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）：我们对幽门螺杆菌如何控制宿主炎症以及我们应该筛选哪些幽门螺杆菌基因产物以预测菌株的疾病潜力的理解存在根本性的差距，这种差距的持续存在阻止了我们。设计诊断工具，使我们能够预测哪些幽门螺杆菌感染将发展为疾病，因此，应该优先治疗全世界和美国数以百万计的幽门螺杆菌感染者。幽门螺杆菌及其相关疾病——溃疡和胃癌是全球第二大癌症死亡原因。在美国，幽门螺杆菌发病率较低但稳定，因此罹患胃癌的人数较少。治愈幽门螺杆菌可能会降低幽门螺杆菌感染仅在一部分感染者中发展为疾病的人数，这是我们研究的长期目标。是创建准确的诊断，识别哪些幽门螺杆菌菌株会引起麻烦，幽门螺杆菌菌株是高度可变的，并且此功能提供了一个可能的入口。我们最近的工作确定了一种新型抗炎幽门螺杆菌毒力因子，我们将其命名为免疫调节自转运蛋白 A (ImaA)。我们的初步数据表明，幽门螺杆菌缺乏 imaA 触发因子。哺乳动物细胞产生大量炎症相关 mRNA 和蛋白质，通过已知的幽门螺杆菌促炎装置 cag PAI 发挥作用，并且是幽门螺杆菌持续磷酸化所必需的。这项工作的具体目标是确定 ImaA 对炎症影响的分子基础、它对幽门螺杆菌疾病的贡献以及它是否作为生物标志物。 我们的中心假设是，ImaA 可以操纵宿主促炎蛋白 CagA 的磷酸化，而 imaA 的缺失会产生幽门螺杆菌，从而在沙鼠和人类中引起特别严重的疾病。将确定幽门螺杆菌 ImaA 减少 cag PAI 依赖性促炎基因表达的分子机制。在第二个目标中，我们将探讨抗炎蛋白 ImaA 如何影响疾病。通过分析imaA的缺失如何影响相关动物模型中的疾病，以及测试imaA的存在是否与幽门螺杆菌人类临床菌株组中的炎症和疾病结果相关，这项研究具有重要意义，因为它将为我们提供更好的结果。了解幽门螺杆菌用于控制炎症的蛋白质，并为我们提供了另一种工具来探测特定幽门螺杆菌菌株的疾病潜力。拟议的研究在待测试的假设中具有创新性：幽门螺杆菌产生抗-也有炎症最终，拟议的工作将告诉我们新型毒力因子如何发挥作用，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。