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）是食管腺癌的强风险因素，在过去30年中，食管腺癌的发生率增加了6倍。BE发展及其肿瘤进展的分子基础尚不清楚。结肠癌发生的分子机制的阐明导致了重要的临床进展，在诊断，预防和治疗结直肠癌。如果在BE患者的治疗方面有类似的进展，我们必须首先了解食管化生和肿瘤形成的分子途径。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）途径，其模式在不同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，酸激活ERK MAPK在食管鳞状粘膜的胃食管反流病（GERD）的患者没有BE，但没有在那些有BE。使用巴雷特癌细胞，我们已经将酸诱导的MAPK活化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，因为癌细胞具有多样性和特征不明显的遗传改变。最近，我们利用端粒酶技术从BE患者和非BE患者中产生永生但良性化生的Barrett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发展和肿瘤进展的分子途径。我们的初步数据表明，酸激活MAPK在化生巴雷特细胞中的模式类似于在体内BE中看到的，但不同于在巴雷特癌细胞中看到的。与酸对那些癌细胞的促增殖作用不同，我们发现酸暴露在我们的良性巴雷特细胞中具有抗增殖作用。我们推测酸对食管癌细胞增殖和凋亡的影响取决于酸诱导的MAPK激活模式以及激活的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这些活化的MAPK蛋白在体内和体外对正常食管鳞状细胞和化生Barrett's细胞的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，以确定这些破坏对酸介导的体外增殖和凋亡的影响。与公共卫生的相关性是确定特定的分子标志物，这些分子标志物可用于选择可能从积极的抑酸治疗中获益的GERD患者亚组，以预防BE的发生，以及选择从预防食管腺癌的干预措施中获益最多的BE患者亚组。 与公共卫生的相关性是确定特定的分子标志物，可用于选择我们许多胃食管反流病患者的一个亚组，这些患者可能受益于积极的抑酸治疗，以防止Barrett食管的发展，以及选择Barrett食管患者的一个亚组，这些患者将从预防食管腺癌的干预措施中获益最多。

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.