Midcareer Investigator Patient-oriented Research Award in Bronchiolitis & Asthma

描述(申请人提供)：哮喘是宿主和环境相互作用的结果。由呼吸道合胞病毒(RSV)和鼻病毒(RV)等病毒引起的下呼吸道感染(LRTI)是婴儿毛细支气管炎的主要原因。婴儿 毛细支气管炎住院不仅发病率很高，而且反复喘息和儿童哮喘的风险也显著增加。我们已经确定，呼吸道合胞病毒感染似乎直接导致哮喘的原因，而不仅仅是简单地确定有可能随后发生喘息的人。婴儿期以外的病毒感染也很重要，因为它们是可改变的环境因素，已被确定为儿童和成人哮喘恶化的最常见原因。这项建议使用临床和实验相结合的平行方法来评估呼吸道合胞病毒和人类鼻病毒在哮喘发展和疾病自然病程中的贡献、因果关系和机制。这些研究都与一个中心假设有关，即病毒作为一个重要的环境因素，改变了哮喘的发病风险，以及流行疾病的自然病史。与这一假设相关的具体可检验问题包括：1)确定RSV和HRV感染者中导致哮喘发生的宿主因素；2)确定婴儿时期感染的时间及其对儿童哮喘发病风险的影响；3)确定RSV和HRV促进哮喘发生的机制，特别是关注肺损伤和对感染的差异免疫反应；4)确定与呼吸道病毒感染的严重程度有关的宿主基因是否存在等位基因变异，这些基因与婴儿毛细支气管炎和儿童哮喘的易感性或抵抗力有关；5)确定RSV基因是否存在等位基因变异，这些变异与婴儿LRTI的严重程度和随后发生哮喘的风险有关。

DESCRIPTION (provided by applicant): Asthma is the result of host and environment interactions. Lower respiratory tract infections (LRTI), caused by viruses such as respiratory syncytial virus (RSV) and rhinovirus (RV), are a leading cause of bronchiolitis in infants. Infants hospitalized with bronchiolitis not only experience significant morbidity, but are also at significantly increased risk for both recurrent wheezing and childhood asthma. We have established that respiratory syncytial viral infections appear to directly contribute to asthma causation, not just simply identify persons at risk for subsequent wheezing. Viral infections outside the infant period are also important, as they are modifiable environmental factors that have been established to be the most common cause of asthma exacerbations in both children and adults. This proposal uses a combined, parallel clinical and experimental approach to evaluate the contribution of, causality, and mechanisms through which respiratory syncytial virus, and human rhinovirus, contribute to asthma development and disease natural history. These studies all relate to the central hypothesis that viruses, as one significant environmental factor, alter the risk for developing asthma, as well as the natural history of prevalent disease. Specific testable questions related to this hypothesis include: 1) to determine the host factors among those with RSV and HRV infection that contribute to asthma development, 2) to determine the timing of infection during infancy and how that impacts the risk of developing childhood asthma; 3) to determine the mechanisms through which RSV and HRV contribute to asthma development, specifically focusing on lung injury and differential immune response to infection; 4) to determine if there are allelic variations in host genes involved with severity of respiratory viral infection that correlate with a predisposition or resistance to both infant bronchiolitis and childhood asthma; 5) to determine if there are allelic variation in RSV genes that are associated with both infant LRTI severity, and subsequent risk of asthma development.