BARRETT'S ESOPHAGUS AND OXIDATIVE STRESS: ROLE OF GASTRIC ACID AND BILE ACID

巴雷特食管和氧化应激：胃酸和胆汁酸的作用

• 批准号: 8073520
• 负责人: Katerina Dvorak
• 金额: $ 34.21万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8073520
• 关键词: 8-hydroxy-2' -deoxyguanosine; Acids; Acute; Antioxidants; Apoptosis; Apoptotic; Barrett Esophagus; Bile Acids; Biological Markers; Biopsy; Cell Line; Cell Membrane Permeability; Cells; Chemopreventive Agent; Chronic; Clinical Trials; DNA Repair; DNA repair protein; Data; Development; Distal; Dysplasia; Enrollment; Epithelial Cells; Esophageal; Esophageal Adenocarcinoma; Esophagus; Exposure to; Gastric Acid; Gastroesophageal reflux disease; Gene Mutation; Generations; Genomic Instability; Goals; Human Cell Line; Hydroxyl Radical; Image Analysis; Immunohistochemistry; In Vitro; Inflammatory; Injury; Lead; Lesion; Liver; Malignant neoplasm of esophagus; Mitochondria; Molecular; Neoplasms; Oxidative Stress; Pathogenesis; Patients; Pattern; Premalignant; Prevention; Preventive; Principal Investigator; Process; Production; Proteins; Reactive Oxygen Species; Reflux; Resistance; Resistance development; Role; Sample Size; Signal Pathway; Superoxide Dismutase; Superoxides; Testing; Ursodeoxycholic Acid; base; catalase; comparative genomic hybridization; cytotoxic; in vivo; lipid peroxidation inhibitor; mitochondrial membrane; novel; oxidative DNA damage; oxidative damage; programs; protective effect; research study; response; survivin; tumor progression

Our major translational goal is to develop a chemopreventive strategy for inhibiting progression of Barrett's esophagus to esophageal adenocarcinoma. We hypothesize that the deleterious effects of hydrophobic bile acids and low pH may be inhibited by the cytoprotective bile acid, ursodeoxycholic acid (UDCA), that was shown to protect cells against oxidative injury. The central hypothesis to be tested in this proposal is that bile acids in combination with low pH induce oxidative stress that leads to DMA damage, genomic instability and apoptosis resistance in Barrett's esophagus. Therefore, an alteration of bile acid composition by ursodeoxycholic acid treatment may be beneficial to Barrett's esophagus patients in the prevention of neoplastic progression. Three specific aims are proposed to test this hypothesis. First, we will evaluate the effect of a bile acid cocktail and/or low pH on the generation of reactive oxygen species (ROS), oxidative, DNA damage, expression of DNA repair proteins, anti-oxidant and anti-apoptotic proteins in vitro in esophageal cell lines and ex vivo, in BE biopsies. We will determine the effect of acute, repeated and chronic exposure to bile acids and/or low pH (1) on the induction of superoxide, (2) formation of 8-OH-dG, a marker of oxidative DNA damage, (3) expression of DNA repair proteins (i.e. Mlh1, Pms2 and PARP), anti-oxidant (i.e. superoxide dismutases and catalase) and anti-apoptotic proteins (i.e. Mcl-1, survivin, Bcl-xL). Furthermore, we plan to identify patterns of DNA alterations using microarray-based comparative genomic hybridization (CGH) in novel esophageal cell lines developed for resistance to bile acids and/or low pH. In specific aim #2 we plan to evaluate the effects of UDCA and its conjugated forms [(tauro-ursodeoxycholic acid (TUDCA), glyco- ursodeoxycholic acid (GUDCA)] on ROS production, oxidative DNA damage, genomic instability and the expression of DNA repair proteins, anti-oxidant and anti-apoptotic proteins induced by low pH and cytotoxic bile acids in vitro. Since UDCA is an excellent scavenger of ROS we anticipate that UDCA will reduce damage caused by bile acids and low pH. Finally, in specific aim #3 we propose to conduct a pilot clinical trial to evaluate UDCA as a potential preventive agent that changes the composition of bile acids in the refluxate so that less toxic bile acids are refluxed to the esophagus. Thus, bile acid composition at the baseline and post UDCA treatment will be determined. Furthermore, markers of oxidative stress (8-OH-dG) and proliferation (Ki-67) will be assessed in BE biopsies at the baseline, 6 months on UDCA and 6 months after discontinuation of UDCA using immunohistochemistry in conjunction with image analysis. Our long-term goal is to evaluate factors and molecular mechanisms leading to BE development and/or progression to esophageal adenocarcinoma and to inhibit these processes.

我们的主要转化目标是开发一种化学预防策略来抑制巴雷特氏病的进展