Inhibition of the Fas/FasL system in experimental acute lung injury

实验性急性肺损伤中 Fas/FasL 系统的抑制

基本信息

项目摘要

 DESCRIPTION (provided by applicant) The acute respiratory distress syndrome (ARDS) is an important clinical problem in the United States, affecting 200,000 patients per year and resulting in death of approximately 75,000 persons. Our laboratory is interested in the role of the Fas/FasL system in the pathophysiology of acute lung injury (ALI) in humans and animal models. This system is comprised of the membrane surface receptor Fas (CD95) and its cognate ligand, FasL (CD178). Binding of Fas to FasL activates signaling pathways that lead to apoptosis and also to cytokine release. We have shown that activation of the Fas/FasL system in animals leads to ALI, whereas mice lacking functional Fas are protected in LPS-induced lung injury. We have also shown that the Fas/FasL system is active in the lungs of humans with ARDS. Recently we have found that the biological activity of sFasL in the lungs is dependent on its structure. Specifically, we determine that sFasL exists in at least two forms: a 144- amino acid short form, consisting primarily of the binding domain, and a 178 amino-acid long form, consisting of the binding domain plus a short juxtamembrane "stalk" region. Only the long form of sFasL, which is the major form that is present in BAL fluid from patients with ARDS. Importantly, we have found that a sFasL mutant in which all 8 charged amino acids of the stalk region have been changed to alanines has decreased function and furthermore, acts as an inhibitor of native sFasL in vitro. We now seek to determine the mechanism of inhibition of the 8-site mutated sFasL and whether it attenuates lung injury in vivo. Hypothesis: The 8-site mutated sFasL acts as an inhibitor of native sFasL by impairing the ability of the Fas receptor to form membrane clusters that are needed to initiate signaling. Therefore, the 8-site mutated sFasL will attenuate the pro-apoptotic activity of human ARDS BALF in vitro and the severity of experimental acute lung injury in vivo. Aim 1: Determine whether the 8-site mutated sFasL inhibits native sFasL by impairing the formation of Fas:FasL clusters and subsequent receptor:ligand capping. Aim 2: Determine whether the 8-site mutated sFasL attenuates the pro-apoptotic activity of BALF from humans with ARDS in vitro. Aim 3: Determine whether the 8-site mutated sFasL attenuates the severity of experimental acute lung injury in vivo. Findings derived from this study will have a transformative impact in the field by refocusing attention on the mechanistic role of pro-apoptotic systems in acute lung injury, and by discovering new potential therapeutic agents for ARDS.
 描述(由申请人提供) 急性呼吸窘迫综合征(ARDS)在美国是一个重要的临床问题,每年影响20万名患者,导致约7.5万人死亡。本实验室对Fas/FasL系统在人和动物急性肺损伤(ALI)病理生理学中的作用感兴趣。该系统由膜表面受体Fas(CD95)及其同源配体FasL(CD178)组成。Fas与FasL的结合激活了导致细胞凋亡和细胞因子释放的信号通路。我们已经证明,动物体内Fas/FasL系统的激活导致ALI,而缺乏功能性Fas的小鼠在脂多糖诱导的肺损伤中受到保护。我们还表明,Fas/FasL系统在患有ARDS的人的肺中是活跃的。最近我们发现sFasL在肺中的生物活性依赖于它的结构。具体地说,我们确定sFasL至少以两种形式存在:144个氨基酸的短形式,主要由结合域组成;178个氨基酸的长形式,由结合域和一个短的靠近膜的“柄”区域组成。只有长形式的sFasL,这是ARDS患者BAL液中的主要形式。重要的是,我们发现了一个sFasL突变体,其中茎区域的8个带电氨基酸都被改变为丙氨酸,它的功能降低了,而且在体外对天然sFasL起到了抑制作用。我们现在试图确定抑制8位点突变的sFasL的机制,以及它是否可以减轻体内的肺损伤。假设:8位点突变的sFasL通过削弱Fas受体形成启动信号所需的膜簇的能力而发挥天然sFasL的抑制作用。因此,8位点突变的sFasL在体外可减弱人ARDS BALF的促凋亡活性,在体内可减轻实验性急性肺损伤的严重程度。目的1:确定8位点突变的sFasL是否通过影响Fas:FasL簇的形成和随后的受体:配体封顶来抑制天然的sFasL。目的:检测8位点突变的sFasL是否在体外抑制ARDS患者BALF的促凋亡活性。目的3:确定8位点突变的sFasL在体内是否减轻实验性急性肺损伤的严重程度。这项研究的发现将对该领域产生革命性的影响,重新关注促凋亡系统在急性肺损伤中的机制作用,并发现新的潜在ARDS治疗药物。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The bioactivity of soluble Fas ligand is modulated by key amino acids of its stalk region.
  • DOI:
    10.1371/journal.pone.0253260
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Kajikawa O;Herrero R;Chow YH;Hung CF;Matute-Bello G
  • 通讯作者:
    Matute-Bello G
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GUSTAVO MATUTE-BELLO其他文献

GUSTAVO MATUTE-BELLO的其他文献

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{{ truncateString('GUSTAVO MATUTE-BELLO', 18)}}的其他基金

"The alveolar epithelium in lung injury and repair"
“肺损伤和修复中的肺泡上皮”
  • 批准号:
    7841316
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Acute Lung Injury: Link Between Apoptosis and Fibrosis
急性肺损伤:细胞凋亡与纤维化之间的联系
  • 批准号:
    7858112
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
The alveolar epithelium in lung injury and repair
肺泡上皮在肺损伤和修复中的作用
  • 批准号:
    7145363
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
"The alveolar epithelium in lung injury and repair"
“肺损伤和修复中的肺泡上皮”
  • 批准号:
    7868026
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
"The alveolar epithelium in lung injury and repair"
“肺损伤和修复中的肺泡上皮”
  • 批准号:
    7257227
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
"The alveolar epithelium in lung injury and repair"
“肺损伤和修复中的肺泡上皮”
  • 批准号:
    7440269
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
"The alveolar epithelium in lung injury and repair"
“肺损伤和修复中的肺泡上皮”
  • 批准号:
    7637445
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
The FastFasL system in lung injury
FastFasL 系统在肺损伤中的应用
  • 批准号:
    7090575
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
The FastFasL system in lung injury
FastFasL 系统在肺损伤中的应用
  • 批准号:
    6787147
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
The FastFasL system in lung injury
FastFasL 系统在肺损伤中的应用
  • 批准号:
    6521602
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:

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成人呼吸窘迫综合征的临床模型
  • 批准号:
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