Hepatocyte Growth Factor Signaling and Airspace Maintenance

项目摘要 我们的总体目标是阐明肝细胞生长因子（HGF）信号传导在慢性炎症中的作用。 阻塞性肺疾病（COPD），以便开发促进肺内修复的疗法 上皮COPD是美国第三大死亡原因，全球发病率正在上升。 在这里，我们寻求利用再生途径，赋予保护和增强肺上皮内的修复 导致空域简化的伤害。我们专注于肝细胞生长因子（HGF）及其 受体cMet基于以下：1）HGF，是一种多营养型形态发生素，并且是cMet的唯一已知配体， 一种在多种上皮细胞类型（包括肺泡II型细胞）上表达的营养生长因子受体 （AECII）; 2）HGF/cMet使形态发生、运动发生、血管生成和抗凋亡信号传导成为可能， 技能设置，特别是指导牙槽骨形成和修复;和3）在我们的实验室和其他研究已经 证实了该途径对肺泡发育和体内平衡的可靠作用。我们先前报道 肺泡上皮细胞（AEC）隔室中cMet信号的丢失通过以下途径损害肺泡形成： 增强氧化应激、凋亡和减少血管形成。部分增强HGF信号传导 在临床前模型中逆转遗传性肺气肿和弹性蛋白酶诱导的肺气肿。然而，空域 HGF/cMet对香烟烟雾（CS）的上皮效应及其与临床肺部疾病的相关性， 仍然大部分未知。在初步数据中，我们表明cMet在COPD肺、肺动脉和肺动脉中下调。 暴露于慢性CS的成年小鼠以及暴露于 CS.远端上皮区室中cMet信号传导的新生儿丢失延迟了气腔成熟， 增加成年小鼠对CS诱导的肺损伤的易感性。靶向cMet下调的Mir 34 a 在COPD肺和暴露于CS的人上皮细胞中增加。一项大型遗传研究发现， MET（编码cMet的基因）和MET（编码cMet的基因）附近的肺功能降低的全基因组显著相关性 HGFAC是HGF的主要激活剂。基于这些令人信服的数据，我们提出了一个中心假设， HGF/cMet信号对发育中和成年肺的空域保护和功能至关重要， 被用来治疗后天性肺气肿我们测试的具体假设是1）维护或 cMet表达或信号传导的增强可以通过以下途径防止CS诱导的空域损伤： 保持肺泡上皮细胞的稳态和动力学，2）CS诱导的miRNA有助于减少 cMet在损伤的气腔上皮中的表达，以及3）锚定在cMet上的整合性多组学 在大的信息队列中的信号传导将识别有助于COPD的分子特征， 易感性

Project Summary Our overall objective is to elucidate the role of hepatocyte growth factor (HGF) signaling in chronic obstructive pulmonary disease (COPD) in order to develop therapies to promote repair within lung epithelium. COPD is the third leading cause of death in the United States and the incidence is rising globally. Here, we seek to exploit regenerative pathways to confer protection and enhance repair within lung epithelium following injuries that result in airspace simplification. We focus on HGF (hepatocyte growth factor) and its receptor cMet based on the following : 1) HGF, is a pleiotrophic morphogen and the only known ligand for cMet, a trophic growth factor receptor expressed on a variety of epithelial cell types, including alveolar type II cells (AECII); 2) HGF/cMet enables morphogenic, motogenic, angiogenic and anti-apoptotic signaling, a complex skill set especially directive of alveolar formation and repair; and 3) studies in our lab and others have demonstrated reliable effects of this pathway on alveolar development and homeostasis. We previously reported that the loss of cMet signaling in the alveolar epithelial cell (AEC) compartment impairs alveolar formation via enhanced oxidative stress, apoptosis and reduced vascularization. Augmentation of HGF signaling partially reverses genetic emphysema and elastase-induced emphysema in preclinical models. However, the airspace epithelial effects of HGF/cMet in response to cigarette smoke (CS) and the relevance to clinical lung disease are still largely unknown. In preliminary data, we show that cMet is downregulated in COPD lungs, airspaces of adult mice exposed to chronic CS and in both murine alveolar and human bronchial epithelial cells exposed to CS. The neonatal loss of cMet signaling in the distal epithelial compartment delays airspace maturation and increases susceptibility to CS-induced lung injury in adult mice. Mir34a which targets cMet for downregulation is increased in COPD lungs and in human epithelial cells exposed to CS. A large genetic study identified genome-wide significant associations for reduced lung function near MET (the gene encoding cMet) and near HGFAC, the major activator for HGF. Based on this compelling data, we offer the central hypothesis that HGF/cMet signaling is critical to airspace protection and function in both the developing and adult lung and can be harnessed to treat acquired emphysema. The specific hypotheses that we test are 1) maintenance or augmentation of cMet expression or signaling can protect against CS-induced airspace injury via preserved alveolar epithelial homeostasis and dynamics, 2) CS-induced miRNAs contribute to reduced cMet expression in the injured airspace epithelium, and 3) integrative multiomics anchored on cMet signaling in large informative cohorts will identify molecular signatures that contribute to COPD susceptibility.