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明显的危险因素，但只有一小部分人会发展成肿瘤。一个与胃癌风险增加相关的幽门螺杆菌决定因素是cag致病性岛，一些cag基因编码IV型分泌系统的成分，该系统将细菌蛋白（如CagA）输出到宿主上皮细胞。我们的研究小组现在已经证明，幽门螺杆菌cag+菌株选择性地激活了胃上皮细胞中影响癌变的宿主效应物ß-catenin、EGF受体（EGFR）和精胺氧化酶（SMO）。我们还证明了与胃癌相关的环境因素，如缺铁和盐，增强了幽门螺杆菌cag+菌株诱导胃癌的能力。因此，本申请的首要目标是描述幽门螺杆菌启动的分子信号事件：上皮细胞接触，调节与胃癌发生相关的表型。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，这些研究人员在胃肠病学、癌症生物学、致癌作用和微生物学领域做出了坚定而明确的研究承诺，并将产生无法通过独立调查获得的结果。这些组成部分的项目是由离散的假设驱动的，但它们是有凝聚力的，因为每个项目都关注幽门螺杆菌：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：

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.