Basic and Clinical Studies on the Role of Bile Acids in Barrett's Esophagus

胆汁酸在巴雷特食管中作用的基础和临床研究

基本信息

批准号：
8434197
负责人：
RHONDA F SOUZA
金额：
$ 23.84万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8434197
关键词：
Acids Adenocarcinoma Adenocarcinoma Cell Adult Affect American Apoptosis Apoptotic Barrett Esophagus Benign Bile Acids Bile Reflux Cell Line Cell Proliferation Cell Survival Cells Chemopreventive Agent Clinical Clinical Data Clinical Research DNA Damage Data Deoxycholic Acid Development Disease Epithelial Epithelial Cells Esophageal Esophageal Adenocarcinoma Esophageal Neoplasms Esophageal Squamous Cell Esophagus Event Exposure to Frequencies Gastric Juice Gastroesophageal reflux disease Growth Homeostasis Human Hydrochloric Acid In Vitro Incidence Intervention Intestines Laboratories Literature Malignant Neoplasms Mediating Metaplasia Metaplastic Metaplastic Cell Metaplastic Columnar Cell Metaplastic Epithelial Cell Modeling Molecular Mutation Neoplasms Pathogenesis Pathway interactions Patients Play Predisposition Prevention strategy Process Proliferating Proteins Proton Pump Inhibitors Public Health Publishing Reflux Resistance Risk Factors Role Signal Pathway Signal Transduction Pathway Specimen Squamous Cell Squamous Epithelium Subgroup Technology Telomerase Tissues Ursodeoxycholic Acid abstracting cancer prevention carcinogenesis in vivo irradiation molecular marker neoplastic prevent protein expression repaired response tumor tumor growth tumor progression

项目摘要

Project Summary/Abstract Gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE), which are exceptionally common disorders in adult Americans, are strong risk factors for esophageal adenocarcinoma. The frequency of BE- associated adenocarcinoma has increased more than six-fold in the past few decades, and the development of chemopreventive therapies for 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, we have preliminary data from in vitro and in vivo studies showing 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. We also have preliminary data showing that ursodeoxycholic acid (UDCA), a hydrophilic bile acid, does not induce genotoxic damage in Barrett's cells in vitro or in vivo, and even protects against the DNA damage caused by DCA exposure. These findings suggest a potential chemopreventive role for UDCA. Recently, we have used telomerase technology to generate immortal, but benign (non-transformed), Barrett's cell lines and esophageal squamous cell lines from GERD patients with and without BE. We propose to use these cell lines as well as tissue specimens to explore the molecular pathways activated by bile-acid reflux that regulate apoptosis, and the role of those pathways in the development and neoplastic progression of BE. We hypothesize that bile acids influence apoptosis in esophageal cells through effects on the NF-¿B pathway. The aims of this study are to delineate the effects of bile acids on DNA damage, on the NF-¿B pathway, and on apoptosis in normal esophageal squamous and metaplastic Barrett's cells in vitro and in patients in vivo, to disrupt the key NF-¿B proteins and determine the effects of those disruptions on bile-acid mediated apoptosis in vitro, and to determine whether UDCA can protect against the effects of the more toxic bile acids on DNA injury and apoptosis in vitro.

项目摘要/摘要胃管反射氏病（GERD）和Barrett的食管（BE），它们异常常见成年美国人的疾病是食管腺癌的强烈危险因素。 be-的频率在过去的几十年中，相关的腺癌增加了六倍以上，并且该致死肿瘤的化学预防疗法受到对分子的了解有限的阻碍 BE发病机理和肿瘤进展的事件。我们有初步数据，显示 Barrett的上皮细胞对脱氧胆酸（DCA）诱导的凋亡更具抗性（一种疏水性胆汁）在反射性胃汁中发现的酸，而不是通常在食道上的鳞状细胞。这样的凋亡抗性可能是巴雷特化生的发病机理和持久性的基础，作为食管鳞状屈服于胆汁酸引起的细胞凋亡的细胞被抗凋亡的Barrett细胞所取代。疏水性胆汁酸（如DCA）也已被证明会导致DNA损伤，并广泛的DNA损伤通常会触发凋亡。但是，我们有来自体外和体内研究的初步数据，表明巴雷特的细胞通过激活抗凋亡生存途径来应对胆汁酸诱导的DNA损伤。这可以通过允许具有持续促进癌症的突变。此外，我们的初步研究表明食管鳞与食管相比来自没有BE的GERD患者的鳞状细胞。食管鳞状细胞的这种倾向屈服于凋亡也可能有助于BE的发展。我们的初步数据表明NF- „ B途径在Barrett Metaplasia的凋亡抗性中起关键作用。我们也有初步数据表明乌索氧化胆酸（UDCA）是一种亲水性胆汁酸，不会诱导遗传毒性损伤 Barrett的细胞在体外或体内，甚至可以防止DCA暴露引起的DNA损伤。这些研究结果表明UDCA潜在的化学预防作用。最近，我们使用了端粒酶技术为了产生不朽但良性（未转化），Barrett的细胞系和食管鳞状细胞系来自有或没有BE的GERD患者。我们建议使用这些细胞系以及组织样品探索通过调节凋亡的胆汁酸反射激活的分子途径，以及那些的作用 BE发育和肿瘤进展的途径。我们假设胆汁酸会影响食管细胞中的凋亡通过对NF- - B途径的影响。这项研究的目的是描述胆汁酸对DNA损伤的影响，NF- - B途径以及正常食管中凋亡的影响在体外和体内患者中，鳞状和化生的Barrett细胞破坏关键NF-€b蛋白和确定这些破坏对体外胆汁酸介导的细胞凋亡的影响，并确定是否是否 UDCA可以预防较有毒的胆汁酸对体外DNA损伤和凋亡的影响。