H. pylori-Induced Inflammation and gastric cancer

幽门螺杆菌引起的炎症和胃癌

• 批准号: 8607664
• 负责人: RICHARD M. PEEK
• 金额: $ 137.11万
• 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/8607664
• 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; DNA Sequence; 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 Genome; Human Resources; Immune response; Individual; Infection; Infectious Agent; Inflammation; International; Investigation; Iron; Lead; Lesion; Letters; Link; Malignant Neoplasms; Medicine; 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; improved; innovation; insight; iron deficiency; malignant stomach neoplasm; microbial; microbial host; molecular imaging; neoplastic; new therapeutic target; novel; novel strategies; pathogen; 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（由申请人提供）：胃腺癌是世界上癌症相关死亡的第二大原因，幽门螺杆菌是这种恶性肿瘤的最强已知危险因素，但只有一小部分定植者患有幽门螺杆菌肿瘤。与胃癌风险增加相关的决定因素是 cag 致病性岛，一些 cag 基因编码 IV 型分泌系统的成分，该系统将细菌蛋白（如 CagA）输出到宿主中我们的小组现已证明幽门螺杆菌 cag+ 菌株选择性激活 ¿连环蛋白、EGF 受体 (EGFR) 和精胺氧化酶 (SMO) 是影响胃上皮细胞癌发生的宿主效应物。我们还证明，与胃癌相关的环境因素，如缺铁和盐，会增强癌发生的能力。因此，本申请的首要目标是描绘幽门螺杆菌：调节上皮细胞接触的分子信号转导事件。该 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，这些研究人员对胃肠病学、癌症生物学、癌发生和微生物学领域的研究做出了坚定而明确的承诺，并将产生以下结果：不可能通过独立调查来实现。各个项目由离散的假设驱动，但具有凝聚力，因为每个项目都关注幽门螺杆菌：诱导具有致癌潜力的细胞反应的上皮相互作用。包括： 项目 1. 铁和 ¿ 的作用胃癌发生中的连环蛋白激活（Pi-Richard Peek）。 项目 2.幽门螺杆菌诱导的胃癌中的 EGFR 激活和多胺（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)。 每个项目的工作将通过与特定核心设施的动态互动进一步统一，其中包括胃组织病理学核心（核心 A）、蛋白质组学核心（核心 B）和管理核心（核心 C）。关于幽门螺杆菌：上皮界面上发生的基本相互作用，该提案的结果不一定会提高我们对胃癌的了解，但也将确定预防和更有效治疗该疾病的潜在治疗靶点。