Regulatory Networks of Helicobacter pylori

描述(由申请人提供)：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。对幽门螺杆菌适应、基因调控和毒力基因表达基本机制的了解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。幽门螺杆菌长期定植于世界一半以上的人口，并导致胃炎、溃疡疾病、胃癌和粘膜相关淋巴组织(MALT)淋巴瘤。我们以前已经证明，幽门螺杆菌调节关键毒力因子和一小部分调控蛋白的表达，以响应环境压力。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压力是至关重要的，并且可能对于幽门螺杆菌在胃环境中的定植和/或持久性是必不可少的。在这里，我们提出了这些因素之一的详细的遗传和生化特征，毛皮。皮毛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Fur调节范例在H.Pylori中要复杂得多，Fur调节其铁结合和载脂蛋白两种形式的基因表达。我们的研究将定义和表征铁结合和apo-Fur调节子，并将寻求确定调节这两种调节模式的Fur的结构决定因素。最后，为了扩大我们对胁迫反应中毒力基因调控的了解，我们将使用报告构建和近饱和的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。这些研究将填补关于幽门螺杆菌适应和调节过程的基本知识空白，并将为幽门螺杆菌提供潜在的新的治疗靶点。此外，它们还将为这种重要病原体利用毛皮调节的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50%以上的人口，并导致了一系列疾病。我们的研究将有助于阐明参与人体生存过程的基因，并应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.