The regulation of Pseudomonas aeruginosa surface colonization

铜绿假单胞菌表面定植的调控

• 批准号: 7572165
• 负责人: THOMAS SCOT MURRAY
• 金额: $ 13.19万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-04 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7572165
• 关键词: Advisory Committees; Affect; Anabolism; Animals; Antibiotic Therapy; Bacteria; Bacterial Infections; Cell Communication; Cell Death; Chronic; Communities; Complement; Complex; Computer software; Confocal Microscopy; Cystic Fibrosis; Defect; Educational process of instructing; Epithelial Cells; Exotoxins; Fimbriae Proteins; Flagella; Flagellin; Genetic Transcription; Goals; Histology; Hospitalization; Image Analysis; Immune response; Immunobiology; In Vitro; Infection; Instruction; Lactate Dehydrogenase; Lead; Learning; Life; Lung; Lung Inflammation; Measures; Mentors; Microbial Biofilms; Microbiology; Modeling; Morbidity - disease rate; Mutation; Organelles; Organism; Pathogenesis; Patients; Pilum; Pneumonia; Premature Mortality; Principal Investigator; Process; Production; Property; Proteins; Pseudomonas Infections; Pseudomonas aeruginosa; Rattus; Recovery; Regulation; Research; Research Personnel; Slide; Surface; Techniques; Testing; Tight Junctions; Time; Training; Translational Research; Virulence Factors; animal care; cell motility; cystic fibrosis patients; cytokine; experience; genetic regulatory protein; in vitro Model; in vivo; in vivo Model; microbial; mortality; mutant; novel; novel strategies; novel therapeutic intervention; pathogen; research study; rhamnolipid; skills; surfactant; tissue culture; tool

DESCRIPTION (provided by applicant): In patients with cystic fibrosis (CF), chronic colonization of the lungs with Pseudomonas aeruginosa results in frequent hospitalizations and in premature mortality. P. aeruginosa can colonize surfaces in multiple ways: swarming motility, sliding motility and the formation of biofilms. Expression of components on the surface of the bacteria (e.g. type IV pili, exopolysaccharide, flagella, and rhamnolipids) is important for these activities, but current understanding of the interactions and co-regulation of these factors is incomplete. Dr. Murray has preliminary evidence that certain regulatory proteins produced by P. aeruginosa each controls multiple factors important for colonization. His research goals are to: 1) Determine the components required for surface colonization co-regulated by these proteins (using strains of P. aeruginosa that variously lack these regulatory proteins and measuring levels of pilin, flagellin, exopolysaccharide, and rhamnolipid during swarming, sliding and formation of biofilms); 2) To quantitate the colonization of surfaces by these strains in a CF tissue culture model of infection (by visualizing bacterial/epithelial cell interactions with confocal microscopy and analyzing these images with COMSTAT software); and 3) To correlate in vitro surface colonization defects with abnormal chronic colonization in vivo (by measuring the recovery of bacteria, histology, and the immune response in the lungs of rats infected with these strains). Understanding these processes may lead to novel therapies. Dr. Murray will complement his experience in microbiology by learning new techniques: real time PCR, confocal microscopy, a CF tissue culture model, and a rat model of chronic pneumonia. Dr Murray's primary mentor has expertise in animal infection models and his advisory committee includes experts in microbial pathogenesis and the director of Yale's CF Center who will teach him these skills. He will take courses in translational research, immunobiology, and animal care. Through this additional training, Dr. Murray will gain the tools to become an independent investigator in the pathogenesis of chronic infection by Pseudomonas. RELEVANCE (See instructions): The bacterium Pseudomonas aeruginosa lives in the lungs of people with cystic fibrosis for many years, resulting in frequent hospitalizations. Current antibiotic therapies are not successful in eliminating the bacteria and new approaches to therapy are needed. The goal of this project is to better understand the properties of P. aeruginosa that allow it to survive in the lung so new therapies may be developed.

描述（由申请人提供）：在囊性纤维化（CF）的患者中，具有铜绿假单胞菌的肺慢性定殖导致频繁住院和过早死亡。铜绿假单胞菌可以通过多种方式定居表面：蜂群的运动性，滑动运动性和生物膜的形成。细菌表面的成分表达（例如IV型Pili，外多糖，鞭毛和鼠李脂脂）对于这些活动很重要，但是当前对这些因素相互作用和共同调节的理解是不完整的。默里博士有初步证据表明，铜绿假单胞菌产生的某些调节蛋白每个控制着对定殖重要的多个因素。他的研究目标是：1）确定由这些蛋白质共同调节的表面定植所需的成分（使用铜绿假单胞菌的菌株，这些蛋白质缺乏这些调节蛋白以及测量PILIN，鞭毛蛋白，外多糖和rhamnolipid的水平，在生物纤维的滑动，滑动和形成过程中）； 2）在CF组织培养模型中，通过这些菌株定量表面的定殖（通过可视化细菌/上皮细胞相互作用与共聚焦显微镜的相互作用，并使用COMSTAT软件分析这些图像）； 3）要将体外表面定植缺陷与体内异常的慢性定殖相关联（通过测量细菌，组织学的恢复和被这些菌株感染的大鼠肺中的免疫反应）。了解这些过程可能会导致新的疗法。 Murray博士将通过学习新技术来补充他在微生物学方面的经验：实时PCR，共聚焦显微镜，CF组织培养模型和慢性肺炎的大鼠模型。默里博士的主要导师在动物感染模型方面具有专业知识，他的咨询委员会包括微生物发病机理的专家和耶鲁大学CF中心主任，他将教他这些技能。他将参加转化研究，免疫生物学和动物护理的课程。通过这项额外的培训，默里博士将获得工具，成为假单胞菌慢性感染发病机理的独立研究者。相关性（请参阅说明）：铜绿细菌铜绿菌生活在患有囊性纤维化的人的肺部多年，导致经常住院。当前的抗生素疗法在消除细菌方面没有成功，需要新的治疗方法。该项目的目的是更好地了解铜绿假单胞菌的特性，该特性使其在肺部生存，从而可以开发出新的疗法。