Clinical Studies on Bile Acids in Barrett's Esophagus

描述(由申请人提供)： 项目摘要/摘要胃食道反流病(GERD)和Barrett‘s食道(BE)是退伍军人患者中异常常见的疾病，是食管腺癌的重要危险因素。在过去的几十年里，与BE相关的腺癌的发生率增加了六倍以上，但由于对BE发病机制和肿瘤进展的分子事件了解有限，阻止这种致命肿瘤的治疗方法的发展一直受到阻碍。我们有初步数据表明，Barrett上皮细胞对脱氧胆酸(DCA)诱导的凋亡具有更强的抵抗力，DCA是一种在反流的胃液中发现的疏水性胆汁酸，而不是正常排列在食道内的鳞状细胞。这种凋亡抵抗可能是Barrett化生发生和持续存在的基础，因为屈从于胆汁酸诱导的凋亡的食道鳞状细胞被抗凋亡的Barrett细胞所取代。疏水性胆汁酸，如DCA，也被证明会导致DNA损伤，而广泛的DNA损伤通常会引发细胞凋亡。然而，我们的初步数据显示，Barrett细胞通过激活抗凋亡生存通路来响应胆汁酸诱导的DNA损伤。这可以通过允许持续致癌突变的细胞存活来促进巴雷特化生的肿瘤性进展。此外，我们的初步研究表明，BE患者的食道鳞状细胞可能比没有BE的GERD患者的食道鳞状细胞更容易受到DNA损伤诱导的细胞凋亡。这种食道鳞状细胞容易发生凋亡的倾向也可能参与了BE的发展。我们的初步数据表明，NF-：B通路在Barrett化生的细胞凋亡抵抗中起着关键作用。此外，我们有初步数据显示，熊去氧胆酸(UDCA)是一种亲水性胆汁酸，不会引起Barrett细胞的遗传毒性损伤，甚至对DCA暴露引起的DNA损伤具有保护作用。这些发现提示UDCA具有潜在的化学预防作用。基于我们的体外研究，我们假设胆汁酸通过影响核因子-B途径影响食道细胞的凋亡。我们现在建议进行临床调查，以确定我们的体外研究结果是否适用于BE患者。本研究的目的是探讨食道胆汁酸灌流对食管鳞状上皮和化生Barrett‘s上皮细胞DNA损伤、核因子-B途径和细胞凋亡的影响，以及UDCA改变胆汁酸成分对DNA损伤和核因子-B途径蛋白的影响。 公共卫生相关性： 项目简介对退伍军人医疗保健的潜在影响是确定特定的分子途径，这些分子途径可以有针对性地防止我们的退伍军人患者巴雷特食道的发展和肿瘤进展。

DESCRIPTION (provided by applicant): Project Summary/Abstract Gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE), which are exceptionally common disorders in Veteran patients, are strong risk factors for esophageal adenocarcinoma. The frequency of BE-associated adenocarcinoma has increased more than six-fold in the past few decades, but the development of therapies to prevent this lethal tumor has been hampered by limited understanding of the molecular events underlying the pathogenesis and neoplastic progression of BE. We have preliminary data showing that Barrett's epithelial cells are more resistant to apoptosis induced by deoxycholic acid (DCA), a hydrophobic bile acid found in refluxed gastric juice, than the squamous cells that normally line the esophagus. Such apoptotic resistance might underlie the pathogenesis and persistence of Barrett's metaplasia, as esophageal squamous cells that succumb to bile acid-induced apoptosis are replaced by apoptosis-resistant Barrett's cells. Hydrophobic bile acids like DCA also have been shown to cause DNA damage, and extensive DNA damage normally triggers apoptosis. However, our preliminary data show that Barrett's cells respond to bile acid-induced DNA damage by activating anti-apoptotic survival pathways. This could facilitate the neoplastic progression of Barrett's metaplasia by allowing the survival of cells that have sustained cancer-promoting mutations. Moreover, our preliminary studies suggest that esophageal squamous cells from patients with BE may be more susceptible to apoptosis induced by DNA damage than esophageal squamous cells from GERD patients without BE. This predisposition of esophageal squamous cells to succumb to apoptosis also may contribute to the development of BE. Our preliminary data suggest that the NF-:B pathway plays a key role in the apoptotic resistance of Barrett's metaplasia. In addition, we have preliminary data showing that ursodeoxycholic acid (UDCA), a hydrophilic bile acid, does not induce genotoxic damage in Barrett's cells, and even protects against the DNA damage caused by DCA exposure. These findings suggest a potential chemopreventive role for UDCA. Based on our in vitro studies, we hypothesize that bile acids influence apoptosis in esophageal cells through effects on the NF-:B pathway. We now propose clinical investigations to determine whether our in vitro findings apply to patients with BE. The objectives of this study are to delineate the effects of esophageal bile acid perfusion on DNA damage, on the NF-:B pathway, and on apoptosis in esophageal squamous and metaplastic Barrett's epithelia in patients and, in those same patients, to determine the effects of altering bile acid composition with UDCA on DNA injury and NF-:B pathway proteins. PUBLIC HEALTH RELEVANCE: Project Narrative The Potential Impact on Veterans Health Care is the identification of specific molecular pathways that can be targeted to prevent the development and neoplastic progression of Barrett's esophagus in our veteran patients.