Epithelial cell homeostasis in airway epithelium is maintained via a network of interacting signaling pathways. Respiratory syncytial virus preferentially affects airway epithelium inducing inflammation and, ultimately, death of the cells. It may also result in long-term changes in the airways (20-35% of infants with serious RSV infections go on to develop increased bronchial hyperreactivity). This application addresses the role of EGFR in modulating RSV-induced inflammation and apoptosis. Our preliminary data demonstrate that RSV activates EGFR and that this is linked to subsequent activation of the MAP kinase, ERK, and PI 3-kinase- dependent Akt. The primary hypothesis of this project is that EGFR plays a central role in the life span and inflammatory potential of RSV infected airway epithelial cells.
In Aim 1 we will explore the hypothesis that RSV activates EGFR, contributing to PI 3-kinase/Akt and ERK activity.
Aim 2 will focus on the role of EGFR in RSV-induced inflammation and mechanisms of delayed apoptosis.
In Aim 3, we will link the early activation of EGFR to later induction of the receptor for double stranded RNA, TLR3. We will study the effect of TLR3 induction on inflammation and apoptosis. Completion of these studies will add to our understanding of mechanisms of RSV infection of airway epithelium and the role of targeted signaling pathways in the subsequent inflammation and life span of infected cells. ? ?
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|Gross, Thomas J; Kremens, Karol; Powers, Linda S et al. (2014) Epigenetic silencing of the human NOS2 gene: rethinking the role of nitric oxide in human macrophage inflammatory responses. J Immunol 192:2326-38|
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|Graff, Joel W; Powers, Linda S; Dickson, Anne M et al. (2012) Cigarette smoking decreases global microRNA expression in human alveolar macrophages. PLoS One 7:e44066|
|Hassan, Ihab H; Zhang, Michael S; Powers, Linda S et al. (2012) Influenza A viral replication is blocked by inhibition of the inositol-requiring enzyme 1 (IRE1) stress pathway. J Biol Chem 287:4679-89|
|Philibert, Robert A; Sears, Rory A; Powers, Linda S et al. (2012) Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression. J Leukoc Biol 92:621-31|
|Reisetter, Anna C; Stebounova, Larissa V; Baltrusaitis, Jonas et al. (2011) Induction of inflammasome-dependent pyroptosis by carbon black nanoparticles. J Biol Chem 286:21844-52|
|Hansdottir, Sif; Monick, Martha M (2011) Vitamin D effects on lung immunity and respiratory diseases. Vitam Horm 86:217-37|
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