H. Pylori-Induced Inflammation and Gastric Cancer

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，幽门螺杆菌是这种恶性肿瘤最强的已确定风险因素，但只有一小部分定植者发生肿瘤。一个H与胃癌相关的pylori决定子是cag致病岛，并且几个cag基因编码IV型分泌系统的组分，该IV型分泌系统将细菌蛋白质如CagA输出到宿主上皮细胞中。我们的小组现在已经证明了H。pylori cag+菌株选择性激活？连环蛋白和表皮生长因子受体（EGFR），影响胃上皮细胞中的致癌作用的宿主效应物。我们还证实了与胃癌相关的环境因素盐增强了H。pylori cag+菌株诱导异常上皮反应。因此，本申请的首要目标是描述由H.幽门：调节胃癌发生相关表型的上皮细胞接触。该PPG将整合生物医学研究人员发起的宿主-病原体相互作用研究，这些研究人员对胃肠病学，癌症生物学，致癌作用和微生物学领域的研究做出了坚定而明确的承诺，并将产生通过独立调查无法实现的结果。项目的组成部分是由离散的假设驱动的，但每个项目都集中在H上。pylori：上皮相互作用，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（PI-Richard Peek）。 项目2. H.幽门螺杆菌诱导的胃癌（PI-Brent Polk）。 项目3。幽门螺杆菌cag致病岛与胃癌发生。 每个项目的努力将通过与特定核心设施的动态互动来进一步统一，这些设施包括胃组织学核心（核心A）、蛋白质组学核心（核心B）和管理核心（核心C）。通过对发生在H. pylori：epithelial interface，结果从这个建议将不仅提高我们对胃癌的理解，但也将有助于识别潜在的治疗靶点，以预防和更有效地治疗这种疾病。

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.