Investigating Effects of Viral Infection on Lung Development

研究病毒感染对肺部发育的影响

基本信息

批准号：
8319424
负责人：
Robert F Lemanske
金额：
$ 48.24万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319424
关键词：
Acute Address Air Animal Model Animals Applications Grants Asthma Biological Markers Biometry Birth Candidate Disease Gene Child Childhood Childhood Asthma Chronic Clinical Cohort Studies Data Defect Development Disease Disease susceptibility Elderly Environmental Risk Factor Epithelial Feedback Fibrosis Genes Genetic Genetic Models Genetic Predisposition to Disease Goals Growth Growth Factor Growth and Development function Health Human Immune Immune response Immune system Immunologics Immunology Individual Infection Interferons Lead Life Link Lung Lung diseases Measures Mediating Modeling Molecular Molecular Genetics Mus Mutant Strains Mice Norway Oscillometry Outcome Patients Pattern Physiology Production Rat Strains Rattus Recurrence Research Research Personnel Residual volume Respiratory Tract Infections Respiratory physiology Rodent Rodent Model Single Nucleotide Polymorphism Spirometry Testing Time Total Lung Capacity Viral Virus Virus Diseases Wheezing abstracting airway obstruction atopy base chemokine cohort critical period cytokine early childhood human data in vivo infancy infant outcome lung development mature animal multidisciplinary preconditioning prevent programs prospective research study respiratory respiratory infection virus response virology weanling animal

项目摘要

DESCRIPTION (provided by applicant): Asthma is a heterogeneous disorder that has its onset in many patients within early childhood. One clinical feature of childhood asthma, loss of lung function, has been of particular concern because it appears to occur in the majority of patients within the first 5-6 years of life and is not reversible over time despite appropriate treatment. Regarding this loss of lung function, two contributing factors have received the most widespread support based on experimental evidence in both animal models and human data generated from prospective birth cohort studies: atopy (related to some form of immune dysregulation) and viral respiratory illnesses in early life. Data generated from rodent models indicate that respiratory viral infection in weanling animals, but not adult animals, initiates long-term structural changes that are associated in later life with chronic and recurrent airway obstruction. Furthermore, these responses are specific to an atopic rodent strain and appear to be regulated through altered cytokine secretion patterns, particularly interferons induced by the viral infection. Most importantly, our research group now has correlative data from a childhood birth cohort asthma study demonstrating that similar alterations in immune response in the context of viral infections in early life can lead to long-term alterations in lung function. These results in both animal and human models lead us now to propose the hypothesis that viral respiratory infections in early life alter long-term lung function by disrupting the normal program of lung development, and genetic factors such as low interferon responses, a key biomarker of atopy in infancy, intensify the impact of these infections. To evaluate this hypothesis, this application proposes to gather a multidisciplinary team of investigators with expertise in lung development, immunology, virology, pulmonary physiology and biostatistics. Cross-species experiments in rodent models and human birth cohorts will test the hypothesis on multiple molecular and genetic levels. Ultimately, the results of the proposed experiments will significantly advance our ability to predict, prevent, and treat recurrent wheezing and childhood asthma. PUBLIC HEALTH RELEVANCE: For many children, the progression from wheezing during infancy to childhood asthma is associated with loss of lung function. This adverse clinical outcome may be initiated by an aberrant immune response to respiratory viral infections during critical periods of lung growth and development in early life. This grant proposal will use animal and human models to investigate interactive effects of respiratory virus infections and host genetic factors on the developing lung, with the goal of increasing our ability to predict, prevent and treat recurrent wheezing and childhood asthma. (End of Abstract)

描述（由申请人提供）：哮喘是一种异质性疾病，许多患者在幼儿期发病。儿童哮喘的一个临床特征，即肺功能丧失，一直受到特别关注，因为它似乎发生在大多数患者出生后的前 5-6 年内，并且即使经过适当的治疗，也不会随着时间的推移而逆转。关于肺功能的丧失，根据动物模型的实验证据和前瞻性出生队列研究产生的人类数据，有两个因素得到了最广泛的支持：特应性（与某种形式的免疫失调有关）和早期的病毒性呼吸道疾病。生活。啮齿动物模型产生的数据表明，断奶动物而非成年动物的呼吸道病毒感染会引发长期的结构变化，这些变化与以后的生活中慢性和复发性气道阻塞有关。此外，这些反应是特应性啮齿动物品系所特有的，并且似乎是通过改变细胞因子分泌模式（特别是由病毒感染诱导的干扰素）来调节的。最重要的是，我们的研究小组现在拥有来自儿童出生队列哮喘研究的相关数据，表明生命早期病毒感染背景下免疫反应的类似改变可能导致肺功能的长期改变。这些在动物和人类模型中的结果使我们现在提出这样的假设：生命早期的病毒性呼吸道感染通过破坏肺发育的正常程序和遗传因素（例如低干扰素反应，这是肺发育不良的关键生物标志物）来改变长期肺功能。婴儿期的特应性加剧了这些感染的影响。为了评估这一假设，本申请建议聚集一个由肺发育、免疫学、病毒学、肺生理学和生物统计学专业知识的多学科研究人员组成的团队。啮齿动物模型和人类出生队列的跨物种实验将在多个分子和遗传水平上检验这一假设。最终，所提出的实验结果将显着提高我们预测、预防和治疗复发性喘息和儿童哮喘的能力。公共卫生相关性：对于许多儿童来说，从婴儿期喘息发展为儿童期哮喘与肺功能丧失有关。这种不良的临床结果可能是由生命早期肺部生长和发育的关键时期对呼吸道病毒感染的异常免疫反应引起的。该拨款提案将使用动物和人体模型来研究呼吸道病毒感染和宿主遗传因素对肺部发育的相互作用影响，目的是提高我们预测、预防和治疗复发性喘息和儿童哮喘的能力。（摘要完）