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

项目摘要 本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 和哮喘恶化的信息，以告知临床预防和治疗管理策略。为实现这一 最后，我们将研究遗传变异在先前确定的17 q21风险增加中的功能影响。 哮喘儿童在RVA和RVC感染期间的位置。许多遗传学研究表明， GSDMB/ORMDL 3基因座遗传变异导致哮喘发生的风险增加， 17q21.为此，我们将开发并验证RNAseq的RNA捕获概率， 同时评价鼻病毒感染和GSDMB、ORMDL 3、ICAM 1、IL 17 和I型干扰素途径。在体外验证该方法后，我们将使用它来阐明基因表达 从急性RV感染期间有和无确定的17 q21风险的儿童中获得的临床样本 多态性我们将检查促炎通路是否存在差异性上调， 在RVA和RVC感染之间确定的哮喘发生和加重的因素 感染，以确定17 q21基因座中遗传变异的影响。综合起来，这些数据将 提供了前所未有的深入了解17 q21基因座遗传变异的后果，在儿科 急性RV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.