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:
  • 金额:
    $ 22.17万
  • 依托单位:
  • 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

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(申请人提供):肺最重要的功能是气体交换。这个关键功能的位置,肺泡,必须有强大的机制来维持和生存的常驻细胞和功能形态的保存。当这些机制受损时,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。肺上皮中生长因子的营养信号传导可诱导促进细胞存活和抑制细胞固有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介质,这些介质整合了增殖/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控制肺的生长和成熟。不适当的营养信号可导致空气空间发育不全(肺气肿、支气管肺发育不良)或肿瘤疾病。尽管引入了旨在增强营养信号的疗法来治疗血液学、神经和内分泌疾病,但这些方法在肺发育不全疾病中的探索仍然不足。在本研究中,我们研究了HGF/c- met介导的营养信号在小鼠破坏性空域扩大模型中减少空域损伤和维持或恢复正常空域形态的作用。在Specific Aim 1中,我们通过对肺气肿TSK模型中补充HGF的详细剂量反应分析,以HGF功能的增加为目标。我们还研究了在肺泡II型细胞中转基因过表达c-met是否足以改善两种肺气肿模型中的空气空间扩大。在特异性目标2中,我们利用在肺泡上皮细胞诱导缺乏c-met的三转基因小鼠来确定TSK和香烟烟雾暴露的肺中缺乏c-met是否会恶化空气区表型和细胞存活指标。在Specific Aim 3中,利用遗传和药理学的功能丧失策略,我们确定了akt1和stat 3在HGF/c-met促进空域修复中的作用,这两种已知的上皮细胞存活介质的激活在研究模型中被改变。如果成功,这些研究将为支持再生肺泡成形术治疗各种肺部疾病提供广泛的治疗手段。

项目成果

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{{ truncateString('Enid R Neptune', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 22.17万
  • 项目类别:
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:
    10470865
  • 财政年份:
    2021
  • 资助金额:
    $ 22.17万
  • 项目类别:
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:
    10626872
  • 财政年份:
    2021
  • 资助金额:
    $ 22.17万
  • 项目类别:
Strategies for Angiotensin Receptor Blocker Mediated Tissue Repair
血管紧张素受体阻滞剂介导的组织修复策略
  • 批准号:
    10469311
  • 财政年份:
    2020
  • 资助金额:
    $ 22.17万
  • 项目类别:
Strategies for Angiotensin Receptor Blocker Mediated Tissue Repair
血管紧张素受体阻滞剂介导的组织修复策略
  • 批准号:
    10649490
  • 财政年份:
    2020
  • 资助金额:
    $ 22.17万
  • 项目类别:
Strategies for Angiotensin Receptor Blocker Mediated Tissue Repair
血管紧张素受体阻滞剂介导的组织修复策略
  • 批准号:
    10210299
  • 财政年份:
    2020
  • 资助金额:
    $ 22.17万
  • 项目类别:
Strategies for Angiotensin Receptor Blocker Mediated Tissue Repair
血管紧张素受体阻滞剂介导的组织修复策略
  • 批准号:
    10065083
  • 财政年份:
    2020
  • 资助金额:
    $ 22.17万
  • 项目类别:
TGFb Modulation: Therapeutic Targeting for COPD-Emphysema
TGFb 调节:COPD 肺气肿的治疗靶向
  • 批准号:
    8073728
  • 财政年份:
    2011
  • 资助金额:
    $ 22.17万
  • 项目类别:
TGFb Modulation: Therapeutic Targeting for COPD-Emphysema
TGFb 调节:COPD 肺气肿的治疗靶向
  • 批准号:
    8262683
  • 财政年份:
    2011
  • 资助金额:
    $ 22.17万
  • 项目类别:
Tissue-based validation of COPD Genetic Studies using Lung Health Study Cohort
使用肺部健康研究队列对慢性阻塞性肺病基因研究进行组织验证
  • 批准号:
    7690854
  • 财政年份:
    2008
  • 资助金额:
    $ 22.17万
  • 项目类别:

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非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
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