Pathogenesis of Helicobacter pylori infection

幽门螺杆菌感染的发病机制

• 批准号: 8397541
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397541
• 关键词: Acids; Animal Model; Bacteria; Bacterial Adhesins; Bacterial Proteins; Cancer Etiology; Caring; Cells; Cessation of life; Clinical; Communicable Diseases; Data; Development; Disease; Distal; Employee Strikes; Epithelial Cells; Exhibits; Gastric Adenocarcinoma; Gastric lymphoma; Gastric mucosa; Gastric ulcer; Gastritis; Genes; Genetic Transcription; Genome; Goals; Gram-Negative Bacteria; Helicobacter Infections; Helicobacter pylori; Human; Immunologics; In Vitro; Infection; Injury; Investigation; Laboratories; Lead; Membrane; Methods; Molecular; Pathogenesis; Pathway interactions; Peptic Ulcer; Persons; Pharmaceutical Preparations; Population; Prevention; Prevention strategy; Production; Property; Proteins; Proteolytic Processing; Proteome; Proteomics; Regimen; Research; Risk; Role; Signal Transduction; Stomach; Stomach Diseases; Surface; T-Lymphocyte; Toxin; Travel; Ulcer; United States; United States Department of Veterans Affairs; Veterans; Virulence Factors; Work; cancer risk; gastric cancer prevention; high risk; in vivo; malignant stomach neoplasm; mutant; novel strategies; paralogous gene; prevent; protein expression; secretion process

DESCRIPTION (provided by applicant): ABSTRACT 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 and peptic ulcer disease. In previous studies, we have conducted detailed analyses of a secreted H. pylori toxin (VacA). The H. pylori genome contains three genes that are distantly related to vacA, and each encodes a protein >250 kDa in size. Similar to VacA, these VacA paralogs are predicted to be secreted by a type V (autotransporter pathway). In contrast to VacA, which has been studied in great detail, thus far there has been very little study of H. pylori VacA paralogs. Hypotheses: The hypotheses of this proposal are as follows: (i) VacA paralogs have important functions in vivo; (ii) the expression of VacA paralogs is transcriptionally regulated; (iii) VacA paralogs are secreted by an autotransporter pathway; and (iv) VacA paralogs modulate interactions of H. pylori with host cells. Study Objectives: The long-term goals of this work are to understand the molecular mechanisms that allow H. pylori to colonize and persist in the human gastric mucosa, to understand the molecular mechanisms by which H. pylori infection leads to the development of gastric cancer or peptic ulcer disease, and to develop effective strategies for the prevention of gastric cancer and peptic ulcer disease. The specific objectives are (i) to analyze VacA paralogs in animal models of H. pylori-induced gastric disease; (ii) to analyze the transcription of H. pylori vacA paralogs; and (iii) to analyze the secretion and functional activities of VacA paralogs. Methods: To investigate the role of VacA paralogs in vivo, we will construct isogenic H. pylori mutant strains. We will then compare the ability of wild-type and mutant strains to colonize the stomach in animal models of H. pylori infection, and we will determine whether these H. pylori proteins modulate the development of gastric inflammation, gastric injury or gastric cancer. We will analyze the transcription of genes encoding VacA paralogs both in vivo and in vitro, and we will elucidate the mechanisms by which the transcription of these genes is regulated. Finally, we will use a combination of proteomic and immunologic methods to analyze the secretion and proteolytic processing of VacA paralogs, and we will compare the interactions of wild-type and mutant strains with cultured gastric epithelial cells.

描述（由申请人提供）： 抽象的幽门螺杆菌是一种革兰氏阴性细菌，可在人类的胃中定位。幽门螺杆菌感染与远端胃癌和消化性溃疡癌的风险增加有关。在先前的研究中，我们对分泌的幽门螺杆菌毒素（VACA）进行了详细的分析。幽门螺杆菌基因组包含三个与VACA相关的基因，每个基因的大小> 250 kDa。与VACA相似，这些VACA旁系同源物被预测由V型（自动转移途径）分泌。与VACA进行了鲜明的研究相反，该研究已经进行了详细的研究，到目前为止，对幽门螺杆菌胶囊旁系同源物的研究很少。假设：该提议的假设如下：（i）VACA旁系同源物在体内具有重要功能； （ii）VACA旁系同源物的表达受到转录调节； （iii）VACA旁系同源物由自动转移途径分泌； （iv）VACA旁系同源物调节幽门螺杆菌与宿主细胞的相互作用。研究目标：这项工作的长期目标是了解使幽门螺杆菌在人类胃粘膜中定植并持续存在的分子机制，以了解幽门螺杆菌感染的分子机制，从而导致胃癌或消毒性乌尔塞氏病的发展，并发展有效的策略，并制定了疾病的有效策略。特定目标是（i）分析幽门螺杆菌诱导的胃病动物模型中的VACA旁系同源物； （ii）分析幽门螺杆菌的转录； （iii）分析VACA旁系同源物的分泌和功能活性。方法：为了研究VACA旁系同源物在体内的作用，我们将构建等源性幽门螺杆菌菌株。然后，我们将比较野生型和突变菌株在幽门螺杆菌感染的动物模型中定居胃的能力，我们将确定这些幽门螺杆菌蛋白是否调节胃炎，胃损伤或胃癌的发展。我们将分析在体内和体外编码VACA旁系同源物的基因的转录，我们将阐明调节这些基因转录的机制。最后，我们将使用蛋白质组学和免疫学方法的组合来分析VACA旁系同源物的分泌和蛋白水解处理，并将比较野生型和突变株与培养的胃皮细胞的相互作用。