Regulatory Mechanisms of Helicobacter pylori

描述(申请人提供)：幽门螺杆菌长期在世界上一半以上的人口中定居，并导致胃炎、溃疡疾病和胃癌等疾病。幽门螺杆菌在胃内定居，在那里它会遇到pH、铁可获得性和其他环境因素的巨大波动。由于这种动态的生态位，以及幽门螺杆菌长期定植的高成功率，细菌必须擅长调节基因表达。我们先前已经证明，编码铁摄取调节因子(Fur)的基因的表达在幽门螺杆菌暴露于酸性pH和铁限制时发生改变。此后，我们和其他研究小组已经证明，毛皮是幽门螺杆菌在低pH值、营养(铁)缺乏以及氧化、亚硝酸盐和渗透胁迫条件下生存所必需的关键调节因子。此外，也许最重要的是，我们已经证明毛发介导的调控对幽门螺杆菌的定植和疾病至关重要；毛发突变株在沙土鼠感染模型中显示出定植动态的改变，以及炎症和胃癌的发展显著减弱。此外，我们随后的研究表明，这种对疾病的影响可能是由于Fur在激活cagA的表达中所起的作用，cagA编码一种IV型分泌的效应蛋白，对癌症的发展至关重要。在此，我们建议描述Fur介导的cagA表达激活过程，并检测CagA在体内的表达和传递，确定已识别的Fur调节基因在应激适应、定植和疾病发展中的作用，并确定Fur在幽门螺杆菌小RNA(SRNA)物种表达中的作用以及这些SRNA物种对基因表达的贡献。我们预测，我们的工作将继续深入了解幽门螺杆菌的基因调控过程。 以帮助确定适应与这种重要的人类病原体感染和最终疾病发展的关系。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。

DESCRIPTION (provided by applicant): Helicobacter pylori chronically colonizes over half of the world's human population and causes diseases such as gastritis, ulcer disease and gastric carcinoma. H. pylori colonizes within the stomach, where it encounters large fluctuations in pH, iron availability and other environmental factors. Because of this dynamic niche and due to H. pylori's high success rate in long-term colonization, the bacterium must be adept at regulating gene expression. We previously showed that expression of the gene that encodes the Ferric Uptake Regulator (Fur) was altered upon exposure of H. pylori to acidic pH and upon iron limitation. Thereafter, our and other groups have shown that Fur is a crucial regulatory factor that is required for survival of H. pylori at low pH, upon nutrient (iron) deprivation, and within oxidative, nitrosative and osmotic stress conditions. Moreover, and perhaps most importantly, we have shown that Fur-mediated regulation is crucial for H. pylori colonization and disease; Fur mutant strains show altered dynamics of colonization in the gerbil model of infection as well as significant attenuation in development of inflammation and gastric cancer. Additionally, our subsequent studies suggest that the effect on disease may be due to a role for Fur in activation of expression of cagA, which encodes a type IV secreted effector protein that is crucial for cancer development. Herein, we propose to characterize the process of Fur-mediated activation of expression of cagA and examine expression and delivery of CagA in vivo, define the role of identified Fur-regulated genes in stress adaptation, colonization and disease development and to determine the role of Fur in expression of H. pylori small RNA (sRNA) species as well as the contribution of these sRNA species to gene expression. We predict that our work will continue to shed significant insight into the process by which gene regulation is mediated in H. pylori as well as help to define how adaptation relates to infection and ultimate disease development by this important human pathogen. 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.