Regulation of Helicobacter pylori pili encoded by the cag pathogenicity island

cag致病岛编码的幽门螺杆菌菌毛调控

• 批准号: 8803322
• 负责人: Jennifer A Gaddy
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803322
• 关键词: Adenocarcinoma; Apical; Area; Bacteria; Binding; Biochemical; Biogenesis; Carcinogenesis Mechanism; Cell surface; Cells; Chronic; Coculture Techniques; Complex; DNA; Data; Development; Diet; Dietary Iron; Dietary Zinc; Disease; Disease Progression; Doctor of Philosophy; Electron Microscopy; Employee Strikes; Environment; Epithelial Cells; Gastric Adenocarcinoma; Gastritis; Genetic; Health; Helicobacter Infections; Helicobacter pylori; Homeostasis; Human; Image; Incidence; Infection; Inflammation; Intake; Iron; Knowledge; Laboratories; Malignant Neoplasms; Membrane; Metals; Microscopic; Molecular Biology Techniques; Molecular Machines; Nutrient; Oncogene Proteins; Oncogenic; Organelles; Pathogenesis; Pathogenicity Island; Peptic Ulcer; Pilum; Population; Postdoctoral Fellow; Process; Prokaryotic Cells; Promoter Regions; Proteins; Regulation; Research; Research Proposals; Resolution; Rhizobium radiobacter; Risk; Risk Factors; Rodent Model; Role; Signal Transduction; Source; Stomach; Stomach Diseases; Structure; Transcriptional Regulation; Transferrin; Translating; Type IV Secretion System Pathway; Ulcer; Variant; Veterans; Virulence; Virulence Factors; Work; Zinc; bacterial genetics; extracellular; in vitro Model; in vivo; in vivo Model; infected vector rodent; malignant stomach neoplasm; mucosa-associated lymphoid tissue lymphoma; new therapeutic target; novel; pathogen; prototype; research study; response; tool; trafficking; uptake

DESCRIPTION (provided by applicant): Title: Regulation of H. pylori pili encoded by the cag pathogenicity island Jennifer A. Gaddy, Ph.D. Helicobacter pylori is the predominant colonizing prokaryote in the human gastric niche, causing persistent chronic inflammation. H. pylori infection is a strong risk factor for the development of peptic ulceration and gastric adenocarcinoma. The development of adenocarcinoma is dependent upon a variety of factors including host genetics, diet, and bacterial factors. One specific feature that contributes to bacterial pathogenesis is the H. pylori cag-pathogenicity island (cag-PAI), which encodes a type IV secretion system (T4SS) responsible for the delivery of the oncogenic protein CagA into gastric epithelial cells. The T4SS apparatus spans two bacterial membranes and includes an extracellular organelle referred to as the T4SS pilus. This organelle is proposed to be responsible for compromising the eukaryotic membrane and thereby allowing translocation of CagA. Although the T4SS has an important role in H. pylori pathogenesis and ultimately carcinogenesis, the mechanisms that regulate assembly of this complex molecular machine are largely obscure. This application proposes experiments that will elucidate mechanisms by which assembly and activity of the cag T4SS are regulated. Preliminary results indicate that metals such as iron and zinc contribute to the regulation of the T4SS. We will use high resolution electron microscopy to visualize the T4SS pilus under different conditions of metal availability in conjunction with biochemical and molecular biology techniques to evaluate the expression of pilus components in these conditions. We will also use bacterial genetics as a tool to investigate the contribution of bacterial metal homeostasis to the regulation of the cag-PAI T4SS. Finally, we will translate the laboratory experiments into an in vivo model by utilizing rodent models of infection and manipulating the dietary metal intake to determine the effect of nutrient metal upon disease progression and the regulation of the T4SS within a vertebrate host. This research plan will advance our knowledge in the area of bacterial pathogenesis, and specifically in the contribution of H. pylori virulence factor regulation to gastric diseases such as cancer.

描述（由申请人提供）： 标题：CAG致病岛Jennifer A. Gaddy博士编码的H. Pyloi Pili的调节。 幽门螺杆菌是人类胃生态裂市场中主要的定植原核生物，导致持续性慢性炎症。幽门螺杆菌感染是开发消化性溃疡和胃腺癌的强大危险因素。腺癌的发展取决于多种因素，包括宿主遗传学，饮食和细菌因素。有助于细菌发病机理的一个特定特征是幽门螺杆菌 CAG-PATONICITICY岛（CAG-PAI）编码负责将致癌蛋白CAGA传递到胃皮细胞中的IV型分泌系统（T4SS）。 T4SS设备跨越了两个细菌膜，并包括一个称为T4SS Pilus的细胞外细胞器。建议该细胞器负责损害真核膜，从而允许CAGA易位。尽管T4SS在幽门螺杆菌的发病机理和最终致癌作用中具有重要作用，但是调节该复杂分子机器的组装的机制在很大程度上是晦涩的。该应用提出了实验，该实验将阐明调节CAG T4S的组装和活性的机制。初步结果表明，铁和锌等金属有助于调节T4SS。我们将使用高分辨率电子显微镜与生化和分子生物学技术结合使用，以在不同的金属可用性条件下可视化T4SS pilus，以评估在这些条件下菌毛成分的表达。我们还将使用细菌遗传学作为研究细菌金属稳态对CAG-PAI T4SS调节的贡献的工具。最后，我们将通过利用啮齿动物的感染模型并操纵饮食金属摄入来确定营养金属对疾病进展的影响以及在脊椎动物宿主中T4S的调节，将实验室实验转化为体内模型。该研究计划将促进我们在细菌发病机理领域的知识，特别是幽门螺杆菌毒力因子调节对癌症（例如癌症）的贡献。