In vivo models for understanding the cellular and molecular pathogenesis of Barrett's Oesophagus

食管癌是一种几乎总是致命的恶性肿瘤，其发病率近年来翻了一番，并继续以惊人的速度增长。食道腺癌起源于巴雷特食管，是一种影响2%人口的癌前病变。在巴雷特病中，食管内壁的正常细胞变得更像肠内壁的细胞。我们已经开发了新的三维细胞培养模型，使我们能够在实验室中重现人类食管内膜的正常分层结构，我们建议使用这些模型来解决巴雷特食管生物学中的关键问题。在目的1中，我们希望确定巴雷特患者的细胞是永久性的还是短暂的改变，并了解胃酸-胆汁和辅助细胞在这种转变中的作用。在目标2中，我们将更仔细地研究驱动巴雷特氏病细胞转化特征的分子变化。我们将通过操纵人类食管细胞中选定基因的表达，并使用我们的细胞培养模型评估这些基因对细胞生长和分化的影响来做到这一点。这些研究的结果将为设计适当的临床策略来治疗巴雷特食管和防止这种癌前状态发展为食管腺癌铺平道路。

The incidence of oesophageal adenocarcinoma, a malignancy that is almost invariably fatal, has doubled in recent years and continues to increase at an alarming rate. Oesophageal adenocarcinoma arises from Barrett's oesophagus, a premalignant condition that effects up to 2% of the population. In Barrett's, the normal cells of the oesophageal lining are changed to become more like cells that line the intestine. We have developed novel 3-dimensional cell culture models that allow us to reproduce the normal layered structure of the human oesophageal lining in the laboratory and we propose to use these models to address key issues in the biology of Barrett's oesophagus. In aim 1, we wish to determine if the cells in patients with Barrett's have been permanently, or only transiently, altered and to understand the role of gastric acid- bile and accessory cells in this transformation. In aim 2 we will look more closely at the molecular changes that drive the cellular transformation characteristic of Barrett's. We will do this by manipulating the expression of selected genes in human oesophageal cells and assessing the effects of these genes on cell growth and differentiation using our cell culture models. The results of these studies will pave the way for the design of appropriate clinical strategies to treat Barrett's oesophagus and prevent the progression of this premalignant condition to oesophageal adenocarcinoma.