Role of Acid in the Development of Barrett's Esophagus

描述（由申请人提供）：慢性胃食管酸反流及其后遗症Barrett食管（BE）是食管腺癌的重要危险因素，在过去30年中，该肿瘤的发病率增加了6倍。导致BE发生及其肿瘤进展的分子事件尚不清楚。结肠癌发生的分子机制的阐明，在结直肠癌的诊断、预防和治疗方面取得了重要的临床进展。如果要在be患者的管理方面取得类似的进展，我们必须首先了解食道化生和瘤变的分子途径。我的实验室发现，酸暴露激活食管细胞中的丝裂原活化蛋白激酶（MAPK）通路，其模式在不同的粘膜类型之间以及不同食管疾病患者的粘膜类型内似乎有所不同。例如，我们已经证明，在没有BE的胃食管反流病（GERD）患者的食管鳞状黏膜中，酸激活ERK MAPK，而在有BE的患者中则没有。使用巴雷特癌细胞，我们已经将酸诱导的MAPK激活与促增殖作用联系起来。然而，对癌细胞的研究结果可能不适用于良性细胞，因为癌细胞具有多种多样且特征不明确的遗传改变。最近，我们已经使用端粒酶技术，从患有和不患有BE的患者身上产生了不朽的，但良性的，化生的巴雷特氏和食管鳞状细胞系。我们建议使用这些细胞系来探索由酸反流激活的导致BE发生和肿瘤进展的分子途径。我们的初步数据显示，酸在化生的巴雷特细胞中激活MAPK的模式与体内的BE相似，但与巴雷特癌细胞不同。与酸对这些癌细胞的促增殖作用不同，我们发现酸暴露对良性巴雷特细胞有抗增殖作用。我们假设酸对食管细胞增殖和凋亡的影响取决于酸诱导的MAPK活化模式以及活化的MAPK蛋白如何影响G1-S细胞周期检查点。本研究的目的是描述激活的MAPK蛋白对体内和体外正常食管鳞状和化生巴雷特细胞G1-S细胞周期检查点的影响，并破坏G1-S细胞周期检查点的关键介质，以确定这些破坏对体外酸介导的增殖和凋亡的影响。与公共卫生相关的是鉴定特定的分子标记物，这些标记物可用于从我们的许多胃食管反流患者中选择一个亚组，这些患者可能受益于积极的抑酸治疗来预防be的发展，也可用于选择一个亚组的be患者，他们将从干预措施中获益最多，以预防食管腺癌。

DESCRIPTION (provided by applicant): Chronic gastroesophageal acid reflux and its sequela, Barrett's esophagus (BE), are strong risk factors for esophageal adenocarcinoma, a tumor whose frequency has increased six-fold over the past 30 years. The molecular events that underlie both the development of BE and its neoplastic progression remain unclear. The elucidation of the molecular mechanisms of carcinogenesis in the colon has resulted in important clinical advances in the diagnosis, prevention and treatment of colorectal cancer. If there are to be similar advances in the management of patients with BE, we must first understand the molecular pathways underlying metaplasia and neoplasia in the esophagus. My laboratory has found that acid exposure activates the mitogen activated protein kinase (MAPK) pathways in esophageal cells in patterns that appear to differ among mucosal types as well as within mucosal types among patients with different esophageal diseases. For example, we have shown that acid activates ERK MAPK in the esophageal squamous mucosa of patients who have gastroesophageal reflux disease (GERD) without BE, but not in those who have BE. Using Barrett's cancer cells, we have linked acid-induced MAPK activation with pro-proliferative effects. However, the results of studies on cancer cells, which have diverse and poorly characterized genetic alterations, may not be applicable to benign cells. Recently, we have used telomerase technology to generate immortal, but benign, metaplastic Barrett's and esophageal squamous cell lines from patients with and without BE. We propose to use these cell lines to explore the molecular pathways activated by acid reflux that lead to the development and neoplastic progression of BE. Our preliminary data show that acid activates MAPK in metaplastic Barrett's cells in a pattern similar to that seen in BE in vivo, but different from that seen in Barrett's cancer cells. Unlike the pro- proliferative effects of acid on those cancer cells, we have found that acid exposure has anti-proliferative effects in our benign Barrett's cells. We hypothesize that the effects of acid on proliferation and apoptosis in esophageal cells depend on the pattern of MAPK activation induced by acid and on how the activated MAPK proteins affect the G1-S cell cycle checkpoint. The aims of this study are to delineate the effects of those activated MAPK proteins on the G1-S cell cycle checkpoint in normal esophageal squamous and metaplastic Barrett's cells in vivo and in vitro, and to disrupt the key mediators of the G1-S cell cycle checkpoint to determine the effects of these disruptions on acid-mediated proliferation and apoptosis in vitro. The relevance to public health is the identification of specific molecular markers that can be used to select a subset of our many patients with GERD who might benefit from aggressive acid suppressive therapy to prevent the development of BE as well as to select a subgroup of patients with BE who would benefit most from interventions to prevent esophageal adenocarcinoma. The relevance to public health is the identification of specific molecular markers that can be used to select a subset of our many patients with gastroesophageal reflux disease who might benefit from aggressive acid suppressive therapy to prevent the development of Barrett's esophagus as well as to select a subgroup of patients with Barrett's esophagus who would benefit most from interventions to prevent esophageal adenocarcinoma.