Pathogenesis of Helicobacter pylori infection

幽门螺杆菌感染的发病机制

• 批准号: 7930158
• 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/7930158
• 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. PUBLIC HEALTH RELEVANCE: Helicobacter pylori infection is common among Veterans, and Veterans are at risk for development of H. pylori-induced diseases such as stomach cancer and peptic ulcers. During travel to various parts of the world, Veterans are at risk for acquiring H. pylori strains that confer a relatively higher risk of gastric cancer compared to strains found in the United States. The Veterans Administration currently spends millions of dollars each year for acid-suppressive drug regimens to prevent H. pylori-induced complications. Investigation of the molecular mechanisms by which H. pylori colonizes the human stomach and causes gastric diseases is likely to lead to the development of new approaches for the prevention and treatment of H. pylori infection, which would have important clinical implications for the care of Veterans.

描述（由申请人提供）： 摘要幽门螺杆菌是一种革兰氏阴性菌，在人体胃内定植。H.幽门螺杆菌感染与远端胃癌和消化性溃疡疾病的风险增加有关。在以前的研究中，我们已经进行了详细的分析分泌H。幽门螺杆菌毒素（VacA）。螺杆pylori基因组包含三个与vacA有较远关系的基因，每个基因编码一个大小>250 kDa的蛋白质。与VacA类似，这些VacA旁系同源物被预测由V型（自身转运途径）分泌。与VacA相比，迄今为止对H. pylori VacA旁系同源物。假设条件：该建议的假设如下：（i）VacA旁系同源物在体内具有重要的功能;（ii）VacA旁系同源物的表达是转录调节的;（iii）VacA旁系同源物通过自转运途径分泌;和（iv）VacA旁系同源物调节H的相互作用。pylori与宿主细胞研究目标：这项工作的长期目标是了解H。pylori在人胃粘膜中的定植和持续存在，以了解H.幽门螺杆菌感染导致胃癌或消化性溃疡病的发展，并制定有效的策略，预防胃癌和消化性溃疡病。具体目标是：（i）在H. pylori诱导的胃病;（ii）分析H. pylori vacA旁系同源物;和（iii）分析VacA旁系同源物的分泌和功能活性。方法：构建VacA同源基因H. pylori突变株。然后，我们将比较野生型和突变株的能力，在动物模型的H。pylori感染，我们将确定这些H.幽门螺杆菌蛋白调节胃炎症、胃损伤或胃癌的发展。我们将在体内和体外分析编码VacA旁系同源物的基因的转录，并阐明这些基因的转录调控机制。最后，我们将结合蛋白质组学和免疫学方法来分析VacA旁系同源物的分泌和蛋白水解加工，并比较野生型和突变株与培养的胃上皮细胞的相互作用。 公共卫生关系： 幽门螺杆菌感染在退伍军人中很常见，退伍军人有发展为幽门螺杆菌的风险。幽门引起的疾病，如胃癌和消化性溃疡。在世界各地旅行期间，退伍军人有感染H的风险。与美国发现的菌株相比，幽门螺杆菌菌株赋予胃癌相对较高的风险。退伍军人管理局目前每年花费数百万美元用于抑酸药物治疗以预防H。幽门引起的并发症探讨了H.幽门螺杆菌在人胃中定植并引起胃疾病可能导致预防和治疗幽门螺杆菌的新方法的开发。幽门螺杆菌感染，这将有重要的临床意义的护理退伍军人。