H. pylori-induced Inflammation and Gastric Cancer

总体总结 胃腺癌是世界上癌症相关死亡的第三大原因。幽门螺杆菌是 这种恶性肿瘤的最强已知危险因素，但只有一小部分殖民者曾患上这种恶性肿瘤 瘤形成。与胃癌风险增加相关的幽门螺杆菌决定因素之一是 cag 致病性 岛，以及几个 cag 基因编码 IV 型分泌系统 (T4SS) 的组件，该系统输出 细菌癌蛋白 CagA 进入宿主细胞。我们的小组已经证明幽门螺杆菌 cag 选择性菌株 激活 β-catenin 和 Lrig1 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子。我们发现 通过脱氧亚精胺合成酶 (DHPS) 从多胺亚精胺形成一种新的氨基酸，亚精胺 被幽门螺杆菌上调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。我们还证明了与胃病相关的环境因素 癌症，例如缺铁或高盐饮食，会增强幽门螺杆菌通过以下方式诱发胃癌的能力： 笼T4SS。因此，本申请的首要目标是描绘分子信号传导 由幽门螺杆菌与宿主细胞接触引发的事件，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与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、致癌作用、胃肠病学等领域的研究， 和微生物学，并将产生通过独立调查无法获得的结果。的 组成项目由离散的假设驱动，但又具有凝聚力，因为每个项目都关注幽门螺杆菌宿主 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导的胃癌发生的影响 (PI-Richard Peek)。 项目 2. 幽门螺杆菌诱导的胃癌中的 EGFR、ODC 和海泡体（PI-Keith T. Wilson）。 项目 3. 通过影响胃癌的饮食因素调节幽门螺杆菌毒力 (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进一步统一， 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）以及 行政核心（核心 C）。通过保持对发生在的基本相互作用的扎根关注 H. pylori：宿主接口，该提案的结果不仅将提高我们对胃癌的认识，而且 还将确定预防和更有效治疗这种疾病的潜在治疗靶点。

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.