Role of Acid in the Development of Barrett's Esophagus

描述(申请人提供)：慢性胃食管酸反流及其后遗症，巴雷特食道(BE)，是食管腺癌的强烈风险因素，在过去30年中，食管腺癌的发生率增加了6倍。BE发生发展和肿瘤进展的分子机制尚不清楚。结肠癌变分子机制的阐明为结直肠癌的诊断、预防和治疗带来了重要的临床进展。如果要在BE患者的治疗上取得类似的进展，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，酸暴露激活了食道细胞中的丝裂原激活蛋白激酶(MAPK)通路，其模式似乎在不同的粘膜类型之间以及不同食道疾病患者的粘膜类型之间有所不同。例如，我们已经证明，酸激活了没有BE的胃食道反流病(GERD)患者食道鳞状上皮中的ERK MAPK，但在那些有BE的患者中没有。利用Barrett‘s癌细胞，我们将酸诱导的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，因为癌细胞具有多样化的、特征不佳的基因变化。最近，我们使用端粒酶技术从患有和不患有BE的患者身上产生了永生的、但良性的、化生的Barrett和食道鳞状细胞系。我们建议使用这些细胞系来探索酸反流激活的导致BE发展和肿瘤进展的分子通路。我们的初步数据显示，酸激活化生的Barrett细胞中的MAPK的方式与体内BE相似，但不同于Barrett的癌细胞。与酸对这些癌细胞的促增殖作用不同，我们发现酸暴露在良性巴雷特细胞中具有抗增殖作用。我们推测，酸对食道细胞增殖和凋亡的影响依赖于酸诱导的MAPK的激活模式，以及激活的MAPK蛋白如何影响G1-S细胞周期检查点。本研究的目的是阐明这些激活的MAPK蛋白在体内外对正常食管鳞癌和化生的Barrett细胞中G1-S细胞周期检查点的影响，并阻断G1-S细胞周期检查点的关键调节因子，以确定这些干扰在体外对酸介导的增殖和凋亡的影响。与公共健康相关的是确定特定的分子标记，这些标记可用于从我们许多GERD患者中选择可能受益于积极的抑酸治疗以防止BE发展的子组，以及选择将从预防食管腺癌的干预措施中受益最大的BE患者子组。 与公共健康相关的是确定特定的分子标记，这些标记可用于从我们许多胃食道反流病患者中选择可能受益于积极的抑酸治疗以防止Barrett‘s食道发展的子组，以及选择将从预防食管腺癌的干预措施中受益最大的Barrett’s食管亚组患者。

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.