H. pylori-induced Inflammation and Gastric Cancer

幽门螺杆菌引起的炎症和胃癌

• 批准号: 10352426
• 负责人: RICHARD M. PEEK
• 金额: $ 132.08万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352426
• 关键词: Academic Medical Centers; Address; Affect; Amino Acids; Animals; Attenuated; Basic Science; Bioinformatics; Biological Models; Cancer Biology; Cancer Burden; Cancer Center; Cancer Etiology; Cells; Cessation of life; Clinical; Core Facility; DL-alpha-Difluoromethylornithine; Development; Diet; Dietary Factors; Disease; Environmental Exposure; Environmental Risk Factor; Epidermal Growth Factor Receptor; Epithelial; Etiology; Evaluation; Event; Financial Support; Funding; Funding Mechanisms; Gastric Adenocarcinoma; Gastroenterology; Genes; Genetic Translation; Genetic Variation; Genomics; Goals; Helicobacter Infections; Helicobacter Pylori-Related Malignant Neoplasm; Helicobacter pylori; Helicobacter pylori induced gastric cancer; Histopathology; Human; Human Genome; Immune response; Incidence; Individual; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Injury; Institutional support resources; International; Intervention; Investigation; Investments; Iron; Laboratories; Lesion; Malignant Neoplasms; Microbiology; Modeling; Molecular; Mucositis; Myelogenous; Neoplasms; Oncoproteins; Ornithine Decarboxylase; Pathogenicity; Pathogenicity Island; Pathologic; Patients; Persons; Phenotype; Polyamines; Population; Prevention; Proteins; Proteomics; Reagent; Regulation; Research; Research Activity; Research Personnel; Resources; Risk; Risk Factors; Rodent Model; Science; Services; Signal Pathway; Signal Transduction; Spermidine; Stomach; Technology; Transgenic Mice; Translating; Translations; Type IV Secretion System Pathway; United States; Virulence; Vision; Work; anticancer research; beta catenin; cancer risk; carcinogenesis; carcinogenicity; cohesion; cohort; deoxyhypusine synthase; deprivation; dietary; disorder risk; effective therapy; gastric cancer prevention; gastric carcinogenesis; high risk population; high salt diet; hypusine; improved; innovation; insight; iron deficiency; macrophage; malignant stomach neoplasm; metabolomics; microbial; microbial genome; microbial host; molecular imaging; mortality; neoplastic; new therapeutic target; novel; novel strategies; pathogen; personalized medicine; premalignant; prevent; programs; recruit; response; square foot; stem cell population; therapeutic target

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.

总结 胃腺癌是世界上与癌症相关死亡的第三大主要原因。幽门螺杆菌是 这种恶性肿瘤的强烈确定的危险因素，但只有殖民者有史以来发展的一部分 肿瘤。 CAG致病性是一只与胃癌风险增加有关的幽门螺杆菌。 岛和几个CAG基因编码IV型分泌系统（T4SS）的组件，该组件出口 细菌癌蛋白CAGA进入宿主细胞。我们的小组证明了幽门螺杆菌CAG+菌株 激活以LRIG1为标志的β-catenin和一个干细胞群，以及EGF受体和鸟氨酸 脱羧酶（ODC），会影响致癌作用的宿主作用。我们发现了 通过脱氧蛋白合酶（DHP）从多胺精子中形成新型氨基酸，脱糖苷 由幽门螺杆菌更新，并导致对促炎蛋白编码的mRNA的靶向翻译， 我们还证明了与胃有关的环境因素 癌症，例如铁缺乏症或高盐饮食，增强了幽门螺杆菌通过 CAG T4SS。因此，此应用的总体目标是描述分子信号 由幽门螺杆菌 - 宿主宿主细胞接触引发的事件，调节与胃癌发生有关的表型。这 PPG将整合有关生物医学研究人员发起的宿主 - 病原体相互作用的研究，这些研究人员已经制作了 在癌症生物学，癌变，胃肠病学领域进行研究的坚定而明确的承诺， 和微生物学，并将产生通过独立研究无法实现的结果。 组件项目由离散的假设驱动，但具有凝聚力，因为每个假设都集中在幽门螺杆菌宿主上 影响细胞反应具有致癌潜力的相互作用： 项目1。铁剥夺对幽门螺杆菌诱导的胃癌发生（PI-Richard PEEK）的影响。 项目2。EGFR，ODC和幽门螺杆菌诱导的胃癌（Pi-Keith T. Wilson）中的弱点。 项目3。通过影响胃癌（PI-Timothy覆盖）的饮食因素来调节幽门螺杆菌病毒。 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）和A 行政核心（核心C）。通过保持对发生在基本互动的基本相互作用的关注 幽门螺杆菌：宿主界面，该提案的结果不仅会改善我们对胃癌的理解，还会提高我们的理解 还将确定预防预防和对该疾病更有效治疗的潜在治疗靶标。