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.

项目概要 人们越来越认识到，囊性纤维化 (CF) 患者的气道通常存在复杂的情况 包含多种细菌物种的多微生物群落。但具体如何变化尚不清楚 这些群落与肺部疾病的进展有关。更具体地说，结构如何变化 和/或气道细菌群落的活动与间歇性肺部病情恶化有关 表征 CF 的 (PEx) 尚未得到系统研究。缺乏呼吸道样本 PEx 之前时期的详细临床数据一直是该领域取得进展的关键障碍。 该项目的科学前提是更好地了解气道微生物群落动态 PEx 将为更好地护理 CF 患者提供新的机会。首要的 假设是这些群落的结构和/或活动的变化驱动了病理生理学 PEx。在短期内，这项研究将确定具有直接转化临床意义的目标。在较长的时间里 从长远来看，该项目将阐明控制微生物群落和宿主相关变化的机制 与 PEx。该项目的具体目标是（i）描述微生物群落和宿主炎症 PEx 发生的变化，(ii) 开发 PEX 分辨率的预测模型，以及 (iii) 开发动态 预测 PEx 期间微生物-微生物和宿主-微生物相互作用的模型。本项目的可行性是 得到一个试点项目的支持，在该项目中，我们前瞻性地从一组 CF 中收集每日痰样本 病程长达两年的患者。每日样本和临床元数据的前瞻性收集 当前项目中提出的多项改进将产生更稳健的结果。下一个- DNA测序和细菌代谢物分析将用于表征结构和 肺部病情恶化期间获得的样本中细菌群落的活性。 将确定与恶化发作、严重程度和恢复相关的微生物群落变化。 这些变化的建模将描述与相关的微生物-微生物和宿主-微生物的相互作用 整个 PEx 周期中临床状态的转变。这些信息将构成后续研究的基础 更好地了解 PEx 在 CF 中的病理生理机制。