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，并发多种人类肺部疾病。表皮生长因子受体（EGFR）介导包括转化生长因子-(TGF-（）在内的一系列生长因子诱导的信号。该实验室和其他实验室的研究表明，在包括特发性肺纤维化（IFF）在内的几种人类纤维化疾病中，EGFR配体增加。TGF-(在转基因小鼠上皮中的表达导致进行性和广泛性肺纤维化，其组织学特征与人类疾病非常相似。TGF-转基因小鼠的纤维化可通过遗传或药理学方法预防或逆转，这表明egfr介导的纤维化是一种可行的治疗靶点。EGFR的磷酸化可诱导多种下游信号通路，包括磷脂酰肌醇3′-激酶(PI3K)-Akt通路。在TGF-转基因小鼠中激活EGFR可使上皮细胞中的Akt磷酸化，而在呼吸道上皮细胞中加入TGF-可通过阻断PI3K信号传导来抑制促纤维化基因的表达。这项应用的长期目标是为治疗人类肺纤维化开发新颖有效的治疗干预策略。本应用的目的是利用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机制，并确定这些途径是否在纤维化的人类肺部疾病中增加。中心假设是通过PI3K增加的EGFR信号诱导肺纤维化。为了验证这一假设，在Aim 1中，我们将使用模型人类细胞系来确定egfr诱导的导致胶原合成和细胞增殖的细胞内信号通路。在Aim 2中，我们将确定EGFR诱导的信号分子在EGFR诱导的肺纤维化转基因模型中在体内表达，并使用具有良好特征的IPF患者档案组织来评估EGFR和类似激酶是否被激活。在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Aim 3中，我们将使用共培养来确定表达TGF-的II型细胞调节肺成纤维细胞的机制。拟议研究的完成将确定EGFR在肺纤维化中的作用，并提出改变人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.