Regulatory Networks of Helicobacter pylori

幽门螺杆菌的调控网络

• 批准号: 7196334
• 负责人: D. SCOTT MERRELL
• 金额: $ 38.2万
• 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/7196334
• 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

DESCRIPTION (provided by applicant): 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. pylori within 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 fundamental gap in knowledge concerning the process of adaptation and regulation in H. pylori and should provide potential new therapeutic targets for H. pylori. Additionally, they will provide novel insight into the unique mechanisms of Fur-regulation utilized by this important pathogen. 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.

描述（由申请人提供）：关于大多数病原微生物如何适应宿主内不断变化的条件的知识是有限的。我们对适应、基因调控和毒力基因表达的基本机制的理解取得进展，将为治疗提供新的分子靶点，以减轻幽门螺杆菌造成的巨大医疗负担，幽门螺杆菌长期寄生在世界一半以上人口中，并导致胃炎、溃疡疾病、胃癌和粘膜相关淋巴组织（MALT）淋巴瘤。我们之前已经证明，幽门螺杆菌可调节关键毒力因子和一小部分调节蛋白的表达以应对环境压力。我们假设这些调节因子调节基因的表达，这些基因对于适应环境应激至关重要，并且可能对于幽门螺杆菌在胃环境中的定植和/或持续存在至关重要。在此，我们提出了这些因素之一毛皮的详细遗传和生化特征。毛皮是唯一一种同时受低 pH 值和铁影响的调节剂。此外，通过对其他细菌的研究建立的经典毛皮调节范式在幽门螺杆菌中要复杂得多，毛皮以铁结合形式和载脂蛋白形式调节基因表达。我们的研究将定义和表征铁结合和脱辅基毛皮调节子，并将寻求确定介导这两种调节模式的毛皮的结构决定因素。最后，为了扩展我们对应激反应毒力基因调控的了解，我们将使用报告基因构建体和近饱和转座子文库来鉴定参与铁调控毒力基因 cagA 和 vacA 表达的其他基因。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。此外，他们还将为这种重要病原体利用的毛皮调节独特机制提供新的见解。与公共卫生的相关性：幽门螺杆菌感染了世界上 50% 以上的人口，并引起一系列疾病。我们的研究将有助于阐明参与人体内生存过程的基因，并为疫苗和治疗设计提供新的靶标。