Clinical Studies on Bile Acids in Barrett's Esophagus

描述（由申请人提供）： 胃食管反流病（GERD）和巴雷特食管（BE）是退伍军人患者中非常常见的疾病，是食管腺癌的强危险因素。在过去的几十年中，BE相关腺癌的发生率增加了6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，因此预防这种致命肿瘤的治疗方法的开发受到阻碍。我们有初步的数据表明，巴雷特上皮细胞更耐脱氧胆酸（DCA）诱导的细胞凋亡，发现在反流的胃液中的疏水性胆汁酸，比鳞状细胞，通常衬食管。这种凋亡抗性可能是巴雷特化生的发病机制和持续性的基础，因为屈服于胆汁酸诱导的凋亡的食管鳞状细胞被凋亡抗性巴雷特细胞所取代。像DCA这样的疏水性胆汁酸也被证明会导致DNA损伤，而广泛的DNA损伤通常会引发细胞凋亡。然而，我们的初步数据表明，巴雷特细胞响应胆汁酸诱导的DNA损伤激活抗凋亡的生存途径。这可以通过允许具有持续促癌突变的细胞存活来促进巴雷特化生的肿瘤进展。此外，我们的初步研究表明，食管鳞状细胞从BE患者可能更容易凋亡诱导的DNA损伤比食管鳞状细胞从GERD患者没有BE。食管鳞状细胞凋亡的倾向也可能导致BE的发生。我们的初步数据表明NF-：B通路在Barrett化生的抗凋亡中起关键作用。此外，我们有初步数据表明，熊去氧胆酸（UDCA），一种亲水性胆汁酸，不会诱导巴雷特细胞的遗传毒性损伤，甚至可以防止DCA暴露引起的DNA损伤。这些结果表明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NF-：B途径影响食管细胞凋亡。我们现在提出临床研究，以确定我们的体外研究结果是否适用于BE患者。本研究的目的是描述食管胆汁酸灌注对患者食管鳞状上皮和化生性Barrett上皮DNA损伤、NF-：B通路和细胞凋亡的影响，并在相同患者中确定UDCA改变胆汁酸组成对DNA损伤和NF-：B通路蛋白的影响。 公共卫生相关性： 对退伍军人医疗保健的潜在影响是确定特定的分子途径，可以有针对性地防止我们的退伍军人患者的巴雷特食管的发展和肿瘤进展。

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.