Adherens Junction Integrity and Barrier Function

粘附连接完整性和屏障功能

基本信息

  • 批准号:
    6775456
  • 负责人:
  • 金额:
    $ 21.58万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2002
  • 资助国家:
    美国
  • 起止时间:
    2002-04-01 至 2006-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The vascular endothelium controls the flux of macromolecules from the vascular space to the interstitium. Understanding the mechanisms that maintain and tighten the endothelial barrier would aid in the elucidation of therapeutic interventions to counter a loss of barrier activity and tissue edema. Both sphingosine 1-phosphate (S1P) and cAMP-enhancing agents increase barrier function. Proposed mechanisms for tightening the barrier include increases in cell-cell or cell-matrix adhesion, and/or a decrease in contractile activity. The increased barrier activity of S1P is independent of cAMP and protein kinases A and G and is not affected by inhibition of myosin light chain (MLC) kinase and extracellular signal-regulated kinase. Furthermore, S1P and cAMP have opposing effects on MLC phosphorylation, cellular tension, and actin stress fibers. We propose that the barrier-enhancing activity of S1P and cAMP is directed at the intercellular junctions. Alternatively, S1P and cAMP may function via different mechanisms. Preliminary data indicate that S1P increases the localization of vinculin, an alpha-catenin/actin linker protein, at cell-cell contacts and increases the association of alpha-catenin with actin. Preliminary data indicate that S1P decreases the peripheral localization of IQGAP1, which competes with alpha-catenin for binding to beta-catenin, increases the activity of Rac1, and increases the interaction of IQGAP1 with Rac1. These findings suggest that S1P increases barrier activity by enhancing adherens junction integrity. Preliminary data also indicate that S1P and cAMP reverse the barrier-decreasing effect of tumor necrosis factor (TNF). We propose that the adherens junction is a common target for S1P and cAMP. These mediators increase barrier function by strengthening the adherens junction via addition of linker proteins such as vinculin and via removal of IQGAP1 by activated Rac1. The three Specific Aims are: S1P and cAMP 1) increase barrier function by enhancing the attachment of alpha-catenin to actin via addition of linker proteins; 2) increase barrier function by removal of IQGAP1 from beta-catenin via activation of Rac1; and 3) rescue the barrier-disrupting effect of a phorbol ester, PMA, and a cytokine, TNF. Experimental approaches include the demonstration of protein interactions by immunofluorescence microscopy and immunoprecipitation and immunoblotting; functional analyses of adherens junctional integrity and endothelial barrier function; and infections with adenoviral recombinants to assess the importance of linker proteins (such as vinculin), alpha-catenin, IQGAP1, and Rac1. The biological significance is the identification of the cellular targets activated by S1P and cAMP that function to tighten the junctions between cells.
描述(由申请人提供):血管内皮控制流量 大分子从血管间隙转移到血管壁。理解 维持和收紧内皮屏障的机制将有助于 阐明对抗屏障丧失的治疗干预措施 活动和组织水肿。1-磷酸鞘氨醇(S1 P)和 cAMP增强剂增加屏障功能。拟议机制 收紧屏障包括增加细胞-细胞或细胞-基质粘附, 和/或收缩活动减少。增加的屏障活性 S1 P不依赖于cAMP和蛋白激酶A和G,并且不受 肌球蛋白轻链(MLC)激酶和细胞外 信号调节激酶此外,S1 P和cAMP对MLC具有相反的作用 磷酸化、细胞张力和肌动蛋白应力纤维。我们建议 S1 P和cAMP的屏障增强活性针对细胞间 交叉点或者,S1 P和cAMP可能通过不同的机制发挥作用。 初步数据表明,S1 P增加黏着斑蛋白的定位, α-连环蛋白/肌动蛋白连接蛋白,在细胞-细胞接触,并增加 α-连环蛋白与肌动蛋白的结合。初步数据显示,S1 P 降低IQGAP 1的外周定位,IQGAP 1与 α-连环蛋白结合β-连环蛋白,增加Rac 1的活性,和 增加IQGAP 1与Rac 1的相互作用。这些发现表明,S1 P 通过增强粘附连接完整性增加屏障活性。 初步数据还表明,S1 P和cAMP逆转了屏障的降低, 肿瘤坏死因子(TNF)的作用。我们认为粘附连接是 S1 P和cAMP的共同靶点。这些介质通过以下方式增加屏障功能: 通过加入连接蛋白,如 黏着斑蛋白和通过激活的Rac 1去除IQGAP 1。三个具体目标 S1 P和cAMP 1)通过增强粘附来增加屏障功能, 通过添加接头蛋白将α-连环蛋白转化为肌动蛋白; 2)增加屏障 通过激活Rac 1从β-连环蛋白中去除IQGAP 1来发挥作用;和3) 挽救佛波酯、PMA和细胞因子的屏障破坏作用, 的tnf实验方法包括蛋白质相互作用的演示 通过免疫荧光显微镜和免疫沉淀和免疫印迹; 粘附连接完整性和内皮屏障的功能分析 功能;和感染腺病毒重组体,以评估重要性 连接蛋白(如黏着斑蛋白)、α-连环蛋白、IQGAP 1和Rac 1。的 生物学意义是识别激活的细胞靶点 通过S1 P和cAMP,其功能是收紧细胞之间的连接。

项目成果

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FRED L MINNEAR其他文献

FRED L MINNEAR的其他文献

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{{ truncateString('FRED L MINNEAR', 18)}}的其他基金

Adherens Junction Integrity and Barrier Function
粘附连接完整性和屏障功能
  • 批准号:
    6703710
  • 财政年份:
    2002
  • 资助金额:
    $ 21.58万
  • 项目类别:
Adherens Junction Integrity and Barrier Function
粘附连接完整性和屏障功能
  • 批准号:
    6469442
  • 财政年份:
    2002
  • 资助金额:
    $ 21.58万
  • 项目类别:
Adherens Junction Integrity and Barrier Function
粘附连接完整性和屏障功能
  • 批准号:
    6623677
  • 财政年份:
    2002
  • 资助金额:
    $ 21.58万
  • 项目类别:
Adherens Junction Integrity and Barrier Function
粘附连接完整性和屏障功能
  • 批准号:
    6881216
  • 财政年份:
    2002
  • 资助金额:
    $ 21.58万
  • 项目类别:
PREVENTION OF INCREASED VASCULAR PERMEABILITY
预防血管通透性增加
  • 批准号:
    2219096
  • 财政年份:
    1988
  • 资助金额:
    $ 21.58万
  • 项目类别:
PREVENTION OF INCREASED VASCULAR PERMEABILITY
预防血管通透性增加
  • 批准号:
    3355344
  • 财政年份:
    1988
  • 资助金额:
    $ 21.58万
  • 项目类别:
PREVENTION OF INCREASED VASCULAR PERMEABILITY
预防血管通透性增加
  • 批准号:
    3355342
  • 财政年份:
    1988
  • 资助金额:
    $ 21.58万
  • 项目类别:
PREVENTION OF INCREASED VASCULAR PERMEABILITY
预防血管通透性增加
  • 批准号:
    3355346
  • 财政年份:
    1988
  • 资助金额:
    $ 21.58万
  • 项目类别:
PREVENTION OF INCREASED VASCULAR PERMEABILITY
预防血管通透性增加
  • 批准号:
    3355345
  • 财政年份:
    1988
  • 资助金额:
    $ 21.58万
  • 项目类别:
PREVENTION OF INCREASED VASCULAR PERMEABILITY
预防血管通透性增加
  • 批准号:
    3355347
  • 财政年份:
    1988
  • 资助金额:
    $ 21.58万
  • 项目类别:

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Cadherins与nectins在青少年期慢性社会应激损害小鼠前额叶形态可塑性与功能中的作用
  • 批准号:
    81401129
  • 批准年份:
    2014
  • 资助金额:
    23.0 万元
  • 项目类别:
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