Epidermal Growth Factor Receptor Activation in Pulmonary Fibrosis

描述（由申请人提供）：肺纤维化是一种进行性且通常致命的疾病，并发于多种类型的人类肺部疾病。表皮生长因子受体（EGFR）介导由包括转化生长因子（TGF-β）在内的生长因子家族诱导的信号。该实验室和其他实验室的研究表明，EGFR配体在几种人类纤维化疾病（包括特发性肺纤维化（IFF））中增加。在转基因小鼠的上皮中TGF-β的表达引起进行性和广泛的肺纤维化，其组织学特征与在人类疾病中所见的非常相似。使用遗传或药理学方法预防或逆转TGF-β转基因小鼠中的纤维化，表明EGFR介导的纤维化是可行的治疗靶点。EGFR的磷酸化可以诱导几种下游信号传导途径，包括磷脂酰肌醇3 '-激酶（PI 3 K）-Akt途径。TGF-β转基因小鼠中EGFR的激活使上皮中的Akt磷酸化，并且加入到呼吸道上皮细胞中的TGF-β刺激促纤维化基因表达，这可以通过阻断PI 3 K信号传导来防止。本申请的长期目标是开发用于治疗人类肺纤维化的新颖且有效的治疗干预策略。本申请的目的是利用来自培养的肺细胞和纤维化转基因模型的数据来确定介导EGFR诱导的肺纤维化的信号传导机制，并确定这些途径是否在纤维化人类肺部疾病中增加。中心假设是通过PI 3 K增加EGFR信号传导诱导肺纤维化。为了验证这一假设，在目标1中，我们将使用模型人细胞系来确定EGFR诱导的导致胶原蛋白合成和细胞增殖的细胞内信号传导途径。在目标2中，我们将确定EGFR诱导的肺纤维化转基因模型中体内表达的EGFR诱导的信号分子，并使用IPF患者的良好表征的存档组织来评估EGFR和类似激酶是否被激活。转基因小鼠体内的初步数据显示，II型细胞产生调节纤维化的调节剂。在目标3中，我们将使用共培养物来确定表达TGF-β的II型细胞调节肺成纤维细胞的机制。完成拟议的研究将确定EGFR在肺纤维化中的作用，并提出改变人类肺纤维化进程的治疗靶点。

DESCRIPTION (provided by applicant): Pulmonary fibrosis is a progressive and often fatal disease complicating many types of human lung diseases. The epidermal growth factor receptor (EGFR) mediates signals induced by a family of growth factors including transforming growth factor-( (TGF-(). Studies from this laboratory and others have shown increased EGFR ligands in several human fibrotic diseases including idiopathic pulmonary fibrosis (IFF). Expression of TGF-( in the epithelium of transgenic mice caused progressive and extensive pulmonary fibrosis with histological features very similar to those seen in human disease. Fibrosis in TGF-( transgenic mice is prevented or reversed using genetic or pharmacological approaches signifying that EGFR-mediated fibrosis is a feasible therapeutic target. Phosphorylation of the EGFR can induce several downstream signaling pathways, including the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway. Activation of EGFR in TGF-( transgenic mice phosphorylates Akt in the epithelium and TGF-( added to respiratory epithelial cells stimulates profibrotic gene expression that can be prevented by blocking PI3K signaling. The long term goal of this application is to develop novel and effective therapeutic intervention strategies for the treatment of pulmonary fibrosis in humans. The objective of this application is to utilize data from cultured lung cells and transgenic models of fibrosis to determine signaling mechanisms mediating EGFR-induced pulmonary fibrosis and determine if these pathways are increased in fibrotic human lung disease. The central hypothesis is that that increased EGFR signaling via PI3K induces pulmonary fibrosis. To test this hypothesis, in Aim 1, we will use model human cell lines to determine EGFR-induced intracellular signaling pathways leading to synthesis of collagen and proliferation of cells. In Aim 2, we will determine EGFR-induced signaling molecules expressed in vivo in the transgenic model of EGFR-induced lung fibrosis and use well-characterized archival tissue of IPF patients to assess whether EGFR and similar kinases are activated. Preliminary data in the transgenic mice in vivo show that Type II cells produce modulators that regulate fibrosis. In Aim 3, we will use co-cultures to determine mechanisms whereby TGF-( expressing Type II cells regulate pulmonary fibroblasts. Completion of the proposed studies will determine a role of EGFR in lung fibrosis and suggest therapeutic targets to alter the course of human lung fibrosis.