Investigating Effects of Viral Infection on Lung Development

描述(由申请人提供)： 哮喘是一种异质性疾病，许多患者在儿童早期就开始发病。儿童哮喘的一个临床特征--肺功能丧失--特别令人担忧，因为它似乎发生在大多数患者生命的头5-6年内，而且即使经过适当的治疗，随着时间的推移，这种情况是不能逆转的。关于这种肺功能的丧失，有两个因素得到了最广泛的支持，这两个因素基于动物模型和预期出生队列研究产生的人类数据的实验证据：特应性(与某种形式的免疫失调有关)和早期生命中的病毒性呼吸道疾病。啮齿动物模型产生的数据表明，在断奶动物中，而不是成年动物中，呼吸道病毒感染会启动长期的结构变化，这些变化在以后的生活中与慢性和反复发生的呼吸道阻塞有关。此外，这些反应是特应性啮齿动物株所特有的，似乎是通过改变细胞因子分泌模式来调节的，特别是病毒感染诱导的干扰素。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，表明在早期生命中病毒感染的背景下，免疫反应的类似变化可以导致肺功能的长期变化。在动物和人类模型中的这些结果导致我们现在提出这样的假设，即早期的病毒呼吸道感染通过扰乱肺发育的正常程序而改变长期的肺功能，而遗传因素，如低干扰素反应，婴儿特应性的关键生物标志物，加剧了这些感染的影响。为了评估这一假设，该应用程序建议聚集一个具有肺部发育、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团队。在啮齿动物模型和人类出生队列中进行的跨物种实验将在多个分子和基因水平上检验这一假说。最终，拟议的实验结果将显著提高我们预测、预防和治疗反复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，从婴儿期的喘息到儿童哮喘的进展与肺功能的丧失有关。这种不良的临床结果可能是由早期生命中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。这项赠款计划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的肺部的交互影响，目的是提高我们预测、预防和治疗反复喘息和儿童哮喘的能力。(摘要结束)

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)