Role of adhesin-receptor interaction in H. pylori-induced gastric carcinogenesis

粘附素-受体相互作用在幽门螺杆菌诱导的胃癌发生中的作用

• 批准号: 8194014
• 负责人: Jennifer McMillan Noto
• 金额: $ 5.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8194014
• 关键词: Address; Adenocarcinoma; Adherence; Affect; Applications Grants; Bacteria; Bacterial Adhesins; Binding; CD55 Antigens; Cancer Etiology; Cell Communication; Cells; Cessation of life; Chronic; Complement; Complement Factor H; Complex; Cytolysis; Cytoskeleton; DNA Sequence Rearrangement; Data; Development; Epithelial Cells; Epithelium; Escherichia coli; Event; Exhibits; Gastric Adenocarcinoma; Gastric mucosa; Gastritis; Genome; Goals; Helicobacter Infections; Helicobacter pylori; Immune response; In Vitro; Individual; Infection; Infectious Agent; Inflammation; Inflammatory Response; Injury; Intercellular Junctions; Laboratories; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane Proteins; Modeling; Mus; Pathogenesis; Pathologic; Pathway interactions; Persons; Play; Population; Prevention; Proteins; Receptor Cell; Recombinants; Risk Factors; Role; Sequence Analysis; Signal Pathway; Signal Transduction; Stomach; Tight Junctions; Viral; Virulence; Wild Type Mouse; Work; carcinogenesis; in vivo; in vivo Model; malignant stomach neoplasm; microbial; microbial host; novel; pathogen; public health relevance; receptor; response

DESCRIPTION (provided by applicant): Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. The strongest risk factor for the development of gastric cancer is chronic inflammation induced by the bacterial pathogen Helicobacter pylori. Adherence of H. pylori to gastric epithelium is a critical step for establishing persistence and permitting survival of this bacterium within the gastric mucosa. Sequence analysis of H. pylori genomes has revealed a large number of predicted outer membrane proteins, many of which have been identified as adhesins, important in H. pylori pathogenesis. This large repertoire of adhesins likely influences virulence of H. pylori by promoting pathologic microbial-host cell interactions. Decay-accelerating factor (DAF) or CD55 is a protein that protects cells from complement-mediated lysis and is also recognized as a receptor by a number of microbial pathogens. DAF was recently identified by our laboratory as a novel receptor that mediates adherence of H. pylori to host epithelial cells. DAF is significantly upregulated in the presence of H. pylori and contributes to H. pylori-mediated gastric inflammation in murine models of gastric cancer. H. pylori-mediated gastric inflammation is dependent on the presence of DAF, as DAF-deficient mice exhibited no inflammation compared with wild-type mice. Recent in vitro work in our lab has revealed a limited number of H. pylori candidate proteins that interact with recombinant DAF. We hypothesize that DAF-mediated adherence of H. pylori to the gastric epithelium is dependent on these microbial proteins and that these interactions activate host cell signaling pathways that are involved in the progression of gastritis to gastric adenocarcinoma. Therefore, the Specific Aims of this application are (1) to define H. pylori constituents required for DAF-mediated adherence to gastric epithelial cells; (2) to identify DAF-mediated H. pylori-induced host cell alterations and tight junction disruption; and finally (3) to determine the role of DAF and DAF-binding adhesins in H. pylori- mediated inflammation, gastric injury, and development of gastric cancer in vivo. The overall aim of this grant application is to further elucidate the complex interactions between H. pylori and host cells that result in progression toward gastric cancer, with the ultimate goal of identifying novel bacterial and/or host targets for prevention and/or therapy of H. pylori-mediated carcinogenesis. PUBLIC HEALTH RELEVANCE: The strongest known risk factor for gastric cancer is colonization by the bacterial pathogen Helicobacter pylori. Preliminary studies have demonstrated the importance of a host protein Decay-accelerating factor (DAF) in H. pylori colonization and chronic inflammation. Therefore, these studies will define H. pylori factors critical for DAF-mediated colonization and delineate the importance of this interaction in H. pylori-induced carcinogenesis.

描述（由申请人提供）：胃腺癌是世界上第二大癌症相关死亡原因。胃癌发生的最大危险因素是由细菌病原体幽门螺杆菌引起的慢性炎症。坚持H。将幽门螺杆菌感染到胃上皮是建立持久性并允许该细菌在胃粘膜内存活的关键步骤。序列分析表明，H. pylori基因组揭示了大量预测的外膜蛋白，其中许多已被鉴定为粘附素，在H. pylori发病机制这种大量的粘附素可能影响H. pylori通过促进病理性微生物-宿主细胞相互作用。衰变加速因子（Decay-accelerating factor，CD 55）是一种保护细胞免受补体介导的裂解的蛋白质，也被许多微生物病原体识别为受体。最近，我们实验室鉴定了一种新的受体，介导了H。pylori宿主上皮细胞。在H. pylori感染，并对H.幽门介导的胃癌小鼠模型中的胃炎症。H.幽门介导的胃炎症依赖于DAF的存在，因为与野生型小鼠相比，DAF缺陷小鼠没有表现出炎症。我们实验室最近的体外研究表明，H. pylori候选蛋白与重组pylori相互作用。我们推测DAF介导的H。幽门螺杆菌与胃上皮的相互作用依赖于这些微生物蛋白，并且这些相互作用激活参与胃炎向胃腺癌进展的宿主细胞信号传导途径。因此，本申请的具体目的是（1）定义H。pylori中DAF介导粘附胃上皮细胞所需的组分; pylori诱导的宿主细胞改变和紧密连接破坏;以及最后（3）确定粘附素和DAF结合粘附素在H. pylori介导的炎症、胃损伤和体内胃癌的发展。这项资助申请的总体目标是进一步阐明H.幽门螺杆菌和宿主细胞导致胃癌进展，最终目标是鉴定用于预防和/或治疗幽门螺杆菌的新的细菌和/或宿主靶标。幽门介导的致癌作用 公共卫生相关性：胃癌最强的已知危险因素是细菌病原体幽门螺杆菌的定植。初步研究表明，宿主蛋白衰变加速因子（Decay-accelerating factor，DAF）在H.幽门定植和慢性炎症。因此，这些研究将定义H。pylori因子对DAF介导的定植至关重要，并描述了这种相互作用在H.幽门诱发癌