Dynamics of airway microbiota at pulmonary exacerbation in cystic fibrosis

囊性纤维化肺部恶化时气道微生物群的动态

• 批准号: 9286133
• 负责人: JOHN J LIPUMA
• 金额: $ 16.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-03 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9286133
• 关键词: Acute; Age; Antibiotic Therapy; Area; Biochemical Pathway; Caregivers; Caring; Cause of Death; Cessation of life; Chronic; Clinical; Clinical Data; Collection; Communities; Complex; Cystic Fibrosis; DNA analysis; DNA sequencing; Data; Drops; Etiology; Event; Functional disorder; Goals; Health Care Costs; Infection; Inflammation; Inflammatory; Lung; Lung Inflammation; Lung diseases; Measures; Metadata; Microbe; Microbiology; Modeling; Patients; Pattern; Persons; Phenotype; Pilot Projects; Play; Predictive Value; Pseudomonas; Pulmonary Cystic Fibrosis; Quality of life; Recovery; Recovery of Function; Reporting; Resolution; Respiratory Failure; Respiratory Signs and Symptoms; Respiratory physiology; Role; Sampling; Severities; Signs and Symptoms; Specimen; Sputum; Statistical Models; Structure; Symptoms; Systems Biology; Testing; Time; Toxic effect; airway inflammation; antimicrobial; cohort; cost; cystic fibrosis patients; density; host-microbe interactions; inflammatory marker; interest; loss of function; mathematical model; metabolome; metabolomics; microbial; microbial community; microbial host; microbiome; microbiota; next generation; novel strategies; pathogen; personalized medicine; predictive modeling; prevent; prospective; respiratory; response; targeted treatment

Project Summary There is an increasing recognition that the airways of persons with cystic fibrosis (CF) typically harbor complex polymicrobial communities that include numerous bacterial species. It is unknown, however, how changes in these communities relate to the progression of lung disease. More specifically, how changes in the structure and/or activity of airway bacterial communities are associated with the intermittent pulmonary exacerbations (PExs) that characterize CF has not been systematically investigated. The lack of respiratory specimens and granular clinical data from periods of time preceding PExs has been a critical barrier to progress in this area. The scientific premise for this project is that a better understanding of airway microbial community dynamics with respect to PExs will provide new opportunities to better care to persons with CF. The overarching hypothesis is that changes in the structure and/or activity of these communities drive the pathophysiology of PExs. In the short term, this study will identify targets of immediate translational clinical interest. In the longer term, this project will elucidate the mechanisms governing microbial community and host changes associated with PExs. The specific aims of this project are to (i) characterize microbial community and host inflammatory changes that occur with PEx, (ii) develop predictive models of PEX resolution, and (iii) develop dynamic models that predict microbe-microbe and host-microbe interactions during PEx. The feasibility of this project is supported by a pilot project in which we prospectively collected daily sputum samples from a cohort of CF patients during the course of up to two years. The prospective collection of daily samples and clinical metadata proposed in the current project incorporates several improvements that will yield more robust results. Next- generation DNA sequencing and analysis of bacterial metabolites will be used to characterize the structure and activity of the bacterial communities in samples obtained around the time of pulmonary exacerbations. Microbial community changes that correlate with exacerbation onset, severity and recovery will be identified. Modeling of these changes will describe the microbial-microbial and host-microbial interactions associated with transitions in clinical state throughout the PEx cycle. This information will form the basis of follow on studies to better understand the pathophysiologic mechanisms of PEx in CF.

项目摘要 人们越来越认识到囊性纤维化（CF）的人的气道通常是藏有复合体 包括许多细菌物种的多数群落。但是，未知的变化是未知的 这些社区与肺部疾病的进展有关。更具体地说，结构如何变化 气道细菌群落的活动与间歇性肺部恶化有关 （PEX）表征CF的（PEX）尚未系统地研究。缺乏呼吸标本和 PEX之前的时期粒状临床数据是该领域进步的关键障碍。 该项目的科学前提是对气道微生物社区动态有更好的了解 关于PEX，将为CF患者提供新的机会。总体 假设是这些社区的结构和/或活动的变化推动了 PEXS。在短期内，这项研究将确定立即转化临床兴趣的靶标。更长的时间 术语，该项目将阐明管理微生物社区的机制，并与主机变化相关 与pexs。该项目的具体目的是（i）表征微生物社区和宿主炎症 PEX发生的变化，（ii）开发PEX分辨率的预测模型，（iii）发展动态 在PEX期间预测微生物和宿主微生物相互作用的模型。这个项目的可行性是 在一个试点项目中的支持 在长达两年的过程中患者。预期的每日样品和临床元数据 在当前项目中提出的一些改进将产生更强大的结果。下一个- 细菌代谢产物的生成DNA测序和分析将用于表征结构和 细菌群落在肺部恶化时获得的样品中的活性。 将确定与加剧，严重性和恢复相关的微生物群落变化。 这些变化的建模将描述与与 在整个PEX周期中，临床状态下的过渡。这些信息将构成以下研究的基础 更好地了解CF中PEX的病理生理机制。