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发病。儿童哮喘的一个临床特征是肺功能丧失，这一点特别令人关注，因为它似乎发生在大多数患者生命的前5-6年内，并且尽管进行了适当的治疗，但随着时间的推移是不可逆的。关于这种肺功能丧失，基于动物模型和前瞻性出生队列研究产生的人类数据的实验证据，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有关）和生命早期的病毒性呼吸道疾病。啮齿动物模型产生的数据表明，呼吸道病毒感染在断奶动物，但不是成年动物，启动长期的结构变化，在以后的生活与慢性和复发性气道阻塞。此外，这些反应是特异性的特应性啮齿动物菌株，似乎是通过改变细胞因子分泌模式，特别是干扰素诱导的病毒感染进行调节。最重要的是，我们的研究小组现在有一项儿童出生队列哮喘研究的相关数据，表明在生命早期病毒感染的背景下，免疫反应的类似改变可能导致肺功能的长期改变。动物和人类模型的这些结果现在使我们提出这样的假设，即早期生命中的病毒性呼吸道感染通过破坏肺发育的正常程序来改变长期肺功能，并且遗传因素如低干扰素反应（婴儿期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，本申请建议召集一个多学科的研究人员团队，他们具有肺发育、免疫学、病毒学、肺生理学和生物统计学方面的专业知识。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遗传水平上检验这一假设。最终，拟议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儿童哮喘的能力。

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.