H. pylori-induced Inflammation and Gastric Cancer

总体摘要 胃腺癌是世界上第三大癌症相关死亡原因。幽门螺杆菌是 这种恶性疾病的最强危险因素，但只有一小部分被殖民的人会发病。 肿瘤。幽门螺杆菌与胃癌风险增加相关的一个决定因素是CAG致病性 几个CAG基因编码IV型分泌系统(T4SS)的组成部分，T4SS输出一种 细菌癌蛋白CagA进入宿主细胞。我们的研究小组已经证明，幽门螺杆菌CAG菌株具有选择性 激活β-连环蛋白和以Lrig1标记的干细胞群，以及表皮生长因子受体和鸟氨酸 脱羧酶(ODC)，影响癌症发生的宿主效应因子。我们已经发现 脱氧亚精氨酸合成酶(DHPS)催化多胺亚精胺合成新型氨基酸--苏氨酸 被幽门螺杆菌上调，并导致编码促炎蛋白的mRNAs的靶向翻译， 尤其是巨噬细胞。我们还证明了与胃相关的环境因素 癌症，如缺铁或高盐饮食，会增强幽门螺杆菌通过以下途径诱发胃癌的能力 CAG T4SS。因此，这一应用的首要目标是描绘分子信号 幽门螺杆菌-宿主细胞接触引发的调节与胃癌发生相关的表型的事件。这 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，这些研究人员已经做出了 坚定而明确地致力于癌症生物学、癌症发生、胃肠病学、 和微生物学，并将产生通过独立调查无法获得的结果。这个 组件项目由离散的假设驱动，但每个组件项目都集中在幽门螺杆菌宿主上，因此具有凝聚力 诱导具有致癌潜力的细胞反应的相互作用： 项目1.缺铁对幽门螺杆菌诱发的胃癌的影响(Pi-Richard Peek)。 项目2.幽门螺杆菌诱发的胃癌中的EGFR、ODC和菌体(Pi-Keith T.Wilson)。 项目3：影响胃癌的饮食因素对幽门螺杆菌毒力的调节(PI-Timothy封面)。 每个项目的努力将通过与特定核心设施的动态交互进一步统一，这些核心设施 包括胃组织病理学核心(核心A)、蛋白质组学和代谢组学核心(核心B)和 管理核心(核心C)。通过保持对发生在 幽门螺杆菌：宿主接口，这一提议的结果不仅将提高我们对胃癌的理解，而且 还将确定预防和更有效治疗这种疾病的潜在治疗目标。

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.