An anti-inflammatory protein of H. pylori: mechanism and diagnostic potential

幽门螺杆菌的抗炎蛋白：机制和诊断潜力

• 批准号: 8582512
• 负责人: Karen M Ottemann
• 金额: $ 17.05万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582512
• 关键词: Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Bacteria; Behavior; Biological Markers; Cancer Etiology; Cessation of life; Clinical; Correlation Studies; Data; Diagnostic; Disease; Disease Outcome; Disease model; Epithelial Cells; Esophageal; Family; Future; Gastritis; Gene Expression; Genes; Gerbils; Goals; Half-Life; Health; Helicobacter Infections; Helicobacter pylori; Hour; Human; Illness impact; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Knowledge; Malignant Neoplasms; Mammalian Cell; Membrane Proteins; Messenger RNA; Microbe; Mission; Modeling; Molecular; Monitor; Names; Organism; Pathway interactions; Phosphorylation; Phosphotransferases; Probiotics; Proteins; Public Health; Research; Sampling; Stomach; Testing; Therapeutic; Ulcer; Variant; Virulence Factors; Work; base; burden of illness; design; improved; innovation; malignant stomach neoplasm; mutant; novel; pathogen; prevent; public health relevance; research study; response; src-Family Kinases; stem; tool

DESCRIPTION (provided by applicant): There is a fundamental gap in our understanding of how Helicobacter pylori controls host inflammation and, concomitantly, which H. pylori gene products we should screen to predict a strain's disease potential. Continued existence of this gap prevents us from designing diagnostic tools that would allow us to predict which H. pylori infections will progress to disease, and therefore, should be high priorities to cure. Millions of people worldwide and in the U.S. are infected by H. pylori and suffer from its associated diseases-ulcers and gastric cancer. Gastric cancer is the second cause of cancer deaths worldwide. In the U.S., fewer people have gastric cancer likely due to lower but stabilized H. pylori incidence, underlying the idea that curing H. pylori would probably lower the number of cancer deaths. H. pylori infection progresses to disease in only a subset of infected individuals. A key variable is a strain's ability to drive inflammation. The long-term goal of our research is create accurate diagnostics that identify which H. pylori strains will cause trouble. H. pylori strains are highly variable, and this feature offers a possible entr¿e to--and basis for--diagnosti tests. Our recent work has identified a novel anti-inflammatory H. pylori virulence factor, which we named immunomodulatory autotransporter A (ImaA). Our preliminary data show that H. pylori that lack imaA trigger mammalian cells to produce large amounts of inflammation-associated mRNA and protein. ImaA acts through the known H. pylori proinflammatory apparatus, the cag PAI, and is required for sustained phosphorylation of the proinflammatory protein CagA. The specific objective of this work is to determine the molecular basis for ImaA's effect on inflammation, its contribution to H. pylori disease, and whether it serves as a biomarker for severe H. pylori human infections. Our central hypothesis is that ImaA acts to manipulate host phosphorylation of the proinflammatory protein CagA, and that loss of imaA creates H. pylori that cause especially severe disease in gerbils and humans. In the first Aim, we will determine the molecular mechanism by which H. pylori ImaA diminishes cag PAI-dependent pro-inflammatory gene expression. In the second Aim, we will probe how the anti-inflammatory protein ImaA impacts illness by analyzing how loss of imaA affects disease in a relevant animal model and by testing whether the presence of imaA correlates with inflammation and disease outcome in a panel of H. pylori human clinical strains. The proposed research is significant because it will give us a better understanding of the proteins used by H. pylori to control inflammation, and give us another tool with which to probe a particular H. pylori strain's disease potential. The proposed research is innovative in the hypothesis to be tested: that H. pylori produces anti-inflammatory as well as pro-inflammatory proteins. Ultimately the proposed work will inform us about how a new type of virulence factor functions, as well as how it will serve as a disease biomarker and advance our ability to prevent ulcers and gastric cancer.

描述（由申请人提供）：在我们对幽门螺杆菌如何控制宿主炎症的理解上存在根本性的差距，同时，幽门螺杆菌是什么？幽门螺杆菌的基因产物，我们应该筛选，以预测菌株的疾病潜力。这种差距的持续存在使我们无法设计诊断工具，使我们能够预测哪些H。幽门螺杆菌感染会发展为疾病，因此，应优先治疗。全世界和美国有数百万人感染H。幽门螺杆菌和遭受其相关的疾病-溃疡和胃癌。胃癌是全球癌症死亡的第二大原因。在美国，更少的人患有胃癌可能是由于较低但稳定的H。pylori发病率，潜在的想法，治愈H。幽门螺杆菌可能会降低癌症死亡人数。H.幽门螺杆菌感染仅在一部分感染个体中发展为疾病。一个关键的变量是菌株驱动炎症的能力。我们研究的长期目标是建立准确的诊断方法，以确定哪些H。pylori菌株会引起麻烦。H.幽门螺杆菌菌株是高度可变的，这一特点提供了一个可能的入口-和基础-诊断测试。我们最近的工作已经确定了一种新的抗炎H。pylori毒力因子，我们将其命名为免疫调节自转运蛋白A（immunomodulatory autotransporter A，ImaA）。初步数据表明，H.缺乏imaA的幽门螺杆菌会触发哺乳动物细胞产生大量炎症相关的mRNA和蛋白质。ImaA通过已知的H起作用。pylori促炎装置，cag PAI，并且是促炎蛋白CagA持续磷酸化所需的。这项工作的具体目标是确定ImaA对炎症作用的分子基础，其对H。幽门螺杆菌疾病，以及它是否可以作为生物标志物 重度H. pylori人类感染。我们的中心假设是，ImaA的作用是操纵宿主的促炎蛋白CagA的磷酸化，而ImaA的缺失会产生H。幽门螺杆菌导致沙鼠和人类特别严重的疾病。在第一个目标中，我们将确定H。pylori ImaA减少cag PAI依赖性促炎基因表达。在第二个目标中，我们将通过分析imaA的缺失如何影响相关动物模型中的疾病，并通过测试imaA的存在是否与一组H. pylori人临床菌株。这项研究具有重要意义，因为它将使我们更好地了解H. pylori来控制炎症，并给我们提供了另一种工具来探测特定的H。pylori菌株的致病潜力。本研究的创新之处在于所要检验的假设：H。幽门螺杆菌产生抗炎蛋白和促炎蛋白。最终，拟议的工作将告诉我们一种新型的毒力因子是如何发挥作用的，以及它将如何作为疾病生物标志物，并提高我们预防溃疡和胃癌的能力。