Regulatory Networks of Helicobacter pylori

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有限。我们对适应、基因调控和毒力基因表达的基本机制的理解的进展将为治疗提供新的分子靶点，以减少幽门螺杆菌造成的巨大医疗负担，幽门螺杆菌长期定植于世界一半以上的人口中，并导致胃炎、溃疡病、胃癌和粘膜相关淋巴组织（MALT）淋巴瘤。我们以前已经证明，H。幽门螺杆菌调节关键毒力因子和一小部分调节蛋白的表达以响应环境应激。我们假设这些调节因子调节基因的表达，这些基因对适应环境胁迫至关重要，并且可能是H.胃内环境中的幽门螺杆菌。在这里，我们提出了详细的遗传和生化特性的这些因素之一，毛皮。毛皮是唯一一种受低pH值和铁影响的调节剂。此外，在其他细菌中研究建立的典型的皮毛调节模式在H.在pylori中，Fur以其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-Fur调节子，并将寻求鉴定介导这两种调节模式中的每一种的Fur的结构决定因素。最后，为了扩展我们对毒力基因调节响应于胁迫的知识，我们将使用报告构建体和近饱和转座子文库鉴定参与铁调节毒力基因cagA和vacA表达的其他基因。这些研究将填补一个基本的知识空白有关的过程中的适应和调节H。pylori感染，为H.幽门。此外，他们将提供新的见解独特的机制，毛皮调节利用这种重要的病原体。公共卫生：H。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生存过程的基因，并为疫苗和治疗设计提供新的靶点。

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.