The Role of Hepatocyte Growth Factor Signaling Airspace Homeostasis

描述(申请人提供)：肺最重要的功能是气体交换。这一关键功能的位置，肺泡，必须拥有强大的机制，既维持和生存的常驻细胞和保存的功能形态。当这些机制受到损害时，就会导致慢性阻塞性肺疾病、支气管肺发育不良和肺纤维化等疾病。肺上皮细胞中生长因子的营养信号诱导分子程序促进细胞存活并抑制固有的细胞死亡机制。这些程序利用一组有限的近端和远端细胞内信号媒介，整合了增殖/抗增殖和凋亡/抗凋亡议程的协调平衡。这种整合可以维持肺泡的动态平衡，并控制肺的生长和成熟。不适当的营养信号可导致肺泡发育不良(肺气肿、支气管肺发育不良)或肿瘤性疾病。尽管已经推出了旨在增强营养信号来治疗血液学、神经和内分泌疾病的疗法，但这些方法在发育不良的肺部疾病中大多仍未被探索。在这项建议中，我们研究了HGF/c-MET介导的营养信号在减少空域损伤和维持或恢复破坏性空域扩大的小鼠模型中的正常空域形态的效用。在特定的目标1中，我们通过在肺气肿的TSK模型中补充HGF的详细的剂量-反应分析来达到HGF功能的目标。我们还确定了在肺泡II型细胞中过表达c-met基因是否足以改善两种肺气肿模型的肺泡扩大。在特定的目标2中，我们利用我们的三转基因小鼠，这些小鼠在肺泡上皮细胞中诱导缺乏c-met，以确定TSK和香烟暴露肺中c-met的缺失是否会恶化肺泡空间表型和细胞存活指数。在具体目标3中，利用遗传学和药理学功能丧失策略，我们确定了AKT1和STAT3在HGF/c-MET促进空隙修复中的作用。AKT1和STAT3是已知的上皮细胞存活的中介，其激活在所研究的模型中发生了改变。如果成功，这些研究将提供广泛的治疗手段，以支持广泛的肺部疾病的再生肺泡化。

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.