Modeling severe respiratory syncytial virus pathogenesis in bronchopulmonary dysplasia

项目摘要/摘要 目前，RSV促进疾病发展的分子和细胞机制 儿童支气管肺发育不良(BPD)的感染是难以捉摸的，主要是由于缺乏动物研究。 在这组高危患者中模拟严重的呼吸道合胞病毒感染。我们最近在临床上建立了一个- 早产儿与BPD实验室相关新生儿高氧模型的建立。在此应用程序中，我们希望使用此 在BPD宿主中检测RSV感染后严重疾病发展机制的模型。二 具体目标被提出：目的1：检验新生儿高氧血症使宿主易感的假设 严重的呼吸道合胞病毒相关疾病。目标2：检验夸大Gadd45b的假设 在BPD宿主中，表达促进急性RSV相关疾病。 关联性陈述 呼吸道合胞病毒(RSV)是婴幼儿严重下呼吸道疾病最常见的病因。 严重的呼吸道合胞病毒感染在早产儿中尤为突出，在患有BPD的儿童中尤其危险。 早产儿的慢性肺部疾病，其特征是发育异常 结构和功能。值得注意的是，由于BPD存活率的提高，BPD的发病率在全球范围内正在增加。 极早产儿。早产儿或BPD婴儿首次出院后，病毒呼吸道 感染，最常见的是RSV，导致住院人数增加，医疗保健利用率增加， 呼吸道疾病。这些临床数据表明，早产患者，特别是bpd患者， 容易感染呼吸道合胞病毒，并在呼吸道合胞病毒感染后发展成严重的肺部疾病。《知识》 这项研究将极大地提高我们对RSV在BPD宿主中致病性的理解。 此外，我们期望这一应用将为新的治疗策略打开大门。 旨在将BPD患者的病毒致病机制和慢性肺部疾病降至最低(例如，针对 Gadd45b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).