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：幽门螺杆菌菌毛的调控由CAG致病岛詹妮弗·A·加迪，Ph.D.幽门螺杆菌是主要的原核生物定植在人的胃壁龛，引起持续的慢性炎症。幽门螺杆菌感染是消化性溃疡和胃腺癌发生的重要危险因素。腺癌的发展依赖于多种因素，包括宿主遗传、饮食和细菌因素。导致细菌致病的一个特殊特征是幽门螺杆菌。 CAG致病岛(CAG-PAI)，编码IV型分泌系统(T4SS)，负责将致癌蛋白CagA运送到胃上皮细胞。T4SS装置跨越两个细菌膜，并包括一个被称为T4SS菌毛的细胞外细胞器。这种细胞器被认为负责破坏真核膜，从而允许CagA的转位。尽管T4SS在幽门螺杆菌的致病和最终致癌过程中发挥了重要作用，但调节这一复杂分子机器组装的机制在很大程度上尚不清楚。本申请提出的实验将阐明CAG T4SS的组装和活性受其调控的机制。初步结果表明，铁和锌等金属参与了T4SS的调节。我们将使用高分辨率电子显微镜来观察不同金属可利用性条件下的T4SS菌毛，并结合生物化学和分子生物学技术来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工具，研究细菌金属稳态对CAG-PAI T4SS调控的贡献。最后，我们将利用啮齿动物的感染模型和控制饮食中金属的摄入量，将实验室实验转化为活体模型，以确定营养金属对疾病进展的影响，以及脊椎动物宿主内T4SS的调节。这项研究计划将促进我们在细菌发病机制领域的知识，特别是在幽门螺杆菌毒力因子调节在胃病(如癌症)中的作用。