Ecology of Cystic Fibrosis

囊性纤维化的生态学

基本信息

批准号：
8197889
负责人：
FOREST L ROHWER
金额：
$ 47.52万
依托单位：
SAN DIEGO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197889
关键词：
Anaerobic Bacteria Antibiotic Therapy Antibiotic susceptibility Antibiotics Bacteriophages Biomass Breathing Cessation of life Chemicals Chronic Cicatrix Clinical Communicable Diseases Communities Computer Simulation Coughing Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Data Set Deoxyribonucleases Disease Dyspnea Ecology Fluorescent in Situ Hybridization Gases Genes Genus staphylococcus Goals Growth Haemophilus influenzae Health Hereditary Disease Human Individual Infection Ion Channel Lead Life Expectancy Link Literature Lobe Lung Measures Mediating Medical Metabolic Metagenomics Methods Metric Microbe Microbial Biofilms Microbiology Microscopy Modeling Mucociliary Clearance Mucous body substance Outcome Patients Physiology Production Pseudomonas aeruginosa Recombinant DNA Respiration Respiratory Failure Respiratory physiology Running Saline Severity of illness Sinusitis Sputum Statistical Models Steroids Streptococcus Taxonomy Testing Time Tissue Sample Treatment Protocols Viral Virulent Virus Work aggressive therapy airway remodeling alternative treatment base cystic fibrosis patients disease-causing mutation experience improved lung lobe metagenome microbial microbial community pathogen public health relevance response therapy design volunteer

项目摘要

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is a genetic disease that dramatically decreases life expectancy and quality. The disease is characterized by polymicrobial infections, which lead to lung remodeling and airway mucus plugging. CF patients experience intermittent exacerbations that cause airway scarring and eventually result in seriously impaired respiration. Despite aggressive therapy, most CF patients will die from respiratory failure caused by the chronic lung infections. Standard clinical microbiological studies and antibiotic susceptibility testing have severe limitations in predicting medical outcomes from specific therapies. This is due in part because the dynamics of microbes and their viral predators (phage) are essentially unknown in the CF lung. The goal of this study is to use metagenomics and microscopy to characterize these two communities and determine how they change in response to perturbations such as disease severity, antibiotic treatments, and chemical treatments designed to break up the mucus plugs. The metagenomic data will be used to determine how the types and metabolic functions of both the viral and microbial communities change. Microbial growth rates and phage-mediated death will also be measured. To better understand the spatial dynamics of the microbial and viral communities, we will also be dissecting lungs of CF patients. Viral and microbial metagenomes from individual lobes will be sequenced. To determine where specific species of microbes reside in the mucus plugs, fluorescent in situ hybridization with 16S rDNA probes will used on tissue samples. Together these data sets will be used to parameterize three complementary ecological models of the CF lung. Then these models will be used as in silico tests of alternative treatment regimes (e.g., adjust timing of antibiotic administration). When completed, we will have generated an unprecedented view of the viral and microbial communities in CF and how they respond to treatments. With the models, we will be able to better understand the dynamics of these communities and test alternative treatment regimes to prolong and improve the lives of CF patients. PUBLIC HEALTH RELEVANCE: It is increasingly recognized that ecological approaches can help control infectious diseases and promote human health. The goal of this proposal is to use microbial ecology methods to better understand and control the devastating disease Cystic Fibrosis.

描述（由申请人提供）：囊性纤维化（CF）是一种遗传疾病，可大大降低预期寿命和质量。该疾病的特征是多数菌感染，导致肺部重塑和气道粘液塞。 CF患者经历了间歇性加重，导致气道疤痕，并最终导致呼吸严重受损。尽管进行了积极的治疗，但大多数CF患者仍会因慢性肺部感染引起的呼吸衰竭而死亡。标准的临床微生物研究和抗生素易感性测试在预测特定疗法的医疗结果方面存在严重限制。这部分是因为在CF肺中，微生物及其病毒捕食者（噬菌体）的动力学本质上是未知的。这项研究的目的是使用宏基因组学和显微镜来表征这两个群落，并确定它们如何改变疾病严重程度，抗生素治疗和旨在打破粘液塞的化学处理的响应。宏基因组数据将用于确定病毒和微生物群落的类型和代谢功能如何变化。还将测量微生物生长速率和噬菌体介导的死亡。为了更好地了解微生物和病毒群落的空间动力学，我们还将解剖CF患者的肺部。将测序来自单个叶的病毒和微生物宏基因组。为了确定特定物种在粘液塞中的位置，将与16S rDNA探针的原位原位杂交在组织样品上使用。这些数据集将共同用于参数化CF肺的三个互补生态模型。然后，这些模型将与替代治疗方案的硅测试（例如，调整抗生素给药的时机）一起使用。完成后，我们将对CF中的病毒和微生物群落以及它们如何应对治疗产生前所未有的观点。有了这些模型，我们将能够更好地了解这些社区的动态，并测试替代治疗方案，以延长和改善CF患者的生活。公共卫生相关性：越来越多地认识到，生态学方法可以帮助控制传染病并促进人类健康。该建议的目的是使用微生物生态学方法更好地理解和控制毁灭性疾病囊性纤维化。