The Effect of 17q21 Locus SNPs on Targeted Host Immune Responses in Children With Rhinovirus-induced Exacerbations of Asthma

项目摘要 这项研究的长期目标是阐明鼻病毒(RV)相关发展的机制驱动因素 以及哮喘的恶化，为临床预防和治疗管理战略提供信息。朝向这个方向 最后，我们将研究基因变异对先前确定的风险增加的功能影响17q21 哮喘儿童RVA和RVC感染时的基因座大量的基因研究揭示了一种 GSDMB/ORMDL3基因座基因变异增加哮喘发病风险 17q21。为此，我们将为RNAseq开发和验证RNA捕获探测集，该探测集将允许 鼻病毒感染与GSDMB、ORMDL3、ICAM1、IL17、 和I型干扰素途径。在体外验证了这种方法之后，我们将使用它来阐明基因的表达 从具有和不具有17q21风险的儿童急性轮状病毒感染期间获得的临床样本 多态现象。我们将检查是否存在促炎途径的差异上调，这些途径是 RVA和RVC感染之间哮喘的发展和恶化的既定贡献者 以确定17q21基因座的遗传变异的影响。综合来看，这些数据将 为儿科患者17q21基因座的遗传变异的后果提供了前所未有的见解 急性轮状病毒感染期间的哮喘人群。

Project Summary It is the long-term goal of this study is to elucidate mechanistic drivers of rhinovirus (RV)-associated development and exacerbations of asthma to inform clinical prevention and therapeutic management strategies. Towards this end, we will investigate the functional impact of genetic variations in the previously identified increased risk 17q21 locus in children with asthma during RVA and RVC infections. Numerous genetic studies have revealed an increased risk of the development of asthma with genetic variations in the GSDMB/ORMDL3 locus located on 17q21. To do this, we will develop and validate a RNA capture probeset for RNAseq which will allow for the simultaneous evaluation of rhinovirus infection and gene expression of the GSDMB, ORMDL3, ICAM1, IL17, and type I interferon pathways. After validation of this method in vitro, we will use it to elucidate gene expression from clinical samples obtained from children during acute RV infections with and without established 17q21 risk polymorphisms. We will examine if there is differential upregulation of pro-inflammatory pathways that are established contributors to the development and exacerbations of asthma between infections with RVA and RVC infections to determine the impact of the genetic variations in the 17q21 locus. Taken together, this data will provide unprecedented insight into the consequences of genetic variation in the 17q21 locus in a pediatric asthmatic population during acute RV infection.