NRG/HER Restoration of the Lung Epithelium After Injury

描述（由申请人提供）：在美国，急性肺损伤及其相关的肺上皮损伤和由此产生的纤维化发生率约为20/10万/年。肺上皮细胞、生长因子及其同源受体在这种恢复中起积极作用。然而，哪些生长因子和受体参与其中，以及它们所指导的过程尚不清楚。我的实验室已经在肺中发现了一个膜结合受体酪氨酸激酶家族，即人表皮生长因子样受体家族（HER2、3和4），其表达局限于肺上皮。我们对HER系统及其配体神经调节蛋白-1 （NRG-1）的研究表明，它们在肺上皮细胞损伤后的恢复中发挥重要作用。在肺损伤期间或之后，肺上皮细胞中HER2/HER3受体的激活通过促纤维化细胞因子级联反应指导纤维化反应，并促进上皮细胞修复。本课题的目标是在体内利用NRG-1/HER2/HER3轴肺特异性缺陷的转基因小鼠来验证这一假设，并在体外确定受体激活和下游信号传导的机制。在这项应用中，我们提出：1)利用具有肺特异性表达显性阴性her受体的独特转基因小鼠菌株，确定HER2/HER3受体复合物在纤维化细胞因子级联反应中的调节作用；2)确定损伤期间HER2/HER3受体激活导致纤维化细胞因子产生的机制；3)使用显性阴性STAT3分子了解HER2/HER3诱导的STAT3激活及其在上皮修复中的作用。博莱霉素和机械损伤模型将在体内和体外启动肺损伤，并确定HER2/HER3受体激活和失活对上皮纤维化、炎症、增殖和凋亡能力的影响。鉴定在肺修复过程中重要的生长因子、受体和诱导信号将为纤维化或其他肺损伤患者确定新的治疗策略奠定基础。

DESCRIPTION (provided by applicant): Acute lung injury with its associated damage to the pulmonary epithelium and the resultant fibrosis affects approximately 20/100,000 /year in the US. Pulmonary epithelial cells, growth factors and their cognate receptors play an active role in this recovery. However, which growth factors and receptors participate and what processes they direct remains unclear. My laboratory has identified a membrane bound receptor tyrosine kinase family in the lung, the human epidermal growth factor-like receptor family (HER2, 3 and 4), whose expression is localized to the pulmonary epithelium. Our studies of the HER system and its ligand, Neuregulin-1 (NRG-1), suggest they play an important role in the recovery of pulmonary epithelial cells from injury. This knowledge has led us to hypothesize that: Activation of the HER2/HER3 receptor in pulmonary epithelial cells during or after lung injury directs a fibrotic response via the elaboration of pro-fibrotic cytokine cascades and promotes epithelial cell repair. The goal of this proposal is to test this hypothesis in vivo using transgenic mice with lung specific defects in the NRG-1/HER2/HER3 axis and define mechanisms of receptor activation and downstream signaling in vitro. In this application we propose to: 1) Define the HER2/HER3 receptor complex's role in the regulation of fibrotic cytokine cascades using unique transgenic mouse strains with lung specific expression of a dominant negative HERS receptor, 2) Define mechanisms of HER2/HER3 receptor activation during injury that results in fibrotic cytokine production, and 3) Use a dominant negative STAT3 molecule to understand the HER2/HER3 induced activation of STAT3, and its role in repair of the epithelium. Bleomycin and mechanical injury models will be used in vivo and in vitro to initiate lung injury and determine the effect(s) of HER2/HER3 receptor activation and inactivation on the epithelium's ability to direct fibrosis, inflammation, proliferation, and apoptosis. The identification of growth factors, receptors, and induced signals important in the pulmonary repair process will lay the groundwork for identification of new therapeutic strategies for patients with fibrotic or otherwise damaged lungs.