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

项目总结

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.