The Role of Hepatocyte Growth Factor Signaling Airspace Homeostasis

描述（由申请人提供）：肺最重要的功能是气体交换。这一关键功能的部位，肺泡，必须具有强大的机制，既维持和生存的居民细胞和功能形态的保护。当这些机制受到损害时，就会导致慢性阻塞性肺病、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传导诱导促进细胞存活和抑制内在细胞死亡机制的分子程序。这些程序利用一组有限的近端和远端细胞内信号传导介质，其整合了增殖/抗增殖和凋亡/抗凋亡议程的协调平衡。这种整合允许维持肺泡内稳态和肺的受控生长和成熟。不适当的营养信号传导可导致气道发育不全（肺气肿、支气管肺发育不良）或肿瘤性疾病。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，但这些方法在肺发育不良疾病中仍然大多未被探索。在这个提议中，我们研究了HGF/c-met介导的营养信号传导在破坏性空域扩大的小鼠模型中减少空域损伤和维持或恢复正常空域形态的效用。在具体目标1中，我们通过在肺气肿的TSK模型中补充HGF的详细剂量反应分析来靶向HGF功能的获得。我们还建立了是否转基因的c-met在肺泡II型细胞的过度表达是足以改善肺气肿的两个模型的空域扩大。在具体目标2中，我们利用我们的在肺泡上皮细胞中诱导性缺乏c-met的三转基因小鼠来确定在TSK和香烟烟雾暴露的肺中c-met的缺乏是否影响了空气空间表型和细胞存活指数。在特定目标3中，使用遗传和药理学功能丧失策略，我们建立了已知的上皮细胞存活介质akt 1和stat 3在HGF/c-met促进的空域修复中的作用，其活化在所研究的模型中改变。如果成功，这些研究将提供一个广泛的治疗设备，以支持再生肺泡化广泛的肺部疾病。

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.