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）：胃腺癌是世界上与癌症相关死亡的第二大主要原因。胃癌发展的最强危险因素是细菌病原体幽门螺杆菌引起的慢性炎症。幽门螺杆菌对胃上皮的遵守是建立该细菌在胃粘膜内的持久性和存活的关键步骤。幽门螺杆菌基因组的序列分析揭示了大量预测的外膜蛋白，其中许多蛋白已被鉴定为粘附素，对幽门螺杆菌的发病机理很重要。这种大的粘附素曲目可能通过促进病理学微生物宿主相互作用来影响幽门螺杆菌的毒力。衰减加速因子（DAF）或CD55是一种蛋白质，可保护细胞免受补体介导的裂解，并且也被许多微生物病原体识别为受体。我们的实验室最近将DAF鉴定为一种新型受体，该受体介导了幽门螺杆菌宿主上皮细胞的依从性。在幽门螺杆菌存在下，DAF显着上调，并在胃癌的鼠模型中导致幽门螺杆菌介导的胃炎。幽门螺杆菌介导的胃部炎症取决于DAF的存在，因为与野生型小鼠相比，DAF缺陷小鼠没有炎症。我们实验室中最近的体外工作显示，与重组DAF相互作用的幽门螺杆菌候选蛋白数量有限。我们假设DAF介导的幽门螺杆菌对胃上皮的粘附取决于这些微生物蛋白，并且这些相互作用激活了与胃炎向胃腺癌发展有关的宿主细胞信号通路。因此，该应用的具体目的是（1）定义DAF介导的遵守胃皮细胞所需的幽门螺杆菌成分； （2）鉴定DAF介导的幽门螺杆菌诱导的宿主细胞改变和紧密的连接破坏；最后（3）确定DAF和DAF结合粘合剂在幽门螺杆菌炎症，胃损伤和体内胃癌的发展中的作用。该赠款应用的总体目的是进一步阐明幽门螺杆菌与宿主细胞之间的复杂相互作用，从而导致胃癌进展，最终目的是鉴定新的细菌和/或宿主靶标，用于预防和/或幽门螺杆菌介导的癌症的癌变。 公共卫生相关性：胃癌最强的危险因素是细菌病原体幽门螺杆菌的定殖。初步研究表明，宿主蛋白衰减加速因子（DAF）在幽门螺杆菌定植和慢性炎症中的重要性。因此，这些研究将定义幽门螺杆菌因DAF介导的定殖至关重要的因子，并描述了这种相互作用在幽门螺杆菌诱导的致癌作用中的重要性。