Viral Pathogenesis of Early Cystic Fibrosis Lung Disease

早期囊性纤维化肺病的病毒发病机制

• 批准号: 8410771
• 负责人: Stephanie Duggins Davis
• 金额: $ 60.53万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410771
• 关键词: Adoption; Age-Months; Air; Australia; Bacterial Infections; Biological Assay; Bronchiectasis; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell Death; Cells; Child; Chloride Channels; Clinical Trials; Cystic Fibrosis; Defect; Detection; Development; Diagnosis; Disease; Environment; Environmental air flow; Epithelial; Etiology; Event; Evolution; Frequencies; Image; Immune; Incidence; Indiana; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Irrigation; Kinetics; Lead; Life; Liquid substance; Lower Respiratory Tract Infection; Lung; Lung diseases; Measurement; Measures; Mediator of activation protein; Methods; Missouri; Modeling; Morbidity - disease rate; Mucociliary Clearance; Neonatal Screening; Normalcy; Nose; Nucleic Acids; Organism; Pathogenesis; Physiological; Pulmonary Cystic Fibrosis; Reporting; Research; Resources; Respiratory physiology; Role; Structure of respiratory epithelium; Surveillance Program; Symptoms; Techniques; Testing; Therapeutic; Time; Universities; Viral Pathogenesis; Virus; Virus Diseases; Washington; abstracting; airway epithelium; airway inflammation; airway obstruction; base; computerized; cystic fibrosis airway; design; early cystic fibrosis; infancy; inflammatory marker; injured airway; innovation; insight; lung volume; mortality; prevent; pulmonary function; respiratory; respiratory infection virus; respiratory virus; treatment strategy

DESCRIPTION (provided by applicant): The development and evolution of CF lung disease can be variable, but it is clear from our previous research that physiological and structural defects begin in infancy and are frequently present prior to the detection of bacterial infection, implicating other etiologies or infectious insults. Little is known about the impact of viruses on bacterial colonization, airway inflammation, physiological measures, and structural changes in the CF lung. In this proposal, we will define the role(s) of viral infections in the origins of eary CF pulmonary disease. Combining the expertise and resources available at the University of Indiana (Indianapolis, Indiana), Washington University (St. Louis, Missouri), and the Australian Early Surveillance Team for Cystic Fibrosis (AREST CF) (Melbourne and Perth, Australia), we will define the incidence and type of viral infections in CF infants. Bronchoalveolar lavage fluid and pharyngeal secretions will be collected at predetermined times during infancy, and highly sensitive nucleic acid-based detection and powerful microbiomic assays will be used to characterize lower respiratory tract infections. Also, we will systematically define the earliest physiological changes in the CF lung, combining analyses for inflammatory markers in lavage fluid, pulmonary function measurements, and computerized x-ray tomographic imaging, in a surveillance program for infants diagnosed shortly after newborn screening. Innovative airway modeling techniques will be applied to better detect and measure airway disease that precedes bronchiectasis. We will examine the relationship between viral infections and initial pathophysiological changes in the CF lung, and test the hypothesis that early respiratory viral infections alter the bacterial flora and inflammatory profile in the airway and accelerate progression of pulmonary disease in CF infants. The proposal has three Specific Aims, which will (i) define the frequency of respiratory virus infections and their impact on the evolution of endobronchial bacterial infection and inflammation in CF infants; (ii) examine the impact of early virus infections on the development of respiratory symptoms and physiological changes in the lungs of CF infants; and (iii) evaluate the relationship between virus infections and airway disease as de- fined by structural and airway modeling techniques. If successful, these studies will provide new insights into the pathogenesis of CF lung disease, aid the design of therapeutic strategies to reduce virus-induced pulmonary morbidity, and potentially prevent the development of irreversible airway disease. (End of Abstract)

描述（由申请人提供）： CF 肺病的发展和演变可能是可变的，但从我们之前的研究中可以清楚地看出，生理和结构缺陷始于婴儿期，并且经常在检测到细菌感染之前出现，从而暗示其他病因或传染性的侮辱。人们对病毒对细菌定植、气道炎症、生理指标和 CF 肺结构变化的影响知之甚少。在本提案中，我们将定义病毒感染在早期 CF 肺部疾病起源中的作用。结合印第安纳大学（印第安纳州印第安纳波利斯）、华盛顿大学（密苏里州圣路易斯）和澳大利亚囊性纤维化早期监测小组 (AREST CF)（澳大利亚墨尔本和珀斯）的专业知识和资源，我们将定义 CF 婴儿病毒感染的发生率和类型。将在婴儿期的预定时间收集支气管肺泡灌洗液和咽部分泌物，并使用高度灵敏的核酸检测和强大的微生物检测来表征下呼吸道感染。此外，我们将在新生儿筛查后不久诊断的婴儿的监测计划中，结合灌洗液中炎症标志物的分析、肺功能测量和计算机 X 射线断层扫描成像，系统地定义 CF 肺的最早生理变化。创新的气道建模技术将用于更好地检测和测量支气管扩张之前的气道疾病。我们将研究病毒感染与 CF 肺部初始病理生理变化之间的关系，并检验早期呼吸道病毒感染改变气道细菌群和炎症特征并加速 CF 婴儿肺部疾病进展的假设。该提案有三个具体目标，即 (i) 确定 CF 婴儿呼吸道病毒感染的频率及其对支气管内细菌感染和炎症演变的影响； (ii) 检查早期病毒感染对 CF 婴儿呼吸道症状和肺部生理变化的影响； (iii) 评估由结构和气道建模技术定义的病毒感染和气道疾病之间的关系。如果成功，这些研究将为 CF 肺部疾病的发病机制提供新的见解，有助于设计治疗策略以减少病毒引起的肺部发病率，并有可能预防不可逆气道疾病的发展。 （摘要完）