Investigating Effects of Viral Infection on Lung Development

研究病毒感染对肺部发育的影响

• 批准号: 8107564
• 负责人: Robert F Lemanske
• 金额: $ 50.19万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/8107564
• 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

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)

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