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: 7714231
• 负责人: Robert F Lemanske
• 金额: $ 51.98万
• 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/7714231
• 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; Figs - dietary; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Goals; Growth; Growth Factor; Growth and Development function; 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; public health relevance; 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)

描述（由申请人提供）： 哮喘是一种异质性疾病，在童年时期许多患者中都有其发作。儿童期哮喘的一个临床特征，肺功能的丧失，特别关心，因为它在生命的头5-6年内似乎发生在大多数患者中，并且尽管有适当的治疗，但随着时间的流逝，这似乎是不可逆转的。关于这种肺功能的丧失，基于动物模型和前瞻性出生队列研究产生的人类数据的两个促成因素得到了最广泛的支持：特应性（与某种形式的免疫失调）和早期的病毒呼吸道疾病有关。由啮齿动物模型产生的数据表明，断奶动物而不是成年动物的呼吸道病毒感染引发了长期结构变化，这些变化与慢性和经常性气道阻塞有关。此外，这些反应是针对特应啮齿动物菌株的特异性，并且似乎通过改变的细胞因子分泌模式（尤其是因病毒感染引起的干扰素）来调节。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，表明在早期病毒感染的背景下，免疫反应的类似变化可能导致肺功能的长期改变。这些导致动物和人类模型的结果使我们现在提出了以下假设：早期生命中的病毒呼吸道感染通过破坏肺部发育的正常程序以及诸如小干扰素反应（婴儿体育体育酶的关键生物标志物）等遗传因素的遗传因素来改变长期的肺功能，这是婴儿体育期间的关键生物标志物，这会增强这些感染的影响。为了评估这一假设，该申请提议收集一个具有肺部发育，免疫学，病毒学，肺部生理学和生物统计学专业知识的研究人员的多学科研究团队。啮齿动物模型和人类出生队列中的跨物种实验将在多个分子和遗传水平上检验假设。最终，提出的实验的结果将显着提高我们预测，预防和治疗复发性喘息和童年哮喘的能力。 公共卫生相关性：对于许多儿童而言，从婴儿期喘息到童年哮喘的进展与肺功能的丧失有关。这种不良临床结果可能是由于对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而引发的。该赠款提案将使用动物和人类模型来研究呼吸道病毒感染和宿主遗传因素对发育中肺的交互作用，以提高我们预测，预测，预防和治疗复发性喘息和童年哮喘的能力。 （抽象的结尾）