H. Pylori-Induced Inflammation and Gastric Cancer

幽门螺杆菌引起的炎症和胃癌

• 批准号: 8011208
• 负责人: RICHARD M. PEEK
• 金额: $ 138.07万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011208
• 关键词: H.; Pylori; Induced; Inflammation; Gastric

DESCRIPTION (provided by applicant): Gastric adenocarcinoma is the second leading cause of cancer-related death in the world, and Helicobacter pylori is the strongest identified risk factor for this malignancy, yet only a fraction of colonized persons ever develop neoplasia. One H. pylori determinant associated with gastric cancer 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 and the EGF receptor (EGFR), host effectors that influence carcinogenesis, in gastric epithelial cells. We have also demonstrated that an environmental factor associated with gastric cancer, salt, augments the ability of H. pylori cag+ strains to induce aberrant epithelial responses. Therefore, the overarching objective of this Application is delineation of the molecular signaling events initiated 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. Mechanisms that regulate Helicobacter pylori-induced ?-catenin activation (PI-Richard Peek). Project 2. EGFR activation in H. pylori-induced gastric cancer (PI-Brent Polk). Project 3. Helicobacter pylori cag pathogenicity island and gastric carcinogenesis (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 only improve our understanding of gastric cancer, but will also facilitate identification of 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，而幽门螺杆菌是这种恶性肿瘤的最强已知危险因素，但只有一小部分被殖民者会患上肿瘤。与胃癌相关的幽门螺杆菌决定簇之一是 cag 致病性岛，并且一些 cag 基因编码 IV 型分泌系统的成分，该系统将细菌蛋白（例如 CagA）输出到宿主上皮细胞中。我们的小组现已证明，幽门螺杆菌 cag+ 菌株可选择性激活胃上皮细胞中的β-连环蛋白和 EGF 受体 (EGFR)，即影响癌发生的宿主效应物。我们还证明，与胃癌相关的环境因素盐可以增强幽门螺杆菌 cag+ 菌株诱导异常上皮反应的能力。因此，本申请的首要目标是描绘由幽门螺杆菌引发的分子信号转导事件：调节与胃癌发生相关的表型的上皮细胞接触。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、致癌作用和微生物学领域的研究做出了坚定而明确的承诺，并将产生通过独立调查无法获得的结果。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：上皮相互作用，诱导具有致癌潜力的细胞反应。个别项目包括： 项目 1. 调节幽门螺杆菌诱导的 β-连环蛋白激活的机制 (PI-Richard Peek)。 项目 2. 幽门螺杆菌诱导的胃癌中的 EGFR 激活 (PI-Brent Polk)。 项目3. 幽门螺杆菌cag致病岛与胃癌发生（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）。通过持续关注幽门螺杆菌：上皮细胞界面上发生的基本相互作用，该提案的结果不仅将提高我们对胃癌的了解，而且还将有助于识别潜在的治疗靶点，以预防和更有效地治疗胃癌疾病。