NRG/HER Restoration of the Lung Epithelium After Injury

描述（由申请方提供）：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的影响率约为20/100，000/年。肺上皮细胞、生长因子及其同源受体在这种恢复中起着积极的作用。 然而，哪些生长因子和受体参与以及它们指导的过程仍然不清楚。 我的实验室已经鉴定了肺中的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（HER 2、3和4），其表达定位于肺上皮。 我们对HER系统及其配体Neuregulin-1（NRG-1）的研究表明，它们在肺上皮细胞损伤的恢复中起重要作用。这一知识使我们假设：在肺损伤期间或之后，肺上皮细胞中HER 2/HER 3受体的激活通过促纤维化细胞因子级联的产生指导纤维化反应并促进上皮细胞修复。 本提案的目的是使用NRG-1/HER 2/HER 3轴中具有肺特异性缺陷的转基因小鼠在体内测试该假设，并定义体外受体激活和下游信号传导的机制。 在本申请中，我们提出：1）使用具有显性阴性HERS受体的肺特异性表达的独特转基因小鼠品系，确定HER 2/HER 3受体复合物在纤维化细胞因子级联调节中的作用，2）确定导致纤维化细胞因子产生的损伤期间HER 2/HER 3受体活化的机制，和3）使用显性负性STAT 3分子来理解HER 2/HER 3诱导的STAT 3活化及其在上皮修复中的作用。 博来霉素和机械损伤模型将在体内和体外用于引发肺损伤并确定HER 2/HER 3受体活化和失活对上皮细胞指导纤维化、炎症、增殖和凋亡的能力的影响。 对肺修复过程中重要的生长因子、受体和诱导信号的鉴定将为鉴定肺纤维化或其他损伤患者的新治疗策略奠定基础。

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.