Modeling severe respiratory syncytial virus pathogenesis in bronchopulmonary dysplasia

项目概要/摘要 目前，RSV增强疾病发展的分子和细胞机制 支气管肺发育不良（BPD）儿童的感染很难确定，主要是由于缺乏动物研究 在这组高危患者中模拟严重RSV感染。我们最近建立了一个临床- 在实验室建立了早产儿和BPD相关的新生儿高氧模型。在本申请中，我们希望使用 模型，以检查BPD宿主中RSV感染后严重疾病发展的机制。两 目的1：验证新生儿高氧易患宿主的假设 严重的RSV相关疾病。目的2：检验夸大Gadd 45 b的假设 表达促进BPD宿主中的急性RSV相关疾病。 相关性说明 呼吸道合胞病毒（RSV）是婴儿严重下呼吸道疾病的最常见原因。 严重的RSV感染在早产儿中是突出的，在患有BPD的儿童中特别危险， 早产儿的慢性肺病，特征是肺发育异常， 结构和功能。值得注意的是，BPD的发病率在全球范围内增加，这是由于BPD患者的生存率提高。 极早产儿在早产儿或BPD婴儿初次出院后， 感染，最常见的是RSV，导致住院治疗，医疗保健利用增加， 呼吸道疾病这些临床数据表明，早产患者，特别是BPD患者， 易受RSV感染并在RSV感染后发展为严重的肺部疾病。知识 本研究的结果将显著提高我们对RSV在BPD宿主中致病性的理解。 此外，我们预计这一应用将有望为新的治疗策略打开大门 旨在最大限度地减少BPD患者的病毒发病机制和慢性肺部疾病（例如，靶向 Gadd 45 b途径）。

Project Summary/Abstract Currently, the molecular and cellular mechanisms underlying the enhanced disease development of RSV infection in children with bronchopulmonary dysplasia (BPD) is elusive, largely due to the lack of animal studies to model severe RSV infection in this at-risk group of patients. We have recently established a clinically- relevant neonatal hyperoxia model of prematurity and BPD in the lab. In this application, we wish to use this model to examine the mechanisms of severe disease development following RSV infection in BPD hosts. Two specific aims are proposed: Aim1: To test the hypothesis that neonatal hyperoxia predisposes the hosts to severe RSV-associated diseases. Aim 2: To test the hypothesis that exaggerated Gadd45b expression promotes acute RSV-associated diseases in BPD hosts. Relevance statement Respiratory syncytial virus (RSV) is the most frequent cause of serious lower respiratory-tract illness in infants. Severe RSV infection is prominent in preterm infants and particularly dangerous in children with BPD, a chronic lung disease of infants born extremely premature and characterized by abnormal development of structure and function. Of note, the incidence of BPD is increasing globally due to the improved survival rate of extremely premature infants. Following initial hospital discharge of preterm or BPD infants, viral respiratory infections, most commonly with RSV, result in increased hospitalization, healthcare utilization, and increased respiratory morbidity. These clinical data suggest that preterm patients, particularly BPD patients, are highly susceptible to RSV infection and develop severe pulmonary diseases following RSV infection. The knowledge generated from this study will significantly improve our understanding on RSV pathogenicity in BPD hosts. Furthermore, we expect that this application will promise to open the door for novel therapeutic strategies aiming to minimize viral pathogenesis and chronic lung conditions in BPD patients (for instance, targeting on Gadd45b pathway).