Spatial characterization of microbial communities in the cystic fibrosis lung

囊性纤维化肺微生物群落的空间特征

• 批准号: 8699293
• 负责人: Ryan Coulson Hunter
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699293
• 关键词: Address; Affect; Attention; Award; Bacteria; Biological Assay; Bronchial Tree; Cells; Chemicals; Chemistry; Childhood; Chronic; Clinical; Collaborations; Communities; Complex; Cystic Fibrosis; Data; Data Set; Development; Diet; Disease; Disease Progression; Ecology; Ecosystem; Environment; Environmental Microbiology; Environmental Risk Factor; Etiology; Gene Expression; Genetic; Goals; Hand; Health; Heterogeneity; Human; Human Microbiome; Human body; In Situ; Individual; Infection; Invaded; Iron; Lead; Life Expectancy; Link; Lung; Marine Sediment; Measurement; Measures; Medical Microbiology; Metabolic; Metabolism; Methodology; Methods; Modeling; Obesity; Outcome; Oxidation-Reduction; Patients; Phase; Phenazines; Population; Protocols documentation; Pseudomonas aeruginosa; Respiratory System; Respiratory physiology; Respiratory tract structure; Sampling; Shapes; Site; Specimen; Sputum; Staging; System; Techniques; Testing; Therapeutic; Variant; antimicrobial; base; cohort; cystic fibrosis airway; cystic fibrosis patients; design; environmental change; human disease; imaging modality; member; microbial; microbial community; microbiome; mortality; novel; novel therapeutics; pathogen; research study; response; stem

Project Summary The human microbiome is gaining widespread attention for its link to host health and disease. This is particularly true of the cystic fibrosis airways, where a complex microbial community is recognized to be the major cause of patient mortality. In addition to Pseudomonas aeruginosa, a recent surge in culture- independent studies has generated a growing list of suspected pathogens and their correlation to disease progression. Yet, our inability to effectively treat these patients remains due to a lack of understanding of the CF lung environment and how specific chemical parameters define the presence or absence of a given bacterial species. In natural environments, such as a marine sediment, defining the effect of environmental chemistry on the microbial community is paramount in fully understanding a given ecosystem. Yet, this approach in a medical microbiology context is seldom used. Here, my overarching goal is to apply standard environmental microbiology principles and methodologies to test the hypothesis that the complex chemistry of the bronchial tree affects its resident microflora on multiple scales. Recently, we discovered a highly significant correlation between a class of microbially-produced metabolites (phenazines), microbiome composition, and lung function decline. In the K99 phase of this award, the overall goal will be to expand on these initial observations, and to broadly investigate the effect of the cystic fibrosis lung environment on its microbiome. Using a cohort of pediatric patients, I will first test that phenazines alter the redox state of iron, which ultimately correlates to a shift in the overall lung microbiome and disease progression. In addition, I will use novel imaging methods to investigate the cellular response of individual species (particularly P. aeruginosa) at the single cell level to changes in environmental chemistry (specifically in response to iron). These studies will reveal the potential of using single cell transcriptional activity as a direct readout of the ambient environment of the airways, and will potentially guide the design of novel therapeutics based on environmental chemistry. Next, we will apply these methods to explanted lung samples in order to better understand the spatial heterogeneity of microbial communities throughout the bronchial tree. With this information in hand, these studies will ultimately be expanded in the R00 phase of the award to include other metabolites and chemical parameters within the respiratory tract, and other sites of infection within the host. Altogether, this systems approach to understanding the ecology of microbial infections will change the way we think about the microbiome and its link to health and disease, and has the potential for development of novel therapeutic strategies.

项目摘要 人类微生物组与宿主健康和疾病的联系广泛关注。这是 在囊性纤维化气道中尤其如此，在该气道中，复杂的微生物群落被认为是 患者死亡率的主要原因。除了铜绿假单胞菌，最近的培养激增 - 独立研究产生了越来越多的可疑病原体及其与疾病的相关性清单 进展。然而，我们无法有效治疗这些患者，这仍然是由于对 CF肺环境以及特定化学参数如何定义给定的存在或不存在 细菌物种。在自然环境中，例如海洋沉积物，定义了环境的影响 微生物群落上的化学反应对于完全理解给定的生态系统至关重要。但是，这个 很少使用医学微生物学环境中的方法。在这里，我的总体目标是应用标准 环境微生物学原理和方法论，以检验以下假设 支气管树在多个尺度上影响其居民菌群。 最近，我们发现了一类微生物生产的代谢产物之间的高度显着相关性 （苯胺），微生物组组成和肺功能下降。在该奖项的K99阶段，总体 目标是扩展这些最初的观察结果，并广泛研究囊性纤维化的效果 其微生物组上的肺部环境。使用一群小儿患者，我将首先测试促苯胺改变 铁的氧化还原状态，最终与整体肺微生物组和疾病的变化相关 进展。此外，我将使用新颖的成像方法研究个体的细胞反应 在单细胞水平上的物种（尤其是铜绿假单胞菌）以变化环境化学（特别是 响应铁）。这些研究将揭示使用单细胞转录活性作为直接的潜力 读取气道环境环境，并有可能指导新型治疗方法的设计 基于环境化学。接下来，我们将将这些方法应用于外植的肺样本，以便 更好地了解整个支气管树中微生物群落的空间异质性。与此 掌握的信息，这些研究最终将在奖项的R00阶段进行扩展，以包括其他 呼吸道内的代谢物和化学参数，以及宿主内的其他感染部位。 总之，这种理解微生物感染生态学的系统方法将改变我们的方式 考虑微生物组及其与健康和疾病的联系，并具有开发新颖的潜力 治疗策略。