Helicobacter Host Interactions in Animal Models

描述（由申请人提供）：胃癌现在是人类第三大最常见的诊断癌症。它是全球癌症相关死亡的第二大常见原因，仅次于吸烟相关的肺癌。幽门螺杆菌感染与胃炎和消化性溃疡以及胃腺癌和胃粘膜相关淋巴组织淋巴瘤（MALT）有因果关系。值得注意的是，一种称为CagA的单一细菌蛋白被认为在从简单炎症到溃疡病和腺癌的转变中发挥主要作用。然而，我们不明白为什么绝大多数感染H。幽门螺杆菌感染者即使经常终生感染，也不会患上严重疾病。 我们的工作重点是了解什么样的宿主因素，以及感染H。幽门螺杆菌，有助于是否有一个相对良性的宿主-微生物关系或更具破坏性的结果，十二指肠溃疡或胃癌。利用细菌遗传学、分子生物学、细胞生物学和功能基因组学的现代工具，我们的研究将试图回答以下问题。幽门螺杆菌是如何突破胃屏障在宿主体内建立并持续存在的？生物体如何操纵宿主的免疫系统，使其持续一生？什么是自然感染不能提供任何免疫力？为什么在我们通过抗生素治疗根除了微生物之后，再次感染对宿主的危害更大？与细菌蛋白CagA磷酸化密切相关的恶性转化的潜在特征是什么？我们对这些问题的实验方法利用了感染的动物模型和宿主对感染的反应的研究，以及细菌遗传结构的修饰对感染性和诱发恶性肿瘤的能力的影响。

DESCRIPTION (provided by applicant): Gastric cancer is now the third most common diagnosed cancer of humans. It is the second most common cause of cancer-related deaths worldwide, only surpassed by smoking-related lung cancer. Infection with the bacterium Helicobacter pylori is causally associated with gastritis and peptic ulcer, as well as gastric adenocarcinoma and gastric lymphoma of mucosa-associated lymphoid tissue (MALT). Remarkably, a single bacterial protein called CagA is thought to play the principal role in the transition from simple inflammation to ulcer disease and adenocarcinoma. However, we don't understand why the vast majority of individuals infected by H. pylori remain free of serious disease even though often infected for a lifetime. Our work focuses on understanding what host factors, together with the genetic make-up of the infecting H. pylori, contribute to whether there is a relatively benign host-microbial relationship or the more devastating outcome of duodenal ulcer or gastric cancer. Using contemporary tools of bacterial genetics, molecular biology, cell biology and functional genomics, our proposed research will try to answer the following questions. How does Helicobacter pylori breach the gastric barrier to establish itself and to persist in the host? How does the organism manipulate the host immune system to persist for a lifetime? What is the failure of a natural infection to afford any immunity at all? Why, after we eradicate the microbe by antibiotic treatment, is re-infection even more deleterious for the host? What are the underlying features of the malignant transformation that are so intimately associated with the phosphorylation of the bacterial protein CagA? Our experimental approach to these questions makes use of animal models of infection and the study of the host response to infection, as well as what modifications of the genetic structure of the bacterium have on infectivity and it's ability to induce malignancy.