Redox stress responses in Clostridium difficile: mechanisms and implications

艰难梭菌的氧化还原应激反应：机制和意义

• 批准号: 8950083
• 负责人: Gayatri Vedantam
• 金额: $ 20.43万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8950083
• 关键词: Affect; Anaerobic Bacteria; Animal Model; Animals; Attenuated; Bacterial Infections; Biological; Biology; Categories; Centers for Disease Control and Prevention (U.S.); Chemicals; Clinical; Clinical Trials; Clostridium difficile; Detection; Disease; Engineering; Enzymes; Exploratory/Developmental Grant; Exposure to; Future; Gastrointestinal tract structure; Goals; Healthcare; Healthcare Systems; Hospitals; Image; In Vitro; Infection; Intervention; Intestines; Intoxication; Investigation; Life; Link; Maps; Mediating; Modification; Mus; NADPH Oxidase; Oxidation-Reduction; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Process; Production; Proteins; Proteomics; Reactive Oxygen Species; Role; Staging; Stress; Sulfhydryl Compounds; Superoxides; Technology; Testing; Therapeutic; Toxin; Tracer; Vaccines; Work; biological adaptation to stress; bioluminescence imaging; clinically relevant; combat; disorder prevention; gastrointestinal; gut microbiota; high risk; in vivo; inhibitor/antagonist; mouse model; mutant; next generation; nitazoxanide; novel; pathogen; prevent; prophylactic; public health relevance; response; superoxide reductase; surveillance study; therapy design

 DESCRIPTION (provided by applicant): The overall goal of this proposal is interrogate gastrointestinal (GI) niche establishment of the diarrheagenic pathogen, Clostridium difficile. We have identified a unique oxygen detoxifying enzyme, superoxide reductase (SOR), which promotes C. difficile survival in the GI tract. The immediate impact of this work will be to validae SOR and other redox proteins as novel targets for interventions designed to prevent C. difficile colonization. Three Specific Aims are proposed. In Aim 1, we will delineate the impact of oxygen and reactive oxygen species (ROS) exposure on C. difficile localization and survival in the GI tract. In Aim 2, we will assess the impact of host ROS deficiency on C. difficile niche establishment. In Aim 3, we will comprehensively map the C. difficile redox-stress response compendium. All the proposed studies will use recent clinical isolates of C. difficile that we have obtained through ongoing disease surveillance studies. For Aims 1 and 2, two animal models will be employed, and bacterial establishment tracked via live-animal and ex vivo imaging using a novel colonization tracer we have specifically developed for these studies. For Aim 3, we will employ next-generation redox proteomics (ROSics) approaches.

 描述（由申请人提供）：该提案的总体目标是询问致腹泻病原体艰难梭菌的胃肠道 (GI) 生态位的建立。我们发现了一种独特的氧解毒酶——超氧化物还原酶（SOR），它可以促进艰难梭菌在胃肠道中的存活。这项工作的直接影响将是验证 SOR 和其他氧化还原蛋白作为旨在预防艰难梭菌定植的干预措施的新靶点。提出了三个具体目标。在目标 1 中，我们将描述氧气和活性氧 (ROS) 暴露对艰难梭菌在胃肠道中的定位和存活的影响。在目标 2 中，我们将评估宿主 ROS 缺乏对艰难梭菌生态位建立的影响。在目标 3 中，我们将全面绘制艰难梭菌氧化还原应激反应概要。所有拟议的研究都将使用我们最近的艰难梭菌临床分离株 通过正在进行的疾病监测研究获得。对于目标 1 和 2，将采用两种动物模型，并使用我们专门为这些研究开发的新型定植示踪剂，通过活体动物和离体成像来跟踪细菌的建立。对于目标 3，我们将采用下一代氧化还原蛋白质组学 (ROSics) 方法。