Helicobacter Host Interactions in Animal Models

描述(申请人提供)：胃癌目前是人类第三种最常见的诊断癌症。它是全球与癌症相关的死亡的第二大常见原因，仅次于与吸烟有关的肺癌。幽门螺杆菌的感染与胃炎和消化性溃疡、胃腺癌和胃粘膜相关淋巴组织淋巴瘤(MALT)有关。值得注意的是，一种名为CagA的单一细菌蛋白被认为在从单纯性炎症向溃疡病和腺癌的转变过程中发挥了主要作用。然而，我们不明白为什么绝大多数感染幽门螺杆菌的人即使经常终身感染，也没有患上严重的疾病。 我们的工作重点是了解哪些宿主因素，以及感染幽门螺杆菌的基因组成，是导致相对良性的宿主-微生物关系，还是更具破坏性的十二指肠溃疡或胃癌的结果。利用当代细菌遗传学、分子生物学、细胞生物学和功能基因组学的工具，我们提出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建立自身并在宿主体内存活的？生物体是如何操纵宿主免疫系统让其终生存活的？自然感染根本负担不起任何免疫力的原因是什么？为什么在我们通过抗生素治疗根除微生物之后，再次感染对宿主的危害更大呢？与细菌蛋白CagA的磷酸化如此密切相关的恶变的潜在特征是什么？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改变对传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.