Role of EGFR in Viral Infected Lung Epithelial Cells

描述（由申请人提供）：气道上皮的上皮细胞稳态是通过相互作用的信号通路网络维持的。呼吸道合胞病毒优先影响气道上皮，诱导炎症并最终导致细胞死亡。它也可能导致气道的长期变化（20-35%的严重呼吸道合胞病毒感染的婴儿继续发展为支气管高反应性增加）。该应用程序解决了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，这与随后MAP激酶、ERK和PI 3激酶依赖性Akt的激活有关。本项目的主要假设是EGFR在RSV感染的气道上皮细胞的寿命和炎症潜能中起核心作用。在Aim 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将重点关注EGFR在rsv诱导的炎症中的作用和延迟细胞凋亡的机制。在Aim 3中，我们将把EGFR的早期激活与双链RNA受体TLR3的后期诱导联系起来。我们将研究TLR3对炎症和细胞凋亡的诱导作用。这些研究的完成将增加我们对呼吸道合胞病毒感染气道上皮的机制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的理解。

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.