Epithelial-Refluxate Interactions in Barrett's Esophagus

超出所提供的空间。我们研究的主要目的是了解正常食管和巴雷特食管（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，在正常食管和巴雷特上皮中识别酸和胆汁刺激的上调或下调基因，并表征所涉及的信号通路，应该为BE食管化生和异常细胞增殖的机制提供潜在的诊断和治疗靶点和重要线索。我们的具体目标和假设是：(i)使用人体微阵列方法，离体，识别在正常食管，BE和十二指肠中响应酸或胆汁而被修饰的基因。这一目的是基于DGE反流以反流成分依赖的方式不同地调节正常食管、BE和十二指肠上皮的遗传程序的假设。（ii）鉴定食管鳞状细胞和巴雷特细胞中酸或胆汁诱导的修饰基因。这一目的是基于这样的假设，即组织培养细胞系，由于它们能够为基因谱分析提供无限的RNA供应，可能为体外活组织检查获得的信息提供补充信息。（iii）研究参与酸/胆汁诱导刺激的蛋白激酶C、Cox-2和Src激酶的信号级联，并确定它们之间的潜在相互作用。这一目的是基于这样的假设，即表征酸和胆汁刺激细胞增殖所涉及的信号通路与微阵列基因谱分析策略相辅相成，并可能为降低BE中不典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化生发生中起作用的分子信号，并调节食管酸和胆汁介导的反应。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================