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)信号在慢性阻塞性肺疾病中的作用。 阻塞性肺病(COPD)，以开发促进肺内修复的治疗方法 上皮组织。慢性阻塞性肺病是美国第三大死因，全球发病率正在上升。 在这里，我们试图利用再生途径来提供保护和增强肺上皮内的修复。 在导致空域简化的伤害之后。我们主要关注HGF(肝细胞生长因子)及其 受体cMET的基础如下：1)HGF，是一种多营养的形态原，是cMET的唯一已知配体， 一种营养生长因子受体，表达于多种上皮细胞类型，包括肺泡II型细胞 (AECII)；2)HGF/cMET使形态发生、运动发生、血管形成和抗凋亡信号，一个复合体 技能集，特别是肺泡形成和修复的指导；以及3)我们实验室和其他实验室的研究 证明了这一途径对肺泡发育和内稳态的可靠作用。我们之前曾报道过 肺泡上皮细胞(AEC)室中cMET信号的丢失通过以下途径损害肺泡形成 氧化应激增强，细胞凋亡和血管形成减少。肝细胞生长因子信号的部分增强 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在香烟烟雾(CS)反应中的上皮作用及其与临床肺部疾病的相关性 这在很大程度上仍然是未知的。在初步数据中，我们显示cMET在慢性阻塞性肺疾病的肺、肺和肺组织中表达下调。 慢性CS染毒成年小鼠及小鼠肺泡和人支气管上皮细胞染毒 CS.新生儿远端上皮室cMET信号的丢失延迟了气泡成熟和 增加成年小鼠对CS所致肺损伤的易感性。Mir34a，针对cMET进行下调 在慢性阻塞性肺疾病肺和暴露于CS的人上皮细胞中增加。一项大规模的基因研究发现 全基因组范围内肺功能降低与MET(编码cMET的基因)和NEAR的显著关联 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信号对肺和成人肺的空隙保护和功能至关重要。 被用来治疗获得性肺气肿。我们测试的具体假设是1)维护或 增强cMET的表达或信号转导可通过以下途径保护CS所致的肺损伤 保存的肺泡上皮的动态平衡和动态平衡，2)CS诱导的miRNAs有助于减少 CMET在损伤的腔隙上皮细胞中的表达，以及3)以cMET为基础的整合多组学 在大量信息队列中发出信号将确定与COPD有关的分子特征 敏感度。

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.