H. Pylori Induced Oxidative Stress

幽门螺杆菌诱导的氧化应激

• 批准号: 7749284
• 负责人: Keith T. Wilson
• 金额: $ 22.94万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749284
• 关键词: Adult; African; Apoptosis; Arginine; Child; Chronic; Clinical; Colombia; DL-alpha-Difluoromethylornithine; DNA; DNA Damage; Data; Disease; Enzymes; Epithelial Cells; Etiology; European; Exhibits; Figs - dietary; Gastric Tissue; Gastric mucosa; Gastritis; Generations; Genes; Genotype; Gerbils; Grouping; Helicobacter Infections; Helicobacter pylori; Hydrogen Peroxide; Immune; Immune response; In Vitro; Individual; Infection; Inflammation; Instruction; Laboratories; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolism; Mus; Mutagens; Natural History; Nitric Oxide; Nitric Oxide Synthase; Ornithine; Ornithine Decarboxylase; Oxidative Stress; Pathologic; Pathway interactions; Patients; Phylogeny; Polyamines; Prevalence; Principal Investigator; Process; Production; Publishing; Putrescine; Pylorus; Reactive Oxygen Species; Regulation; Reporting; Risk; Role; Signal Pathway; Source; Spermidine; Spermine; Stomach; Stomach Carcinoma; Tissues; Work; antimicrobial; arginase; cancer risk; carcinogenesis; cohort; high risk; human NOS2A protein; human subject; in vivo; inhibitor/antagonist; innovation; macrophage; malignant stomach neoplasm; microbial; neoplastic; nitrosative stress; novel; oxidation; oxidative DNA damage; polyamine oxidase; programs; response

The etiology of H. pylori-induced gastric cancer is multifactorial, but one important component is the dysregulated immune response that leads to chronic inflammation and resulting cellular damage. Our lab has discovered a novel pathway for the generation of oxidative stress-induced DNA damage in H. pylori- iniected gastric epithelial cells that results from oxidation of the polyamine spermine by the enzyme spermine oxidase (SMO), producing hydrogen peroxide (H2O2). Increased substrate for SMO is generated by synthesis of polyamines from L-ornithine by the enzyme ornithine decarboxylase (ODC). We have also previously implicated nitric oxide (NO), reporting that the enzyme inducible NO synthase (INOS) that produces high levels of NO, a known mutagen, is upregulated by H. pylori in vitro and in vivo. Work supported by this P01 has demonstrated dramatically different rates of gastric cancer in Colombia, such that individuals from the high risk region of the Andean mountains have a 25-fold greater risk of developing cancer than those from the low risk coastal region, despite identical prevalence rates of H. pylori infection. Our preliminary studies using genotype-matched H. pylori clinical isolates indicate that when compared to strains from the low risk region, strains from the high risk region induce significantly more SMO and oxidative DNA damage in gastric epithelial cells in vitro that correlates with similar findings in the gastritis tissues from the source patients for these strains. We also found that high risk strains induce more INOS in vitro and in vivo. Importantly, we show that Colombian clinical isolates can infect mice and gerbils, and that a high risk strain induces dyplasia in gerbils. Evolutionary analysis of 6 strains by multi-locus sequence typing revealed that the 3 strains from the high risk region clustered together and with reference strains of European origin and the 3 strains from the low risk region clustered together and with strains of African origin. Our hypothesis is that oxidative stress from SMO, and nitrosative stress from iNOS are determinants of neoplastic risk in H. pylori infection, and these pathways are differentially modulated by H. pylori strains from regions of high vs. low gastric cancer risk. Our Specific Aims are: 1.) To demonstrate that H. pylori strains from the high vs. low gastric cancer risk region exhibit increased ability to induce responses that lower the threshold for carcinogenesis; 2.) To demonstrate that polyamine synthesis by ODC, oxidation of spermine by SMO, and generation of NO by INOS are mediators of gastric cancer risk in vivo; and 3.) To define microbial determinants of oxidative and nitrosative stress, and gastric cancer risk by studying H. pylori strains from longitudinal Colombian cohorts in adults and children. The studies proposed are innovative and tightly ntegrated with this P01 as a whole, as they seek to define specific mechanisms of gastric carcinogenesis induced by H. pylori strains from regions of divergent cancer risk in the Colombian natural laboratory. RELEVANCE (See Instructions): This project examines damage to the stomach lining caused by oxygen radicals and nitric oxide in order to determine if these agents have a causal role in the gastric cancer induced by H. pylori.

H.幽门螺杆菌引起的胃癌是多因素的，但一个重要的组成部分是 免疫反应失调，导致慢性炎症和细胞损伤。我们实验室 已经发现了一种新的途径，产生氧化应激诱导的DNA损伤的H。幽门- 由酶氧化多胺精胺而产生的受感染胃上皮细胞 精胺氧化酶（SMO），产生过氧化氢（H2 O2）。生成SMO的底物增加 通过鸟氨酸脱羧酶（ODC）从L-鸟氨酸合成多胺。我们还 以前涉及一氧化氮（NO），报告说，酶诱导型NO合酶（INOS）， 产生高水平的NO，一种已知的诱变剂，被H上调。pylori的体外和体内研究。工作 由这一P01支持的研究表明，哥伦比亚的胃癌发病率存在显著差异， 来自安第斯山脉高风险地区的人患上艾滋病的风险要高出25倍。 尽管H.幽门感染 我们利用基因型匹配的H.幽门螺杆菌临床分离株表明， 来自低风险地区的菌株，来自高风险地区的菌株诱导显著更多的SMO和氧化 体外胃上皮细胞的DNA损伤与慢性胃炎组织中的类似发现相关 这些菌株的源头患者我们还发现，高风险菌株在体外和体内诱导更多的INOS。 vivo.重要的是，我们表明哥伦比亚临床分离株可以感染小鼠和沙鼠， 菌株诱导沙鼠发育不良。通过多位点序列分型对6个菌株进行进化分析， 来自高风险地区的3种菌株聚集在一起，并与欧洲来源的参考菌株聚集在一起 3株低危区菌株聚在一起，与非洲来源菌株聚在一起。我们的假设 SMO引起氧化应激和iNOS引起的亚硝化应激是H. pylori感染，并且这些途径被H.幽门螺杆菌菌株从高地区与 胃癌风险低。我们的具体目标是：（1）证明H.幽门螺杆菌菌株从高与低 胃癌风险区域表现出增加的诱导反应的能力， 致癌作用; 2.）为了证明通过ODC合成多胺，通过SMO氧化精胺， 由INOS产生的NO是体内胃癌风险的介质;和3.）定义微生物 氧化和亚硝化应激的决定因素，胃癌的风险，通过研究H。幽门螺杆菌菌株， 哥伦比亚成人和儿童纵向队列。所提出的研究具有创新性， 与此P01整合为一个整体，因为他们试图定义胃癌发生的具体机制 由H.来自哥伦比亚自然实验室不同癌症风险地区的幽门螺杆菌菌株。 相关性（见说明）： 这个项目研究了氧自由基和一氧化氮对胃粘膜的损伤， 确定这些药物是否在H诱导的胃癌中起因果作用。幽门。