Role of EGFR in Viral Infected Lung Epithelial Cells

描述（由申请方提供）：气道上皮细胞的稳态通过相互作用的信号通路网络维持。呼吸道合胞病毒优先影响气道上皮细胞，诱导炎症，并最终导致细胞死亡。它还可能导致气道的长期变化（20-35%的严重RSV感染婴儿继续发展支气管高反应性增加）。本申请涉及EGFR在调节RSV诱导的炎症和细胞凋亡中的作用。我们的初步数据表明RSV激活EGFR，并且这与随后的MAP激酶、ERK和PI 3-激酶依赖性Akt的激活有关。该项目的主要假设是EGFR在RSV感染的气道上皮细胞的寿命和炎症潜力中起核心作用。在目的1中，我们将探讨RSV激活EGFR，促进PI 3-激酶/Akt和ERK活性的假设。目的2：探讨EGFR在RSV诱导的炎症反应中的作用及延迟凋亡的机制。在目标3中，我们将EGFR的早期激活与双链RNA受体TLR 3的后期诱导联系起来。我们将研究TLR 3诱导对炎症和细胞凋亡的影响。这些研究的完成将增加我们对呼吸道上皮细胞RSV感染机制的理解，以及靶向信号通路在随后的炎症和感染细胞寿命中的作用。

DESCRIPTION (provided by applicant): 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.