H. pylori-Induced Inflammation and gastric cancer

幽门螺杆菌引起的炎症和胃癌

• 批准号: 8821584
• 负责人: RICHARD M. PEEK
• 金额: $ 137.54万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821584
• 关键词: Academic Medical Centers; Address; Adverse effects; Animal Model; Attenuated; Award; Bacterial Infections; Bacterial Proteins; Basic Science; Bioinformatics; Biological; Biological Models; Cancer Biology; Cancer Etiology; Carcinogens; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Sciences; Clinical and Translational Science Awards; Core Facility; Development; Diet; Dietary Factors; Disease; Environmental Risk Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Esophageal Adenocarcinoma; Etiology; Evaluation; Event; Exposure to; Financial Support; Funding; Funding Mechanisms; Future; Gastric Adenocarcinoma; Gastroenterology; Genes; Genetic Variation; Genomics; Goals; Helicobacter pylori; High Prevalence; Histopathology; Housing; Human; Human Resources; Immune response; Individual; Infection; Infectious Agent; Inflammation; International; Investigation; Iron; Lead; Lesion; Letters; Link; Malignant Neoplasms; Microbiology; Molecular; Neoplasms; Oncogenic; Pathogenicity Island; Persons; Pharmacology; Phenotype; Physiology; Polyamines; Population; Premalignant; Prevention; Proteomics; Reagent; Receptor Activation; Recruitment Activity; Regulation; Research; Research Activity; Research Personnel; Resources; Risk; Risk Factors; Rodent Model; Role; Signal Pathway; Signal Transduction; Sodium Chloride; Stomach; System; Technology; Testing; Translating; Translational Research; Translations; Type IV Secretion System Pathway; Variant; Virulence; Work; World Health Organization; anticancer research; antimicrobial; cancer risk; carcinogenesis; cost; disorder risk; effective therapy; gastric cancer prevention; high risk; human DNA sequencing; human genome sequencing; improved; innovation; insight; iron deficiency; malignant stomach neoplasm; microbial; microbial host; molecular imaging; neoplastic; new therapeutic target; novel; novel strategies; pathogen; personalized medicine; polyamine oxidase; programs; response; square foot; therapeutic target

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 ¿-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 ¿ -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.

描述(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的最强危险因素，然而只有一小部分被殖民的人会发展成肿瘤。幽门螺杆菌与胃癌风险增加相关的一个决定因素是CAG致病岛，几个CAG基因编码IV型分泌系统的组件，该系统将细菌蛋白如CagA输出到宿主上皮细胞。我们的团队现在已经证明，幽门螺杆菌CAG+菌株选择性地激活胃上皮细胞中影响癌变的宿主效应因子-连环蛋白、表皮生长因子受体(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+菌株诱发胃癌的能力。因此，本申请的首要目标是描述由幽门螺杆菌引发的分子信号事件：调节与胃癌发生相关的表型的上皮细胞接触。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，这些研究人员坚定而明确地致力于胃肠病学、癌症生物学、癌症发生和微生物学领域的研究，并将产生通过独立研究无法获得的结果。这些组成部分的项目由离散的假设驱动，但都是有凝聚力的，因为每个项目都专注于幽门螺杆菌：上皮细胞的相互作用，诱导具有致癌潜力的细胞反应。个别项目包括： 项目1.铁和连环蛋白激活在胃癌发生中的作用(Pi-Richard Peek)。 项目2.幽门螺杆菌诱发的胃癌中的EGFR激活和多胺(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互动进一步统一，这些核心设施包括胃组织病理学核心(核心A)、蛋白质组学核心(核心B)和行政核心(核心C)。通过将重点放在幽门螺杆菌：上皮界面上发生的基本相互作用上，这项提议的结果不仅将提高我们对胃癌的理解，还将确定预防和更有效治疗这种疾病的潜在治疗靶点。