Role of adhesin-receptor interaction in H. pylori-induced gastric 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幽门螺杆菌引起的慢性炎症。幽门螺杆菌粘附于胃上皮是建立持久性和允许这种细菌在胃粘膜内存活的关键步骤。幽门螺杆菌基因组序列分析揭示了大量预测的外膜蛋白，其中许多已被鉴定为黏附蛋白，在幽门螺杆菌的发病机制中起重要作用。大量的粘附素可能通过促进病理性微生物与宿主细胞的相互作用来影响幽门螺杆菌的毒力。腐烂加速因子（DAF）或CD55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。我们的实验室最近发现DAF是一种介导幽门螺杆菌粘附宿主上皮细胞的新型受体。在幽门螺杆菌存在时，DAF显著上调，并在胃癌小鼠模型中参与幽门螺杆菌介导的胃炎症。幽门螺杆菌介导的胃炎症依赖于DAF的存在，因为DAF缺乏的小鼠与野生型小鼠相比没有炎症。最近在我们实验室的体外研究中发现了有限数量的幽门螺杆菌候选蛋白与重组DAF相互作用。我们假设daf介导的幽门螺杆菌对胃上皮的粘附依赖于这些微生物蛋白，并且这些相互作用激活了参与胃炎向胃腺癌进展的宿主细胞信号通路。因此，本应用的具体目的是：(1)确定daf介导的胃上皮细胞粘附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连接破坏；最后(3)在体内确定DAF及DAF结合粘连素在幽门螺杆菌介导的炎症、胃损伤及胃癌发生中的作用。本资助申请的总体目标是进一步阐明幽门螺杆菌与宿主细胞之间导致胃癌进展的复杂相互作用，最终目标是确定新的细菌和/或宿主靶点，以预防和/或治疗幽门螺杆菌介导的癌变。

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.