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危险因素，但只有一小部分定植者发生肿瘤。一个H与胃癌风险增加相关的幽门螺杆菌决定簇是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。幽门螺杆菌cag+菌株选择性地激活胃上皮细胞中的β-连环蛋白、EGF受体（EGFR）和精胺氧化酶（SMO），它们是影响癌发生的宿主效应物。我们也证明了与胃癌相关的环境因素，如缺铁和盐，增加了H。pylori cag+菌株诱发胃癌。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。铁和β-连环蛋白激活在胃癌发生中的作用（Pi-Richard Peek）。 项目2. EGFR活化与多胺在H. pylori诱导的胃癌（Pi-Keith T. Wilson）。 项目3。调节H.幽门螺杆菌毒力的饮食因素影响胃癌（Pi-Timothy Cover）。 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，该提案的结果不仅会提高我们对胃癌的认识，而且还将确定潜在的治疗靶点，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. Helicobacter pylori is the strongest identified risk factor fr this malignancy, yet only a fraction of colonized persons ever develop neoplasia. One H. pylori determinant associated with increased gastric cancer risk 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 ß-catenin, the EGF receptor (EGFR), and spermine oxidase (SMO), host effectors that influence carcinogenesis, in gastric epithelial cells. We have also demonstrated that environmental factors associated with gastric cancer, such as iron deficiency and salt, augment the ability of H. pylori cag+ strains to induce gastric cancer. Therefore, the overarching objective of this Application is delineation of the molecular signaling events initiate 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. Role of iron and ß-catenin activation in gastric carcinogenesis (Pi-Richard Peek). Project 2. EGFR activation and polyamines in H. pylori-induced gastric cancer (Pi-Keith T. Wilson). Project 3. Regulation of H. pylori virulence by dietary factors that impact gastric cancer (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 nly improve our understanding of gastric cancer, but will also identify potential therapeutic targets for prevention and more effective treatment of this disease.