Regulatory Networks of Helicobacter pylori

了解大多数病原微生物如何适应宿主内不断变化的条件是 有限的。我们对适应的基本机制--基因调控的了解进展 毒力基因的表达将为治疗提供新的分子靶点 幽门螺杆菌造成的医疗负担，幽门螺杆菌长期在世界上一半以上的 引起胃炎、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，幽门螺杆菌调节基因的表达 关键毒力因子和一小部分调节蛋白对环境的响应 压力。我们假设这些调节因子调节至关重要的基因的表达。 以适应环境压力，并可能是殖民和/或 幽门螺杆菌在胃环境中的持久性。在这里，我们提出了详细的遗传和 这些因素之一的生化特征，毛皮。皮尔是唯一一家监管机构 受低pH和铁的影响。此外，毛皮管制的经典范式也建立了 通过对其他细菌的研究，幽门螺杆菌的情况要复杂得多，毛皮调节基因 以铁结合和载脂蛋白的形式表达。我们的研究将定义和描述铁- 结合和脱脂毛皮的规则，并将寻求确定毛皮的结构决定因素中介 这两种监管模式中的每一种。最后，为了扩大我们对毒力基因的认识 调控为了应对压力，我们将识别更多参与铁表达的基因- 利用报告构建和近饱和的基因调控毒力基因cagA和via 转座子文库。这些研究将填补关于这一过程的基础知识鸿沟 幽门螺杆菌的适应和调控，有望为H. 幽门螺杆菌。此外，它们还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所利用。 与公共卫生的相关性：幽门螺杆菌感染了超过50%的世界人口，并导致 一系列疾病。我们的研究将有助于阐明与生存过程有关的基因 并应为疫苗和治疗设计提供新的靶点。

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.