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Pathogenesis of Helicobacter pylori infection

幽门螺杆菌感染的发病机制

基本信息

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
项目类别：
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

项目摘要

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，在人的胃中定植。幽门螺杆菌感染是