Regulatory Networks of Helicobacter pylori

幽门螺杆菌的调控网络

• 批准号: 7329166
• 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/7329166
• 关键词: Affect; Amino Acids; Bacteria; Binding; Biochemical Genetics; Biological Assay; Code; Complex; Condition; Data; Development; Disease; Doctor of Philosophy; Environment; Fibrinogen; Gastritis; Gene Expression; Gene Expression Regulation; Genes; 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; Range; Rate; 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; novel; novel therapeutics; 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内不断变化的条件 有限的。我们对适应、基因调控基本机制的理解取得进展 毒力基因表达将为治疗提供新的分子靶点，以减少大 幽门螺旋杆菌造成的医疗负担，长期寄生在世界一半以上的地区 人群并导致胃炎、溃疡病、胃癌和粘膜相关疾病 淋巴组织（MALT）淋巴瘤。我们之前已经证明幽门螺杆菌调节表达 关键毒力因子和一小部分调节蛋白响应环境 压力。我们假设这些调节因子调节至关重要的基因表达 用于适应环境压力，并且可能对于殖民化和/或 幽门螺杆菌在胃环境中持续存在。在此，我们提出了详细的遗传和 这些因素之一的生化特征，毛皮。皮草是唯一的监管者之一 受低 pH 值和铁的影响。此外，毛皮监管的经典范式已建立 根据对其他细菌的研究，幽门螺杆菌中的毛皮调节基因要复杂得多 以其铁结合形式和apo 形式表达。我们的研究将定义和表征铁 结合和 apo-Fur 调节子，并将寻求确定介导 Fur 的结构决定因素 这两种监管模式中的每一种。最后，扩大我们对毒力基因的认识 为了应对压力，我们将鉴定参与铁表达的其他基因 使用报告构建体和近饱和的调节毒力基因 cagA 和 vacA 转座子库。这些研究将填补有关该过程的知识的根本空白 幽门螺杆菌的适应和调节，应该为幽门螺杆菌提供潜在的新治疗靶点。 幽门螺杆菌。此外，他们将为毛皮调节的独特机制提供新的见解 被这种重要的病原体利用。 与公共卫生的相关性：幽门螺杆菌感染了世界上超过 50% 的人口，并导致 疾病范围。我们的研究将有助于阐明参与生存过程的基因 人体内，应该为疫苗和治疗设计提供新的靶点。