cAMP in Enothelial Permeability

内皮细胞通透性中的 cAMP

基本信息

  • 批准号:
    7217671
  • 负责人:
  • 金额:
    $ 32.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-08-01 至 2011-07-31
  • 项目状态:
    已结题

项目摘要

Pulmonary microvascular endothelial cells (PMVECs) possess strongly adherent cell-cell junctions that are necessary to limit fluid, solute and macromolecule permeability into interstitial and alveolar compartments, which is important for efficient gas exchange. PMVEC junction strength is dynamically adjusted by intracellular cAMP concentrations. The type 6 adenylyl cyclase (AC6) synthesizes cAMP at the cell membrane. cAMP signaling is targeted to physiologically relevant effector molecules by type 4 phosphodiesterases (PDE4), specifically the -D4 isoform, which is membrane-localized by spectrin. The membrane-localized cAMP pool strengthens PMVEC barrier function. In contrast, Pseudomonas aeruginosa introduces a soluble adenylyl cyclase toxin, ExoY, into PMVECs that generates a cytosolic cAMP pool. cAMP synthesis within the cytosol disrupts, rather than strengthens, the PMVEC barrier. To determine whether membrane or cytosolic AC activity dominates in control of endothelial cell barrier function, we utilized a chimeric mammalian soluble AC enzyme that could be activated by forskolin. Simultaneous stimulation of membrane and cytosolic AC activity by forskolin disrupts, rather than strengthens, the PMVEC barrier, indicating soluble AC activity dominantly controls barrier strength. Preliminary data suggest soluble ACs associate with the centrosome and its associated microtubules, and may therefore reorganize microtubule architecture necessary to induce PMVEC gaps. Thus, this proposal tests the overall hypothesis that membrane-localized ACs produce a cAMP pool that strengthens, whereas cytosolic ACs produce a cAMP pool that disrupts, the PMVEC barrier. Specific Aims test the related Hypotheses that: [1] AC6 generates a membrane cAMP pool that is maintained by a spectrin and PDE4(D4) interaction; [2] Soluble ACs generate a cytosolic cAMP pool that controls microtubule organization; and, [3] cAMP that accesses the cytosolic compartment disassembles microtubules and disrupts the endothelial cell barrier. Completion of this work will contribute to our understanding of how cAMP acts to control PMVEC barrier strength, and will seek to resolve pathogenic mechanisms of bacteria like Pseudomonas aeruginosa, which utilize adenylyl cyclase toxins to disrupt the endothelial cell barrier and increase permeability.
肺微血管内皮细胞(PMVECs)具有很强的黏附细胞-细胞连接

项目成果

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Troy Stevens其他文献

Troy Stevens的其他文献

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{{ truncateString('Troy Stevens', 18)}}的其他基金

Soluble adenylyl cyclases in lung endothelial tauopathy
肺内皮tau蛋白病中的可溶性腺苷酸环化酶
  • 批准号:
    10636060
  • 财政年份:
    2023
  • 资助金额:
    $ 32.33万
  • 项目类别:
Lung Endothelial Aß in infectious proteinopathy
肺内皮 A 与感染性蛋白病的关系
  • 批准号:
    10650303
  • 财政年份:
    2020
  • 资助金额:
    $ 32.33万
  • 项目类别:
Lung Endothelial Aß in infectious proteinopathy
肺内皮 A 与感染性蛋白病的关系
  • 批准号:
    10438793
  • 财政年份:
    2020
  • 资助金额:
    $ 32.33万
  • 项目类别:
Lung Endothelial Aß in infectious proteinopathy
肺内皮 A 与感染性蛋白病的关系
  • 批准号:
    10207758
  • 财政年份:
    2020
  • 资助金额:
    $ 32.33万
  • 项目类别:
Lung Endothelial Cell Phenotypes
肺内皮细胞表型
  • 批准号:
    7822683
  • 财政年份:
    2009
  • 资助金额:
    $ 32.33万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7217675
  • 财政年份:
    2006
  • 资助金额:
    $ 32.33万
  • 项目类别:
Cell Culture and Microscopy
细胞培养和显微镜检查
  • 批准号:
    7217676
  • 财政年份:
    2006
  • 资助金额:
    $ 32.33万
  • 项目类别:
Determinants of Pulmonary Endothelial Cell Function Conf
肺内皮细胞功能的决定因素
  • 批准号:
    6707800
  • 财政年份:
    2004
  • 资助金额:
    $ 32.33万
  • 项目类别:
Training in Cell Signaling and Lung Pathobiology
细胞信号传导和肺部病理学培训
  • 批准号:
    9061755
  • 财政年份:
    2004
  • 资助金额:
    $ 32.33万
  • 项目类别:
Training in Cell Signaling and Lung Pathobiology
细胞信号传导和肺部病理学培训
  • 批准号:
    8607821
  • 财政年份:
    2004
  • 资助金额:
    $ 32.33万
  • 项目类别:

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腓骨肌萎缩症蛋白 Mfn2 对钙通量和线粒体裂变的控制。
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