H. pylori-induced Inflammation and Gastric Cancer

总体汇总 胃腺癌是世界上第三大癌症相关死亡原因。幽门螺杆菌是 这种恶性肿瘤的最强确定的风险因素，但只有一个子集的殖民者曾经发展 肿瘤形成一个H pylori决定因素与胃癌风险增加相关的是cag致病性 岛，和几个cag基因编码IV型分泌系统（T4 SS）的组分，该系统输出一种 细菌癌蛋白CagA进入宿主细胞。本课题组证明了H. pylori cag+菌株选择性 激活β-连环蛋白和Lrig 1标记的干细胞群，以及EGF受体和鸟氨酸 脱羧酶（ODC），影响致癌作用的宿主效应物。我们发现 通过脱氧羟腐胺赖氨酸合酶（DHPS）从多胺亚精胺形成新的氨基酸羟腐胺赖氨酸 被H.幽门螺杆菌并导致编码促炎蛋白的mRNA的靶向翻译， 特别是在巨噬细胞中。我们还证明了与胃溃疡相关的环境因素， 癌症，如缺铁或高盐饮食，增强了H。幽门螺杆菌诱发胃癌 CAG T4SS因此，本申请的首要目标是描绘分子信号传导 由H发起的事件。幽门-宿主细胞接触调节胃癌发生相关表型。这 PPG将整合生物医学研究人员发起的宿主-病原体相互作用的研究，这些研究人员已经做出了一项 对癌症生物学，致癌作用，胃肠病学， 和微生物学，并将产生无法通过独立调查获得的结果。的 组成项目是由离散的假设驱动的，但由于每个项目都关注H，因此是有凝聚力的。幽门宿主 诱导具有致癌潜力的细胞反应的相互作用： 项目1。铁剥夺对H.幽门诱导的胃癌发生（PI-Richard Peek）。 项目2. EGFR、ODC和H. pylori诱导的胃癌（PI-Keith T.威尔逊）。 项目3。调节H.幽门螺杆菌毒力的饮食因素，影响胃癌（PI-蒂莫西盖。 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， 包括胃组织学核心（核心A）、蛋白质组学和代谢组学核心（核心B）和 核心C（Core C）。通过保持对发生在世界各地的基本相互作用的关注， H. pylori：宿主界面，该提案的结果不仅将提高我们对胃癌的认识， 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。

Overall Summary Gastric adenocarcinoma is the third leading cause of cancer-related death in the world. Helicobacter pylori is the strongest identified risk factor for this malignancy, yet only a subset 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 (T4SS) which exports a bacterial oncoprotein, CagA, into host cells. Our group has demonstrated that H. pylori cag+ strains selectively activate β-catenin and a stem cell population marked by Lrig1, as well as the EGF receptor and ornithine decarboxylase (ODC), host effectors that influence carcinogenesis. We have made the discovery that formation of a novel amino acid, hypusine, from the polyamine spermidine by deoxyhypusine synthase (DHPS) is upregulated by H. pylori and leads to targeted translation of mRNAs encoding for pro-inflammatory proteins, specifically in macrophages. We have also demonstrated that environmental factors associated with gastric cancer, such as iron deficiency or a high salt diet, augment the ability of H. pylori to induce gastric cancer via the cag T4SS. Therefore, the overarching objective of this application is delineation of the molecular signaling events initiated by H. pylori-host 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 cancer biology, carcinogenesis, gastroenterology, 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-host interactions that induce cellular responses with carcinogenic potential: Project 1. Effect of iron deprivation on H. pylori-induced gastric carcinogenesis (PI-Richard Peek). Project 2. EGFR, ODC and the hypusome 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 and Metabolomics Core (Core B), and an Administrative Core (Core C). By maintaining a grounded focus on fundamental interactions that occur at the H. pylori:host interface, results from this proposal will not only improve our understanding of gastric cancer, but will also identify potential therapeutic targets for prevention and more effective treatment of this disease.