The Role of Hepatocyte Growth Factor Signaling Airspace Homeostasis

肝细胞生长因子信号传导空腔稳态的作用

基本信息

批准号：
7842032
负责人：
Enid R Neptune
金额：
$ 22.17万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7842032
关键词：
Adult Alleles Alveolar Alveolus Apoptosis Apoptotic Attenuated Biological Models Biological Preservation Bone Marrow Transplantation Bronchopulmonary Dysplasia Caliber Cell Death Cell Survival Cells Chronic Chronic Obstructive Airway Disease Cigarette Clinical Complex Cutis Laxa Deposition Detection Development Disease Distal Dose Elastases Elements Endocrine System Diseases Epithelial Epithelial Cells Epithelium Equilibrium Gases Genes Genetic Glycoproteins Growth Growth Factor Hepatocyte Growth Factor Hereditary Disease Histology Homeostasis Human Inflammation Inflammatory Injury Intervention Lesion Lung Lung diseases Maintenance Marfan Syndrome Mediating Mediator of activation protein Methods Modeling Molecular Morphogenesis Morphology Multiple Abnormalities Mus Mutation Natural regeneration Necrosis Neptune Oxidative Stress Pathogenesis Phenotype Predisposition Principal Investigator Protein C Inhibitor Proteins Pulmonary Emphysema Pulmonary Fibrosis Research Personnel Respiratory physiology Right-On Rodent Model Role Signal Transduction Site Smoke Study models Supplementation Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Tretinoin alveolar homeostasis alveolar type II cell cell injury cigarette smoke-induced cigarette smoking cytokine fibrillin gain of function gene function human disease improved in vivo indexing loss of function lung injury lung maturation meetings migration neoplastic overexpression postnatal pro-hepatocyte growth factor programs receptor regenerative relating to nervous system repaired research study response young adult

项目摘要

DESCRIPTION (provided by applicant): The most vital function of the lung is gas-exchange. The site of this critical function, the alveolus, must harbor robust mechanisms for both the maintenance and survival of resident cells and the preservation of functional morphology. When these mechanisms are compromised, diseases such as chronic obstructive pulmonary disease, bronchopulmonary dysplasia and pulmonary fibrosis result. Trophic signaling by growth factors in the lung epithelium induces molecular programs that promote cell survival and suppress the intrinsic cell death machinery. These programs utilize a restricted set of proximal and distal intracellular signaling mediators that integrate the coordinated balance of proliferative/antiproliferative and apoptotic/anti- apoptotic agendas. This integration allows for maintenance of alveolar homeostasis and controlled growth and maturation of the lung. Inappropriate trophic signaling can result in either airspace hypoplasia (emphysema, bronchopulmonary dysplasia) or neoplastic disease. Despite the introduction of therapies aimed at enhancing trophic signaling to treat hematologic, neural and endocrine disorders, these approaches remain mostly underexplored in hypoplastic lung disease. In this proposal, we examine the utility of HGF/c- met mediated trophic signaling to reduce airspace injury and maintain or restore normal airspace morphology in murine models of destructive airspace enlargement. In Specific Aim 1, we target gain of HGF function with a detailed dose-response analysis of HGF supplementation in the TSK model of emphysema. We also establish whether transgenic overexpression of c-met in alveolar type II cells is sufficient to ameliorate airspace enlargement in two models of emphysema. In Specific Aim 2, we utilize our tri- transgenic mice that are inducibly deficient in c-met in alveolar epithelial cells to determine whether the absence of c-met in the TSK and cigarette-smoke exposed lung worsens the airspace phenotype and the indices of cellular survival. In Specific Aim 3, using genetic and pharmacologic loss-of-function strategies, we establish the roles of akt1 and stat 3, known mediators of epithelial cell survival whose activation is altered in the studied models, in HGF/c-met promoted airspace repair. If successful, these studies will provide an extensive therapeutic armamentarium to support regenerative alveolarization for a wide range of pulmonary disorders.

描述（由申请人提供）：肺的最重要功能是气体交换。该关键功能的位置，肺泡，必须具有鲁棒的机制，以维持居民细胞的维持和存活和功能形态的保存。当这些机制受到损害时，诸如慢性阻塞性肺部疾病，支气管肺发育不良和肺纤维化的疾病。肺上皮生长因子的营养信号传导可诱导促进细胞存活并抑制内在细胞死亡机械的分子程序。这些程序利用了一组受限的近端和远端细胞内信号传导介质，这些介体整合了增殖/抗增殖和凋亡/替代/抗凋亡议程的协调平衡。这种整合允许维持肺泡稳态以及肺的控制生长和成熟。不适当的营养信号会导致空域发育不全（肺气肿，支气管肺发育异常）或肿瘤疾病。尽管引入了旨在增强营养信号传导以治疗血液学，神经和内分泌疾病的疗法，但这些方法在低肿瘤肺部疾病中仍未得到充实。在此提案中，我们研究了HGF/c- MET介导的营养信号传导的效用，以减少空域损伤并维持或恢复破坏性空域增大的鼠模型中的正常空域形态。在特定的目标1中，我们针对HGF功能的增益，对肺气肿TSK模型中HGF补充的详细剂量反应分析。我们还确定在肺泡II型细胞中C-MET的转基因过表达是否足以在两种模型的肺气肿模型中改善空域扩大。在特定的目标2中，我们利用肺泡上皮细胞中C-MET缺乏的三转基因小鼠来确定在TSK中不存在C-MET和烟雾-smoke Smoke裸露的肺是否会使空体表观型和细胞存活的指数恶化。在使用遗传和药理丧失功能策略的特定目标3中，我们确定了Akt1和Stat 3的作用，这是上皮细胞存活的已知介体，其在研究模型中的激活在HGF/C-MET中改变了空间空间修复。如果成功的话，这些研究将为多种肺部疾病提供广泛的治疗性武器库，以支持再生肺泡化。