体目标和假设是：（i）使用人类微阵列方法，离体，以确定在正常食管，BE和十二指肠中响应于酸或胆汁而被修饰的基因。这一目的是基于这样的假设，即DGE反流调节正常食管，BE和十二指肠上皮细胞的遗传程序不同，在反流成分依赖的方式。(ii)确定食管鳞状细胞和Barrett细胞系中酸或胆汁诱导的修饰基因。这一目的是基于这样的假设，即组织培养的细胞系由于其提供用于基因谱分析的无限制的RNA供应的能力，可以提供使用离体活检获得的补充信息。(iii)研究参与酸/胆汁诱导刺激的蛋白激酶C、考克斯-2和Src激酶的信号级联，并确定其潜在的相互作用。这一目标是基于这样的假设，即表征参与酸和胆汁刺激的细胞增殖的信号通路补充了微阵列基因分析策略，并可能为降低BE中异型增生和腺癌的风险提供潜在的互补靶点。总的来说，我们的研究旨在确定在发生化生中发挥作用的分子信号，以及调节食管中酸和胆汁介导的反应。