Regulatory Networks of Helicobacter pylori

幽门螺杆菌的调控网络

• 批准号: 7545907
• 负责人: D. SCOTT MERRELL
• 金额: $ 37.47万
• 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: 2006
• 资助国家: 美国
• 起止时间: 2006-12-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545907
• 关键词: Affect; Amino Acids; Bacteria; Binding; Biochemical; Biological Assay; Code; Complex; Data; Development; Disease; Doctor of Philosophy; Environment; Fibrinogen; Gastritis; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Helicobacter pylori; Human; Human body; In Vitro; Individual; Infection; Iron; Knowledge; Libraries; Light; Mediating; Medical; Microbe; Molecular Target; Mucous Membrane; Mutagenesis; Mutation; Population; Printing; Process; Proteins; Public Health; Pylorus; Regulation; Regulon; Reporter; Role; Site; Starvation; Stomach; Stomach Carcinoma; Stress; Structure; Tissues; Ulcer; Virulence; Virulence Factors; Work; design; foot; genetic regulatory protein; insight; mucosa-associated lymphoid tissue lymphoma; mutant; new therapeutic target; novel; pathogen; promoter; response; success; therapeutic target; therapeutic vaccine

Knowledge of how most pathogenic microbes adapt to changing conditions within the host is limited. Advances in our understanding of the basic mechanisms of adaptation, gene regulation and virulence gene expression will provide new molecular targets for therapy to reduce the large medical burden imposed by Helicobacter pylori, which chronically colonizes over half of the world's human population and causes gastritis, ulcer disease, gastric carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. We have previously shown that H. pylori regulates expression of key virulence factors and a small subset of regulatory proteins in response to environmental stress. We hypothesize that these regulatory factors modulate expression of genes that are crucial for adaptation to environmental stress and are likely to be essential for colonization and/or persistence of H. pyloriwithin the gastric environment. Herein, we propose detailed genetic and biochemical characterization of one of these factors, Fur. Fur is the only one of the regulators affected by both low pH and iron. Additionally, the classic paradigm of Fur regulation established by studies in other bacteria is considerably more complex in H. pylori', Fur regulates gene expression in both its iron-bound and apo forms. Our studies will define and characterize the iron- bound and apo-Fur regulons, and will seek to identify structural determinants of Fur that mediate each of these two modes of regulation. Finally, to expand our knowledge of virulence gene regulation in response to stress, we will identify additional genes involved in expression of the iron- regulated virulence genes cagA and vacA using reporter constructs and a near-saturating transposon library. These studies will fill a fundamentalgap in knowledge concerning theprocess of adaptation and regulation in H. pylori and should provide potential new therapeutic targets for H. pylori. Additionally, they willprovide novelinsight into the unique mechanisms of Fur-regulation utilized by this importantpathogen. Relevance to Public Health: H. pylori infects more than 50% of the worlds population and causes a range of diseases. Our studies will help to shed light on genes involved in the process of surviving in the human body and should provide novel targets for vaccine and therapeutic design.

了解大多数病原微生物如何适应宿主体内不断变化的条件， 有限公司我们对适应的基本机制，基因调控的理解 毒力基因的表达将为治疗提供新的分子靶点， 幽门螺杆菌长期定植在世界上一半以上的 与引起人群胃炎、溃疡病、胃癌及粘膜相关 淋巴组织（MALT）淋巴瘤。我们以前已经证明，H。pylori调控表达 关键毒力因子和一小部分调节蛋白对环境 应力我们假设这些调节因子调节了基因的表达，这些基因是至关重要的， 适应环境压力，可能是殖民和/或 H.的持久性pylori在胃环境中。在此，我们提出了详细的遗传和 这些因素之一的生化特性，毛皮。皮草是唯一一家 受低pH值和铁的影响。此外，毛皮监管的经典范式建立了 在其他细菌中的研究是相当复杂的H。pylori '，Fur调控基因 以其铁结合和载脂蛋白形式表达。我们的研究将定义和描述铁- 结合和apo-Fur调节子，并将寻求确定Fur的结构决定因素， 这两种监管模式。最后，为了扩大我们对毒力基因的认识， 调节响应压力，我们将确定其他基因参与表达的铁- 调节毒力基因cagA和vacA使用报告构建体和一个接近饱和的 转座子文库。这些研究将填补有关这一过程的基本知识空白 H. pylori感染，为H. 幽门。此外，他们将提供新的洞察力的独特机制，毛皮调节 被这种重要的病原体利用。 公共卫生：H。幽门螺杆菌感染了世界上50%以上的人口， 一系列疾病。我们的研究将有助于阐明参与生存过程的基因 这将为疫苗和治疗设计提供新的靶点。