Hepatocyte Growth Factor Signaling and Airspace Maintenance

肝细胞生长因子信号传导和空域维护

• 批准号: 10316452
• 负责人: Enid R Neptune
• 金额: $ 75.98万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316452
• 关键词: Adult; Alleles; Alveolar; Apoptosis; Apoptotic; Architecture; Attenuated; Cause of Death; Cell Compartmentation; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical; Complex; DNA Methylation; Data; Development; Disease; Disease susceptibility; Distal; Dose; Down-Regulation; Elastases; Epigenetic Process; Epithelial; Epithelial Cells; Exposure to; Gene Expression Regulation; Genetic; Genetic study; Growth Factor Receptors; HGF gene; Homeostasis; Human; Impairment; Incidence; Inflammatory; Injury; Intervention; Ligands; Lung; Lung diseases; MET gene; Maintenance; Mediating; MicroRNAs; Molecular Profiling; Morphogenesis; Mus; Neonatal; Oxidative Stress; Pathway Analysis; Pathway interactions; Pharmacology; Phenotype; Pre-Clinical Model; Predisposition; Pulmonary Emphysema; Regenerative pathway; Regulation; Reporting; Role; Sampling; Signal Transduction; Structure of parenchyma of lung; Surveys; Testing; Therapeutic Effect; Tissues; Trans-Omics for Precision Medicine; United States; Vascularization; alveolar epithelium; alveolar type II cell; base; bronchial epithelium; case control; cell type; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced lung injury; cohort; exposure to cigarette smoke; gain of function; genetic variant; genome sequencing; genome-wide; hepatocyte growth factor activator; human disease; injured; loss of function; lung injury; miRNA expression profiling; morphogens; multiple omics; preservation; prevent; protective effect; pulmonary function; receptor; reduce symptoms; regenerative; repaired; response; reverse genetics; skills; therapy development; transcriptome sequencing; transcriptomics; whole genome

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.

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（COPD），以开发疗法以促进肺部修复 上皮。 COPD是美国的第三大死亡原因，而且发生率在全球范围内正在上升。 在这里，我们试图利用再生途径来提供保护并增强肺上皮内的维修 遵循导致空域简化的伤害。我们专注于HGF（肝细胞生长因子）及其 基于以下内容的受体CMET：1）HGF，是一种多毒性形态学，是CMET唯一已知的配体， 以多种上皮细胞类型表达的营养生长因子受体，包括肺泡II型细胞 （AECII）; 2）HGF/CMET可实现形态学，动作，血管生成和抗凋亡信号传导 牙槽形成和修复的技能集尤其是指令； 3）我们实验室的研究和其他研究 该途径对肺泡发育和稳态表现出可靠的影响。我们以前报道了 肺泡上皮细胞（AEC）室中CMET信号传导的丧失损害了肺泡形成 增强的氧化应激，凋亡和血管形成减少。 HGF信号的增强部分 在临床前模型中逆转遗传性肺气肿和弹性酶诱导的肺气肿。但是，领空 HGF/CMET响应香烟烟（CS）和与临床肺部疾病的相关性的上皮作用是 仍然在很大程度上未知。在初步数据中，我们表明CMET在COPD肺中被下调 暴露于慢性CS的成年小鼠，在鼠肺泡和人支气管上皮细胞中均暴露于 CS。远端上皮室中CMET信号传导的新生儿损失延迟了空域的成熟和 增加了成年小鼠对CS诱导的肺损伤的敏感性。 MiR34a靶向CMET下调 在COPD肺和暴露于Cs的人类上皮细胞中增加。一项大型遗传研究发现 全基因组的显着关联，可降低MET附近的肺功能（基因编码CMET）和附近 HGFAC，HGF的主要激活剂。基于此引人入胜的数据，我们提供了一个中心假设，即 HGF/CMET信号对于发育和成人肺的空域保护和功能至关重要 要利用治疗获得的肺气肿。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防止CS诱导的空域伤害 保留的肺泡上皮稳态和动力学，2）CS诱导的miRNA有助于减少 受伤的空域上皮中的CMET表达，3）锚定在CMET上的综合多组合 大量信息组的信号传导将确定有助于COPD的分子特征 敏感性。