Role of Acid in the Development of Barrett's Esophagus

描述（由申请方提供）：胃食管反流病（GERD）已被确定为食管腺癌的强风险因素。GERD可并发食管炎，以及食管鳞状粘膜被Barrett食管（BE）的化生粘膜替代。在持续性消化道损伤的情况下，BE可引起食管腺癌。目前尚不清楚为什么只有少数GERD患者发生BE，或者为什么只有少数BE患者发生食管腺癌。这种空白的一个原因是介导BE发展和肿瘤进展的酸反流引发的分子事件的特征很差。我们实验室的初步数据表明，酸激活BE患者化生粘膜、正常受试者和未发生BE的GERD患者鳞状粘膜中的丝裂原活化蛋白激酶（MAPK）途径。相反，我们发现酸不能激活BE患者鳞状粘膜中的MAPK通路。我们推测，酸激活MAPK依赖的信号转导途径，增加细胞周期蛋白D1的表达，并触发细胞增殖的增加和细胞凋亡的减少，在正常食管鳞状上皮和化生上皮BE。根据我们的初步数据，这一基本假设对BE的发展和肿瘤进展具有临床意义。在正常患者和未发生BE的患者的食管鳞状上皮中，MAPK依赖性通路的酸激活可能促进酸损伤食管粘膜的修复;在发生BE的患者中，酸未能激活MAPK通路可能阻止酸损伤鳞状粘膜的再生，并易于通过化生进行修复。然而，一旦BE发生，MAPK依赖性通路的酸刺激可能易诱发食管腺癌的发生。我们研究的目的是评估酸诱导的ERK，p38和JNK MAP激酶通路，AP-1家族的转录因子，细胞周期蛋白D1表达的影响，以及其对细胞增殖和凋亡的影响，在Barrett化生和食管鳞状粘膜使用在体内和体外系统。我们的长期目标是确定BE的分子标志物和分子靶点，以指导BE和食管腺癌患者的化学预防和化疗药物。

DESCRIPTION (provided by applicant): Gastroesophageal reflux disease (GERD) has been established as a strong risk factor for esophageal adenocarcinoma. GERD can be complicated by esophagitis, and by replacement of esophageal squamous mucosa with the metaplastic mucosa of Barrett's esophagus (BE). In the setting of continued peptic injury, BE can give rise to esophageal adenocarcinoma. It is not known why only a minority of individuals with GERD develop BE, or why only a minority of individuals with BE develop esophageal adenocarcinoma. One reason for this void is that the molecular events triggered by acid reflux which mediate the development and neoplastic progression of BE are poorly characterized. Preliminary data from our laboratory demonstrate that acid activates the mitogen activated protein kinase (MAPK) pathways in the metaplastic mucosa of patients with BE, and in the squamous mucosa of normal subjects and of patients with GERD who do not develop BE. In contrast, we found that acid fails to activate the MAPK pathways in the squamous mucosa of patients with BE. We hypothesize that acid activates the MAPK-dependent signal transduction pathways which increase expression of cyclin D1, and trigger an increase in cell proliferation and a decrease in apoptosis in normal esophageal squamous epithelium and in the metaplastic epithelium of BE. Based on our preliminary data, this basic hypothesis has clinical implications for both the development and neoplastic progression of BE. In the esophageal squamous epithelium from normal patients and patients who do not develop BE, acid activation of MAPK-dependent pathways may promote repair of the acid damaged esophageal mucosa; in patients who develop BE, failure of acid to activate MAPK pathways may prevent regeneration of the acid damaged squamous mucosa and predispose to repair through metaplasia. However, once BE develops, acid stimulation of MAPK-dependent pathways may predispose to the development of esophageal adenocarcinoma. The aims of our study are to evaluate the acid induced effects on the ERK, p38, and JNK MAP kinase pathways, the AP-1 family of transcription factors, cyclin D1 expression, and its effect on cell proliferation and apoptosis in Barrett's metaplasia and esophageal squamous mucosa using in vivo and in vitro systems. Our long term goals are to identify molecular markers of BE and molecular targets at which to direct chemopreventive and chemotheapeutic agents for patients with BE and esophageal adenocarcinoma.