Metal-dependent regulation of the H. pylori Cag type IV secretion system

幽门螺杆菌 Cag IV 型分泌系统的金属依赖性调节

• 批准号: 8398573
• 负责人: Jennifer A Gaddy
• 金额: $ 4.82万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398573
• 关键词: Adenocarcinoma; Apical; Bacteria; Biogenesis; Carcinogenesis Mechanism; Cell surface; Cells; Chronic; Coculture Techniques; Complex; DNA; Development; Diet; Dietary Iron; Dietary Zinc; Disease; Electron Microscopy; Employee Strikes; Environment; Epithelial Cells; Gastric Adenocarcinoma; Genetic; Genetic Transcription; Guns; Helicobacter Infections; Helicobacter pylori; Human; Image; In Vitro; Incidence; Inflammation; Intake; Iron; Knowledge; Lead; Leukocyte L1 Antigen Complex; Light; Membrane; Metals; Microscopic; Modeling; Molecular Biology Techniques; Molecular Machines; Oncogene Proteins; Oncogenic; Organelles; Pathogenesis; Pathogenicity Island; Peptic Ulcer; Pilum; Population; Postdoctoral Fellow; Prevention; Process; Prokaryotic Cells; Proteins; Regulation; Research; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Rhizobium radiobacter; Risk Factors; Rodent Model; Role; Scanning Electron Microscopy; Signal Transduction; Source; Stomach; Structure; Surface; Transferrin Receptor; Type IV Secretion System Pathway; Ulcer; Variant; Work; X ray spectroscopy; Zinc; extracellular; in vivo; infected vector rodent; malignant stomach neoplasm; mucosa-associated lymphoid tissue lymphoma; novel strategies; pathogen; polarized cell; prototype; research study; response; trafficking

DESCRIPTION (provided by applicant): Helicobacter pylori is the predominant colonizing prokaryote in the human gastric niche. H. pylori infection results in persistent chronic inflammation, and 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 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 the mechanisms by which the cag T4SS is regulated. Specifically, we hypothesize that assembly of the T4SS pilus is regulated by the availability of metals such as iron and zinc. We will utilize a combination of electron microscopy, quantitative RT-PCR, and molecular biology techniques to shed light upon the complex regulatory networks that govern the biogenesis of this important organelle. PUBLIC HEALTH RELEVANCE: Helicobacter pylori is a bacterium that colonizes the human stomach and contributes to gastric cancer and peptic ulcer disease. This research seeks to understand how this bacterium regulates the cag type IV secretion system, which translocates carcinogenic effectors into host cells. This knowledge may lead to new approaches for the prevention and treatment of stomach cancer and peptic ulcer disease.

描述（由申请人提供）：幽门螺杆菌是人胃微环境中主要定植的原核生物。幽门螺杆菌感染会导致持续的慢性炎症，是消化性溃疡和胃腺癌发展的重要危险因素。腺癌的发生取决于多种因素，包括宿主遗传学、饮食和细菌因素。有助于细菌发病机制的一个具体特征是幽门螺杆菌 cag 致病性岛 (cag PAI)，它编码 IV 型分泌系统 (T4SS)，负责将致癌蛋白 CagA 递送到胃上皮细胞中。 T4SS 装置跨越两个细菌膜，并包括一个称为 T4SS 菌毛的细胞外细胞器。该细胞器被认为负责损害真核细胞膜和 CagA 易位。尽管 T4SS 在幽门螺杆菌发病机制和最终致癌过程中发挥着重要作用，但调节这种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 的调节机制。具体来说，我们假设 T4SS 菌毛的组装受到铁和锌等金属的可用性的调节。我们将结合电子显微镜、定量 RT-PCR 和分子生物学技术来揭示控制这一重要细胞器生物发生的复杂调控网络。 公共卫生相关性：幽门螺杆菌是一种定植于人类胃中的细菌，会导致胃癌和消化性溃疡病。这项研究旨在了解这种细菌如何调节 cag IV 型分泌系统，该系统将致癌效应物转移到宿主细胞中。这些知识可能会带来预防和治疗胃癌和消化性溃疡病的新方法。