Regulation of alveolar barrier function by claudins

密蛋白对肺泡屏障功能的调节

基本信息

  • 批准号:
    8732735
  • 负责人:
  • 金额:
    $ 38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-07-01 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Acute respiratory distress syndrome (ARDS), is a devastating syndrome of respiratory failure that contributes to nearly 75,000 deaths annually in the United States. Therapy for acute lung injury is primarily supportive and currently no pharmacologic therapies are available. The pathophysiology of acute lung injury is characterized by inflammation and disruption of alveolar-capillary barrier. Recovery from acute lung injury requires re- establishment of the alveolar epithelial barrier, including the formation f low-permeability tight junctions between epithelial cells. To advance the field, a more complete understanding of alveolar epithelial barrier regulation and repair is needed. Claudin proteins are central to barrier function. Claudins are transmembrane proteins that are required for tight junction formation, but likely participate in other cellular processes important to repair. Therefoe we have investigated the functions and regulation of claudins in the alveolar epithelium. Our work has shown that two of the most abundantly expressed claudins in the alveolar epithelium are selectively regulated during lung injury. This proposal will investigate the specific functions and regulation of claudins-18 and -4 in mechanistic detail using an integrative approach that includes experimental models of lung injury, primary cell culture, and studies in ex vivo perfused human lungs. In Aim 1 we will determine the unique functions of lung-specific claudin-18.1, and the mechanisms for its selective down regulation in acute lung injury. Will we test the hypothesis that claudin-18 is required for the macromolecule permeability barrier in the lung and that the loss of claudin-18 contributes to more severe lung injury. We propose that claudin-18 forms homotypic tight junction strands that uniquely limit macromolecule permeability. During injury, TNF-¿ mediates the selective loss of claudin-18 from intact tight junctions, in part through effects on the cytoskeleton. In Aim 2 we will follow up on our previous finding that claudin-4 is consistently induced in acute lung injury. We will determine if claudin-4 is required for EGFR-mediated epithelial repair in lung injury. We hypothesize that claudin-4 is induced by EGFR in response to epithelial cell injury and the loss of cell-cell contact. We propose claudin-4 acts to accelerate repair through a previously unknown interaction with active Rap1 that speeds tight junction sealing and promotes cell spreading. Preliminary data show that claudin-4 is consistently induced in several models of lung injury and in human lungs in association with more preserved barrier function. Claudin- 4 is required for repair and preferentially associates with active Rap1. In Aim 3 we will determine the clinical significance of differences in claudin expression to epithelial barrier function using the ex vivo perfused human lung model. We hypothesize that claudin-18 is the predominant claudin in human type 1 cells and the specific loss of claudin-18 results in increased alveolar epithelial permeability in the ex vivo model and greater lung injury in donors. We will investigate the mechanism for the regulation of claudin-18 and claudin-4 using a bacterial pneumonia model in the ex vivo system. These studies will provide novel insights into the contributions of claudin proteins to the loss and recovery of alveolar epithelial barrier function in acute lung injury.
描述(由申请人提供):急性呼吸窘迫综合征(ARDS)是一种毁灭性的呼吸衰竭综合征,在美国每年导致近75,000例死亡。急性肺损伤的治疗主要是支持性的,目前没有可用的药物治疗。急性肺损伤的病理生理学特征是炎症和肺泡-毛细血管屏障的破坏。急性肺损伤的恢复需要重新建立肺泡上皮屏障,包括上皮细胞之间形成低渗透性紧密连接。为了推进这一领域,需要更全面地了解肺泡上皮屏障的调节和修复。Claudin蛋白是屏障功能的核心。紧密连接蛋白是紧密连接形成所需的跨膜蛋白,但可能参与对修复重要的其他细胞过程。因此,我们研究了肺泡上皮细胞中claudins的功能和调节。我们的工作表明,在肺泡上皮细胞中表达最丰富的两种claudin在肺损伤期间被选择性地调节。本提案将探讨具体职能 以及使用包括肺损伤的实验模型、原代细胞培养和离体灌注人肺的研究的综合方法在机制细节上调节密蛋白-18和-4。在目标1中,我们将确定肺特异性claudin-18.1的独特功能,以及其在急性肺损伤中选择性下调的机制。我们将检验以下假设:claudin-18是肺中大分子通透性屏障所必需的,claudin-18的缺失导致更严重的肺损伤。我们提出,claudin-18形成同型紧密连接链,独特地限制大分子的渗透性。在损伤过程中,TNF-α介导完整紧密连接中claudin-18的选择性丢失,部分是通过对细胞骨架的影响。在目标2中,我们将跟进我们先前的发现,即紧密连接蛋白-4在急性肺损伤中持续诱导。我们将确定在肺损伤中EGFR介导的上皮修复是否需要claudin-4。我们推测,claudin-4是由表皮生长因子受体诱导的上皮细胞损伤和细胞-细胞接触的损失。我们提出claudin-4通过与活性Rap 1的先前未知的相互作用来加速修复,该活性Rap 1加速紧密连接密封并促进细胞扩散。初步数据显示,紧密连接蛋白-4在几种肺损伤模型和人肺中一致诱导,与更保留的屏障功能相关。Claudin- 4是修复所必需的,并优先与活性Rap 1相关。在目的3中,我们将使用离体灌注的人肺模型确定紧密连接蛋白表达差异对上皮屏障功能的临床意义。我们假设密蛋白-18是人1型细胞中主要的密蛋白,并且密蛋白-18的特异性损失导致离体模型中肺泡上皮通透性增加和供体中更大的肺损伤。我们将在离体系统中使用细菌性肺炎模型研究claudin-18和claudin-4的调节机制。这些研究将为claudin蛋白在急性肺损伤肺泡上皮屏障功能丧失和恢复中的作用提供新的见解。

项目成果

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JAMES A FRANK其他文献

JAMES A FRANK的其他文献

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{{ truncateString('JAMES A FRANK', 18)}}的其他基金

Claudin-18 deficiency in the pathogenesis of asthma
Claudin-18 缺乏症与哮喘发病机制的关系
  • 批准号:
    8370482
  • 财政年份:
    2012
  • 资助金额:
    $ 38万
  • 项目类别:
Claudin-18 deficiency in the pathogenesis of asthma
Claudin-18 缺乏症与哮喘发病机制的关系
  • 批准号:
    8522224
  • 财政年份:
    2012
  • 资助金额:
    $ 38万
  • 项目类别:
Regulation of alveolar epithelial barrier function by claudins
密蛋白对肺泡上皮屏障功能的调节
  • 批准号:
    7867413
  • 财政年份:
    2009
  • 资助金额:
    $ 38万
  • 项目类别:
Regulation of alveolar epithelial barrier function by claudins
密蛋白对肺泡上皮屏障功能的调节
  • 批准号:
    7822365
  • 财政年份:
    2009
  • 资助金额:
    $ 38万
  • 项目类别:
Regulation of alveolar epithelial barrier function by claudins
密蛋白对肺泡上皮屏障功能的调节
  • 批准号:
    7322301
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
Regulation of alveolar epithelial barrier function by claudins
密蛋白对肺泡上皮屏障功能的调节
  • 批准号:
    7475058
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
Regulation of alveolar epithelial barrier function by claudins
密蛋白对肺泡上皮屏障功能的调节
  • 批准号:
    7664294
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
Regulation of alveolar epithelial barrier function by claudins
密蛋白对肺泡上皮屏障功能的调节
  • 批准号:
    7898589
  • 财政年份:
    2007
  • 资助金额:
    $ 38万
  • 项目类别:
VENTILATOR-ASSOCIATED ALVEOLAR EPITHELIAL INJURY
呼吸机相关的肺泡上皮损伤
  • 批准号:
    6460878
  • 财政年份:
    2002
  • 资助金额:
    $ 38万
  • 项目类别:
VENTILATOR-ASSOCIATED ALVEOLAR EPITHELIAL INJURY
呼吸机相关的肺泡上皮损伤
  • 批准号:
    6764069
  • 财政年份:
    2002
  • 资助金额:
    $ 38万
  • 项目类别:

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组合细胞因子包被的巨噬细胞用于急性肺损伤的靶向免疫调节
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