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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.

项目概要/摘要胃食管反流病 (GERD) 和巴雷特食管 (BE) 非常常见美国成年人的疾病是食管腺癌的重要危险因素。 BE 的频率过去几十年来，相关腺癌增加了六倍多，并且对这种致命肿瘤的化学预防疗法由于对分子机制的了解有限而受到阻碍。 BE 发病机制和肿瘤进展的潜在事件。我们有初步数据表明巴雷特上皮细胞对脱氧胆酸（DCA）（一种疏水性胆汁）诱导的细胞凋亡具有更强的抵抗力反流胃液中发现的酸，比正常排列在食道上的鳞状细胞要多。这样的凋亡抵抗可能是 Barrett 化生发病机制和持续存在的基础，如食管鳞状细胞癌死于胆汁酸诱导的细胞凋亡的细胞被抗细胞凋亡的巴雷特细胞所取代。 DCA 等疏水性胆汁酸也已被证明会导致 DNA 损伤，并且是广泛的 DNA 损伤通常会引发细胞凋亡。然而，我们的体外和体内研究初步数据表明 Barrett 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以下特征的细胞存活来促进巴雷特化生的肿瘤进展持续的促癌突变。此外，我们的初步研究表明食管鳞状细胞 BE 患者的细胞可能比食管细胞更容易受到 DNA 损伤诱导的细胞凋亡的影响来自没有 BE 的 GERD 患者的鳞状细胞。食管鳞状细胞的这种倾向死于细胞凋亡也可能促进 BE 的发展。我们的初步数据表明 NF- ¿B 途径在 Barrett 化生的细胞凋亡抵抗中发挥关键作用。我们也有初步数据表明熊去氧胆酸（UDCA）是一种亲水性胆汁酸，不会引起基因毒性损伤 Barrett 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 具有潜在的化学预防作用。最近，我们利用了端粒酶技术产生永生但良性（未转化）的巴雷特细胞系和食管鳞状细胞系来自患有和不患有BE的GERD患者。我们建议使用这些细胞系和组织样本探索胆汁酸反流激活的调节细胞凋亡的分子途径及其作用 BE 的发展和肿瘤进展的途径。我们假设胆汁酸影响通过影响 NF-¿B 通路导致食管细胞凋亡。本研究的目的是描绘胆汁酸对正常食管 DNA 损伤、NF-¿B 通路和细胞凋亡的影响在体外和患者体内的鳞状细胞和化生 Barrett 细胞中，破坏关键的 NF-¿B 蛋白并确定这些干扰对体外胆汁酸介导的细胞凋亡的影响，并确定是否 UDCA 可以防止毒性更大的胆汁酸对体外 DNA 损伤和细胞凋亡的影响。