Pressure in lung development and congenital diaphragmatic hernia

肺部发育压力与先天性膈疝

基本信息

  • 批准号:
    9918958
  • 负责人:
  • 金额:
    $ 38.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-04-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Congenital diaphragmatic hernia (CDH) is a devastating structural birth defect, resulting in significant perinatal morbidity and mortality. In CDH, a failure of the diaphragm to completely close allows abdominal organs to move into the thoracic cavity, compressing the developing lung and resulting in often lethal pulmonary hypoplasia. As the high morbidity and mortality of CDH is linked to a structural defect (abdominal organs compressing the lung) with no consistent genetic defect, identifying signaling pathways to target therapeutically is difficult. To date, treatment strategies have focused on surgically occluding the trachea and increasing fluid accumulation in the lung, which has been linked to accelerated lung growth in animal models. However, these strategies have resulted in minimal improvement to neonatal survival rates, especially in light of the risks of any prenatal surgery. A major challenge in successfully translating these findings from animal models is a poor understanding of how mechanical signals, such as the elevated pressure caused by fluid accumulation, are transduced into accelerated lung growth and branching. Several aspects of this mechanotransduction system have identified. Airway smooth muscle (ASM) has been long known to exhibit peristalsis in the lung, and this has been hypothesized to provide an essential dynamic stimulus to induce branching and growth of the airway. In support of this, we have recently shown that airway pressure directly regulates the timing of branching events, and that this depends on ASM function. In this proposal, we focus on the molecular mechanotransduction pathways downstream of lung pressure. Specifically, we hypothesize novel mechanotransduction pathways connecting pressure to three distinct aspects of lung growth. First, we test the role of the mechanosensitive TRPV4 ion channel and myosin light chain kinase in linking airway smooth muscle function. Secondly, we test the role of TRPV4 and K- Ras in mediating the proliferation and branching of the airway epithelium. Third, we test a positive feedback system, where pressure activated expression of FGF7 leads to increased fluid secretion and further pressurization. To test these aims we utilize ex vivo culture of mouse lungs using our novel microfluidic culture device, allowing us to directly control pressures within the developing lung. Further, we will employ pharmacological inhibition and activation of our proposed pathways. To extend and validate our ex vivo findings, we will additionally use siRNA and plasmid transfection with in vitro culture models. By identifying molecular mechanisms that underlie pressure-based lung morphogenesis, this work will provide a framework for future studies to explore mechanotransduction events central to both normal lung development and the dysregulation that occurs in CDH. Further, this work will identify potential therapeutic targets that can be exploited as adjuncts to or replacements for current surgical CDH treatments.
抽象的 先天性隔膜疝(CDH)是一种毁灭性的结构性先天缺陷,导致显着 围产期发病率和死亡率。在CDH中,隔膜无法完全关闭 器官进入胸腔腔,压缩发育的肺,并经常致命 肺部发育不全。由于CDH的高发病率和死亡率与结构缺陷有关(腹部缺陷 不一致的遗传缺陷压缩肺的器官,识别靶标的信号通路 在治疗上很难。迄今为止,治疗策略的重点是手术阻塞气管和 肺中的液体积累增加,与动物模型中的肺部生长有关。 但是,这些策略导致新生儿生存率的提高最少,尤其是在光下 任何产前手术的风险。成功地从动物转化这些发现的主要挑战 模型对机械信号的理解很差,例如流体引起的压力升高 积累,被转导为加速的肺部生长和分支。这几个方面 机械转导系统已经确定。气道平滑肌(ASM)长期以来表现出来 肺中的蠕动,这已被认为是提供必不可少的动态刺激以诱导的 气道的分支和生长。为此,我们最近表明气道压力直接 调节分支事件的时间,这取决于ASM功能。 在此提案中,我们专注于下游的分子机械转导途径 肺部压力。具体而言,我们假设将压力与 肺部生长的三个不同方面。首先,我们测试机械敏感的TRPV4离子通道的作用和 肌球蛋白轻链激酶在连接气道平滑肌功能时。其次,我们测试了TRPV4和K-的作用 RAS介导气道上皮的增殖和分支。第三,我们测试积极的反馈 系统,压力激活的FGF7表达会导致流体分泌增加,进一步增加 加压。为了测试这些目标,我们使用新型的微流体培养物利用小鼠肺的体内培养物 设备,使我们能够直接控制发育中的肺部压力。此外,我们将雇用 我们提出的途径的药理抑制和激活。扩展和验证我们的前体体 调查结果,我们还将与体外培养模型一起使用siRNA和质粒转染。 通过确定基于压力的肺形态发生的分子机制,这项工作将 为将来的研究提供了一个框架,以探索正常肺中心的机械转导事件 CDH中发生的发育和失调。此外,这项工作将确定潜在的治疗 可以用作当前手术CDH治疗的辅助或替换的靶标。

项目成果

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Jason Paul Gleghorn其他文献

Jason Paul Gleghorn的其他文献

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{{ truncateString('Jason Paul Gleghorn', 18)}}的其他基金

Cell-Mediated Antiretroviral Drug Transport in the Lymph Node
细胞介导的抗逆转录病毒药物在淋巴结中的转运
  • 批准号:
    10469495
  • 财政年份:
    2021
  • 资助金额:
    $ 38.34万
  • 项目类别:
Biomimetic Models Core
仿生模型核心
  • 批准号:
    10596509
  • 财政年份:
    2021
  • 资助金额:
    $ 38.34万
  • 项目类别:
Biomimetic Models Core
仿生模型核心
  • 批准号:
    10190232
  • 财政年份:
    2021
  • 资助金额:
    $ 38.34万
  • 项目类别:
Biomimetic Models Core
仿生模型核心
  • 批准号:
    10395580
  • 财政年份:
    2021
  • 资助金额:
    $ 38.34万
  • 项目类别:
Cell-Mediated Antiretroviral Drug Transport in the Lymph Node
细胞介导的抗逆转录病毒药物在淋巴结中的转运
  • 批准号:
    10327086
  • 财政年份:
    2021
  • 资助金额:
    $ 38.34万
  • 项目类别:
Pressure in lung development and congenital diaphragmatic hernia
肺部发育压力与先天性膈疝
  • 批准号:
    9311116
  • 财政年份:
    2017
  • 资助金额:
    $ 38.34万
  • 项目类别:
Arsenic-mediated fibrosis and developmental dysregulation in the fetal lung
砷介导的胎儿肺纤维化和发育失调
  • 批准号:
    9453861
  • 财政年份:
    2017
  • 资助金额:
    $ 38.34万
  • 项目类别:

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