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）：幽门螺杆菌长期殖民到世界人口的一半以上，并引起诸如胃炎，溃疡和胃癌等疾病。幽门螺杆菌在胃内定居，在胃中遇到pH，铁的可用性和其他环境因素的大波动。由于这种动态生态位，并且由于幽门螺杆菌在长期定殖方面的高成功率，因此必须擅长调节基因表达。我们先前表明，在幽门螺杆菌暴露于酸性pH和铁限制后，对编码铁摄取调节剂（毛皮）的基因表达发生了改变。此后，我们和其他组表明，毛皮是幽门螺杆菌在低pH值，营养（铁）剥夺以及氧化性，硝化和渗透胁迫条件下生存所必需的至关重要的调节因素。此外，也许最重要的是，我们已经表明，皮草介导的调节对于幽门螺杆菌定植和疾病至关重要。毛皮突变菌株显示出在炎症和炎症和胃癌发育中的明显衰减中，在沙鼠模型中的定殖动力学改变了。此外，我们随后的研究表明，对疾病的影响可能是由于毛皮在激活CAGA表达中的作用，该caga的作用编码了IV型分泌效应蛋白，这对于癌症的发展至关重要。在此，我们建议表征毛皮介导的CAGA表达激活的过程，并检查体内CAGA的表达和传递，定义鉴定出的毛皮调节基因在压力适应，定殖和疾病发展中的作用，并确定毛皮在幽门螺杆菌的表达中的作用，并确定这些srna srna srna srna srna srna srna的作用。我们预测，我们的工作将继续对幽门螺杆菌中介导的基因调节的过程有重大见解 有助于定义适应与这种重要人类病原体的感染和最终疾病发展的关系。这些研究将填补有关幽门螺杆菌适应和调节过程的知识的基本差距，并应为幽门螺杆菌提供潜在的新治疗靶标。