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: 8543295
• 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/8543295
• 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; 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; public health relevance; 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.

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