Regulatory Mechanisms of Helicobacter pylori

幽门螺杆菌的调节机制

• 批准号: 8710811
• 负责人: D. SCOTT MERRELL
• 金额: $ 35.72万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710811
• 关键词: Bacteria; Binding; Biology; Cells; Complex; DNA-Directed RNA Polymerase; Defect; Development; Disease; Disease Progression; Environment; Environmental Risk Factor; Exposure to; Gastritis; Gene Expression; Gene Expression Regulation; Genes; Genome; Gerbils; Helicobacter pylori; Human; Infection; Inflammation; Iron; Knowledge; Link; Malignant Neoplasms; Mediating; Microbe; Modeling; Nucleic Acids; Nutrient; Oncogene Proteins; Pathogenesis; Play; Population; Process; Proteins; Regulation; Relative (related person); Role; Signal Transduction; Site; Small RNA; Stomach; Stomach Carcinoma; Stomach Diseases; Stress; Testing; Type IV Secretion System Pathway; Ulcer; Work; attenuation; deprivation; global health; in vivo; insight; malignant stomach neoplasm; mutant; new therapeutic target; novel; null mutation; pathogen; promoter; success; uptake

DESCRIPTION (provided by applicant): Helicobacter pylori chronically colonizes over half of the world's human population and causes diseases such as gastritis, ulcer disease and gastric carcinoma. H. pylori colonizes within the stomach, where it encounters large fluctuations in pH, iron availability and other environmental factors. Because of this dynamic niche and due to H. pylori's high success rate in long-term colonization, the bacterium must be adept at regulating gene expression. We previously showed that expression of the gene that encodes the Ferric Uptake Regulator (Fur) was altered upon exposure of H. pylori to acidic pH and upon iron limitation. Thereafter, our and other groups have shown that Fur is a crucial regulatory factor that is required for survival of H. pylori at low pH, upon nutrient (iron) deprivation, and within oxidative, nitrosative and osmotic stress conditions. Moreover, and perhaps most importantly, we have shown that Fur-mediated regulation is crucial for H. pylori colonization and disease; Fur mutant strains show altered dynamics of colonization in the gerbil model of infection as well as significant attenuation in development of inflammation and gastric cancer. Additionally, our subsequent studies suggest that the effect on disease may be due to a role for Fur in activation of expression of cagA, which encodes a type IV secreted effector protein that is crucial for cancer development. Herein, we propose to characterize the process of Fur-mediated activation of expression of cagA and examine expression and delivery of CagA in vivo, define the role of identified Fur-regulated genes in stress adaptation, colonization and disease development and to determine the role of Fur in expression of H. pylori small RNA (sRNA) species as well as the contribution of these sRNA species to gene expression. We predict that our work will continue to shed significant insight into the process by which gene regulation is mediated in H. pylori as well as help to define how adaptation relates to infection and ultimate disease development by this important human pathogen. These studies will fill a fundamental gap in knowledge concerning the process of adaptation and regulation in H. pylori and should provide potential new therapeutic targets for H. pylori.

描述（由申请人提供）：幽门螺杆菌长期定植于世界上一半以上的人口中，并引起胃炎、溃疡病和胃癌等疾病。幽门螺杆菌在胃内定殖，在那里它会遇到 pH 值、铁可用性和其他环境因素的大幅波动。由于这种动态生态位以及幽门螺杆菌长期定殖的高成功率，该细菌必须善于调节基因表达。我们之前表明，当幽门螺杆菌暴露于酸性 pH 值和铁限制时，编码铁摄取调节剂 (Fur) 的基因的表达会发生改变。此后，我们和其他小组表明，毛皮是幽门螺杆菌在低 pH 值、营养（铁）缺乏以及氧化、亚硝化和渗透应激条件下生存所需的关键调节因子。此外，也许最重要的是，我们已经证明毛皮介导的调节对于幽门螺杆菌定植和疾病至关重要。毛皮突变株显示出沙鼠感染模型中定植动态的改变以及炎症和胃癌发展的显着减弱。此外，我们随后的研究表明，对疾病的影响可能是由于 Fur 在激活 cagA 表达中发挥的作用，cagA 编码对癌症发展至关重要的 IV 型分泌效应蛋白。在此，我们建议描述 Fur 介导的 cagA 表达激活过程，并检查 CagA 在体内的表达和递送，定义已识别的 Fur 调节基因在应激适应、定植和疾病发展中的作用，并确定Fur 幽门螺杆菌小 RNA (sRNA) 种类的表达以及这些 sRNA 种类对基因表达的贡献。我们预测我们的工作将继续深入了解幽门螺杆菌中介导的基因调控过程 有助于定义适应如何与这种重要的人类病原体的感染和最终疾病发展相关。这些研究将填补有关幽门螺杆菌适应和调节过程的基本知识空白，并为幽门螺杆菌提供潜在的新治疗靶点。