Pathogenesis of Helicobacter pylori infection

幽门螺杆菌感染的发病机制

• 批准号: 10250299
• 负责人: TIMOTHY L COVER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250299
• 关键词: Acids; Adherence; Bacteria; Bacterial Adhesins; Bacterial Proteins; Bar Codes; Cancer Etiology; Carcinogens; Caring; Cells; Cessation of life; Clinical; Development; Disease; Distal; Duodenal Ulcer; Epithelial Cells; Family; Gastric Adenocarcinoma; Gastric lymphoma; Gastric mucosa; Gastric ulcer; Genes; Genome; Goals; Gram-Negative Bacteria; Helicobacter Infections; Helicobacter pylori; High-Throughput Nucleotide Sequencing; Human; Individual; Infection; Inflammatory Response; Investigation; Label; Lead; Libraries; Mediating; Membrane Proteins; Methods; Molecular; Mus; Mutagenesis; Mutation; Nucleotides; Pathogenesis; Peptic Ulcer; Persons; Pharmaceutical Preparations; Population; Prevention approach; Prevention strategy; Process; Proteins; Regimen; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Signal Transduction; Stomach; Stomach Diseases; Surface; System; Travel; United States; United States Department of Veterans Affairs; Veterans; Work; World Health Organization; cancer risk; disorder prevention; experimental study; high risk; in vivo; insight; malignant stomach neoplasm; member; mutant; novel strategies; prevent; promoter; transcriptome; transcriptome sequencing

Helicobacter pylori is a Gram-negative bacterium that colonizes the human stomach. H. pylori infection is associated with an increased risk of cancer of the distal stomach, as well as peptic ulcer disease. The World Health Organization has classified H. pylori as a type I carcinogen, and gastric cancer is the third leading cause of cancer-related death worldwide. The long-term goals of this work are to understand the molecular mechanisms that allow H. pylori to persistently colonize the human gastric mucosa, to understand the molecular mechanisms by which H. pylori infection leads to the development of gastric cancer or peptic ulceration, and to develop effective strategies for the prevention of these diseases. To achieve these long-term goals, we seek to understand the actions of bacterial proteins that are localized on the surface of H. pylori. H. pylori genomes contain more than 50 genes that are predicted to encode outer membrane proteins (OMPs). Several OMPs have been reported to mediate H. pylori adherence to gastric epithelial cells, but the functions of most H. pylori OMPs are not known. The overall hypothesis of this proposal is that H. pylori utilizes specific OMPs at various stages of the infectious process to optimize initial colonization of the stomach and to facilitate persistent colonization in the presence of a gastric mucosal inflammatory response, thereby contributing to the development of gastric disease. The specific aims are (i) To define the role of two- component signal transduction systems (TCSs) in regulating genes encoding OMPs, (ii) To define OMPs that have a dominant role in promoting H. pylori colonization of the stomach, and (iii) To define temporal features of processes by which specific OMPs promote H. pylori colonization of the stomach and modulate development of gastric disease. To accomplish Aim 1, we will compare the transcriptomes of wild-type and mutant strains, using RNA-seq and quantitative RT-PCR methods. To accomplish Aim 2, we will infect mice with a library of strains containing mutations in OMP-encoding proteins, each labeled with a distinct nucleotide bar code, and then will use high throughput sequencing to analyze the bacterial populations colonizing the stomach. To accomplish Aim 3, we will regulate the expression of selected OMP-encoding genes in vivo through use of an inducible promoter. Collectively, these experiments will provide important new insights into the roles of specific OMPs in promoting initial colonization of the stomach, persistence and disease.

幽门螺杆菌是一种革兰氏阴性细菌，可在人类胃中定位。幽门螺杆菌感染是 与远端癌症的风险增加以及消化性溃疡疾病有关。世界 卫生组织将幽门螺杆菌归类为I型致癌物，胃癌是第三大领先 全球与癌症有关的死亡原因。这项工作的长期目标是了解分子 允许幽门螺杆菌持续定植人类胃粘膜的机制，可以理解 幽门螺杆菌感染导致胃癌或消化性发展的分子机制 溃疡，并制定有效的策略来预防这些疾病。实现这些长期 目标，我们试图了解细菌蛋白的作用，该蛋白质位于幽门螺杆菌表面。 H. 幽门螺杆菌基因组包含50多个基因，这些基因被预测编码外膜蛋白（OMP）。 据报道，几种OMP介导了幽门螺杆菌对胃皮细胞的粘附，但是这些功能 在大多数幽门螺杆菌中，尚不清楚。该提议的总体假设是幽门螺杆菌使用 在感染过程的各个阶段的特定OMP，以优化胃的初始定植和到 在存在胃粘膜炎症反应的情况下促进持续定殖，从而 有助于胃病的发展。具体目的是（i）定义两个 - 组件信号转导系统（TCSS）在调节编码OMPS的基因中，（ii）定义opps 在促进胃幽门螺杆菌定植和（iii）方面具有主要作用，以定义 特定OMP促进幽门螺杆菌定植并调节发育的过程 胃病。为了完成目标1，我们将比较野生型和突变菌株的转录组， 使用RNA-seq和定量RT-PCR方法。为了完成目标2，我们将用一个图书馆感染小鼠 在编码蛋白中含有突变的菌株，每种都标有不同的核苷酸条形码，并且 然后，将使用高通量测序分析细菌群体定植的胃。到 完成目标3，我们将通过使用一个在体内调节所选的OMP编码基因的表达 诱导启动子。总的来说，这些实验将为特定的角色提供重要的新见解 在促进胃，持久性和疾病的初始定植方面。