Role of the Epithelial Growth Factor Receptor in SARS Coronavirus Pathogenesis

描述（由申请人提供）：高致病性呼吸道病毒，如流感病毒和严重急性呼吸道冠状病毒（SARS-CoV），对整体公共卫生和全球经济稳定构成重大威胁。它们引起急性肺损伤（ALI），并迅速发展为ARDS，前者在老年人中最明显。此外，在病毒清除后，许多SARS和H5 N1患者发展为组织化阶段弥漫性肺泡损伤（DAD），其通常进展为肺纤维化（PF），这是另一种影响全球500万人的毁灭性终末期肺病，其特征在于伤口修复期间细胞增殖失调。我们已经建立了一个遗传学上易于处理的模型，诱导急性肺损伤使用SARS-CoV。我们将使用该模型来研究决定从急性肺损伤到肺纤维化的进展的宿主因素和细胞类型。 我们的初步研究表明，表皮生长因子受体（EGFR）是SARS冠状病毒感染后急性肺损伤的关键介质，EGFR是调节急性肺损伤的先天性和创伤愈合反应的关键中间体。在目标1中，我们将确定EGFR过度活化如何导致疾病恶化。在目标2中，我们将检查EGFR信号传导的抑制是否可以保护宿主免于疾病进展，并且在目标2中，我们将鉴定EGFR对于疾病进展是必需的细胞类型。这些研究将使我们能够确定负责急性肺疾病和ARDS发展的细胞。目前肺纤维化的治疗是钝的，治疗整个个体，而不是针对特定的细胞群体。这些疗法仅在一小部分患者中起作用，并且可能产生比治疗更多的损伤。这些研究将确定导致急性肺疾病诱导和进展的特定细胞类型，从而允许细胞定向治疗和靶向干预。

DESCRIPTION (provided by applicant): Highly pathogenic respiratory viruses, like the influenza virus and Severe Acute Respiratory Coronavirus (SARS-CoV), represent significant threats to the overall public health and to global economic stability. They cause an acute lung injury (ALI) that rapidly progresses to ARDS, the former most notably in the elderly. Moreover, after virus clearance many SARS and H5N1 patients developed an organizing phase diffuse alveolar damage (DAD) that oftentimes progresses to pulmonary fibrosis (PF), another devastating end stage lung disease effecting 5 million people globally, characterized by dysregulated cell proliferation during wound repair. We have developed a genetically tractable model of induced acute lung injury using the SARS-CoV. We will use this model to study the host factors and cell types that determine the progression from acute lung injury to pulmonary fibrosis. Our preliminary studies demonstrate that the Epithelial Growth Factor Receptor (EGFR) is a key mediator of acute lung injury after infection with the SARS Coronavirus and EGFR is a key intermediate in the regulation of both the innate and wound healing response to acute lung injury. In Aim 1 we will identify how EGFR over activation causes exacerbated disease. In Aim 2 we will examine whether inhibition of EGFR signaling can protect the host from disease progression and in Aim 2 we will identify the cell type where EGFR is necessary for disease progression. These studies will allow us to identify the cells that are responsible for the development of acute lung disease and ARDS. The current therapy for pulmonary fibrosis is blunt and treats the whole individual rather than targeting a specific cell population. These therapies work in only a fraction of the patients and can potentially produce more damage than they treat. These studies will identify the specific cell types that lead to acute lung disease induction and progression, allowing for cell directed therapies and targets interventions.