H. Pylori-Induced Inflammation and Gastric Cancer

描述(申请人提供)：胃腺癌是世界上第二大癌症相关死亡原因，幽门螺杆菌是这种恶性肿瘤的最大危险因素，但只有一小部分移居者曾患上肿瘤。幽门螺杆菌与胃癌相关的一个决定因素是CAG致病岛，几个CAG基因编码IV型分泌系统的组件，该系统将细菌蛋白如CagA输出到宿主上皮细胞。我们的团队现在已经证明，幽门螺杆菌CAG+菌株选择性地激活胃上皮细胞中影响癌变的宿主效应因子？-连环蛋白和表皮生长因子受体(EGFR)。我们还证明了与胃癌相关的环境因素SALT增强了幽门螺杆菌CAG+菌株诱导异常上皮反应的能力。因此，本申请的首要目标是描述由幽门螺杆菌引发的分子信号事件：调节与胃癌发生相关的表型的上皮细胞接触。这个PPG将整合由生物医学研究人员发起的宿主-病原体相互作用的研究，这些研究人员坚定而明确地致力于胃肠病学、癌症生物学、癌症发生和微生物学领域的研究，并将产生通过独立研究无法获得的结果。这些组成部分的项目由离散的假设驱动，但都是有凝聚力的，因为每个项目都专注于幽门螺杆菌：上皮细胞的相互作用，诱导具有致癌潜力的细胞反应。个别项目包括： 项目1.调节幽门螺杆菌诱导的？-连环蛋白激活的机制(PI-Richard Peek)。 项目2.幽门螺杆菌诱导的胃癌中EGFR的激活(PI-Brent Polk)。 项目3.幽门螺杆菌CAG致病岛与胃癌发生(PI-Timothy封面)。 每个项目的努力将通过与特定核心设施的动态互动进一步统一，这些核心设施包括胃组织病理学核心(核心A)、蛋白质组学核心(核心B)和行政核心(核心C)。通过将重点放在幽门螺杆菌：上皮界面上发生的基本相互作用上，这项提议的结果不仅将提高我们对胃癌的理解，还将有助于确定预防和更有效治疗这种疾病的潜在治疗靶点。

DESCRIPTION (provided by applicant): Gastric adenocarcinoma is the second leading cause of cancer-related death in the world, and Helicobacter pylori is the strongest identified risk factor for this malignancy, yet only a fraction of colonized persons ever develop neoplasia. One H. pylori determinant associated with gastric cancer is the cag pathogenicity island, and several cag genes encode components of a type IV secretion system which exports bacterial proteins such as CagA into host epithelial cells. Our group has now demonstrated that H. pylori cag+ strains selectively activate ?-catenin and the EGF receptor (EGFR), host effectors that influence carcinogenesis, in gastric epithelial cells. We have also demonstrated that an environmental factor associated with gastric cancer, salt, augments the ability of H. pylori cag+ strains to induce aberrant epithelial responses. Therefore, the overarching objective of this Application is delineation of the molecular signaling events initiated by H. pylori:epithelial cell contact that regulate phenotypes related to gastric carcinogenesis. This PPG will integrate studies of host-pathogen interactions initiated by biomedical researchers who have made a strong and clear commitment to research within the fields of gastroenterology, cancer biology, carcinogenesis, and microbiology, and will generate results that would not be attainable through independent investigation. The component Projects are driven by discrete hypotheses, yet are cohesive in that each focuses on H. pylori:epithelial interactions that induce cellular responses with carcinogenic potential. The individual projects include: Project 1. Mechanisms that regulate Helicobacter pylori-induced ?-catenin activation (PI-Richard Peek). Project 2. EGFR activation in H. pylori-induced gastric cancer (PI-Brent Polk). Project 3. Helicobacter pylori cag pathogenicity island and gastric carcinogenesis (PI-Timothy Cover). The efforts of each Project will be further unified by dynamic interactions with Specific Core facilities, which include the Gastric Histopathology Core (Core A), the Proteomics Core (Core B), and an Administrative Core (Core C). By maintaining a grounded focus on fundamental interactions that occur at the H. pylori:epithelial interface, results from this proposal will not only improve our understanding of gastric cancer, but will also facilitate identification of potential therapeutic targets for prevention and more effective treatment of this disease.