Regulation of H. Pylori Virulance by Dietary Factors that Impact Gastric Cancer

影响胃癌的饮食因素对幽门螺杆菌毒力的调节

• 批准号: 9274163
• 负责人: TIMOTHY L COVER
• 金额: $ 28.2万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9274163
• 关键词: Affect; Animal Model; Bacterial Infections; Bacterial Proteins; Cancer Etiology; Carcinogens; Cell Culture Techniques; Cessation of life; Characteristics; Chronic; Collaborations; Development; Diet; Diet Modification; Dietary Factors; Disease Outcome; Employee Strikes; Environment; Environmental Risk Factor; Epidemiology; Epidermal Growth Factor Receptor; Epithelial Cells; Exhibits; Funding; Gastric Adenocarcinoma; Gastric lymphoma; Genes; Genetic; Genetic Variation; Gerbils; Goals; Gram-Negative Bacteria; Helicobacter Infections; Helicobacter pylori; Histopathology; Human; Incidence; Individual; Infection; Inflammation; Iron; Lead; Lesion; Link; Malignant Neoplasms; Membrane Proteins; Modeling; Molecular; Organ Culture Techniques; Organoids; Pathogenesis; Pathogenicity Island; Pathway interactions; Patients; Pattern; Peptic Ulcer; Persons; Population; Premalignant; Prevention; Prevention approach; Prevention therapy; Production; Proteins; Proteomics; Regulation; Research; Resources; Risk; Risk Factors; Role; Sodium Chloride; Stomach; Surface; Up-Regulation; Variant; Virulence; Work; World Health Organization; beta catenin; cancer risk; carcinogenesis; carcinogenicity; experimental study; high salt diet; improved; in vivo; iron deficiency; malignant stomach neoplasm; novel strategies

Persistent colonization of the human stomach with the Gram-negative bacterium Helicobacter pylori is associated with an increased risk for the development of gastric adenocarcinoma. Gastric cancer is the second leading cause of cancer-related death worldwide, and H. pylori has been classified as a type I carcinogen by the World Health Organization. Among H. pylori-infected persons, the risk of gastric cancer is determined by multiple variables, including characteristics of H. pylori strains, host genetic characteristics, and environmental factors. The long-term goal of this work is to define the mechanisms by which H. pylori infection can lead to gastric cancer, and to develop improved approaches for identifying individuals who have an increased risk for gastric cancer. In previous studies, we have shown that persons infected with GagA-positive H. pylori strains have an increased gastric cancer risk compared to persons infected with GagA-negative strains. H. pylori-induced gastric cancer in the Mongolian gerbil model is GagA-dependent, and we have shown that both a high-salt diet and a low-iron diet increase the risk of gastric cancer in H. pylori-infected gerbils. Furthermore, we have shown that exposure of H. pylori to high-salt conditions stimulates upregulation of GagA production. In this project, we propose to investigate further the regulation of H. pylori virulence by dietary factors that impact gastric cancer. Aim 1 proposes to define the roles of three salt-regulated H. pylori outer membrane proteins (HopQ and two VacA-Iike proteins) in gastric cancer development. We will use multiple experimental approaches, including conventional cell culture, gastric organ culture and gastric organoid culture, and the Mongolian gerbil model of H. pylori-induced gastric cancer. Aim 2 will identify shared .features of the pathways by which a high-salt diet and a low-iron diet augment gastric cancer risk in the H. pylori-infected gerbil model. Aim 3 will analyze regulation of salt-responsive H. pylori genes in vivo and analyze adaptation of H. pylori to a carcinogenic gastric environment. These aims will interdigitate with work proposed in Projects 1 and 2 (which each focus on H. pylori-induced epithelial cell alterations) and will utilize both the Gastric Histopathology and Proteomics Cores. These studies should lead to important advances in our understanding of the molecular mechanisms by which H. pylori infection and relevant dietary factors promote the development of gastric cancer. Ultimately, these studies should lead to advances in the prevention and therapy of malignancies that develop in the setting of chronic inflammation.

革兰氏阴性菌幽门螺杆菌在人胃中的持续定植与胃腺癌发生的风险增加有关。胃癌是世界范围内癌症相关死亡的第二大原因，H。幽门螺杆菌已被世界卫生组织归类为I型致癌物。在H.幽门螺杆菌感染的人，胃癌的风险是由多个变量，包括H。pylori菌株、宿主遗传特征和环境因素。这项工作的长期目标是确定H。幽门螺杆菌感染可导致胃癌，并开发改进的方法来识别胃癌风险增加的个体。在以前的研究中，我们已经证明感染GagA阳性H。与感染GagA阴性菌株的人相比，幽门螺杆菌菌株具有增加的胃癌风险。H.幽门螺杆菌诱导的蒙古沙鼠胃癌模型是GagA依赖性的，我们已经证明高盐饮食和低铁饮食都增加了H.感染幽门的沙鼠此外，我们已经表明，暴露的H。pylori对高盐条件的耐受刺激GagA产生的上调。在这个项目中，我们建议进一步研究H。幽门螺杆菌的毒力受饮食因素的影响而影响胃癌的发生。目标1提出界定三个方面的作用 盐调节H. pylori外膜蛋白（HopQ和两个VacA样蛋白）在胃癌发生中的作用。本研究采用多种实验方法，包括常规细胞培养、胃器官培养和胃类器官培养，建立了蒙古沙鼠H。幽门诱发胃癌目的2将确定高盐饮食和低铁饮食增加H。幽门感染沙鼠模型。目的3分析盐敏感性H. pylori基因，并分析H.幽门螺杆菌致癌胃环境。这些目标将与项目1和项目2中提出的工作相互交织（项目1和项目2分别侧重于H。pylori诱导的上皮细胞改变），并将利用胃组织学和蛋白质组学核心。这些研究将使我们对H。幽门螺杆菌感染和相关的饮食因素促进胃癌的发生。最终，这些研究应该导致在慢性炎症背景下发展的恶性肿瘤的预防和治疗方面的进展。