Regulation of Fas-Mediated Lung Cell Apoptosis

Fas 介导的肺细胞凋亡的调节

基本信息

  • 批准号:
    7838821
  • 负责人:
  • 金额:
    $ 13.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-01 至 2011-06-30
  • 项目状态:
    已结题

项目摘要

Defects in apoptosis or programmed cell death regulation contribute to many human diseases, including those of the lung. Recent evidence indicates that Fas(CD95)-mediated apoptosis plays an important role in the pathogenesis of several pulmonary diseases. However our understanding of the mechanisms involved in the process is limited. Failure to understand such mechanisms directly limits the effectiveness of prevention and therapeutic efforts. The overall objective of this study is to provide a scientific basis for a mechanistic understanding of the molecular events involved in Fas-mediated apoptosis and its regulation in specific lung cells. Our preliminary findings indicate that while Fas can trigger apoptosis of lung cells, the expression level of Fas and its activation by Fas ligand (FasL) do not correlate with the susceptibility toFas- mediated cell death, indicating that regulators of the apoptosis-signaling pathway must exist. In this project we will seek to identify key regulators controlling Fas-mediated cell death of lung cells and elucidate their mechanisms. The project will specifically test the hypotheses that susceptibility to Fas-mediated apoptosis and associated lung pathologies may be determined by the expression level of cellular FLICE-inhibitory protein (c-FLIP) and that alterations of this protein by certain pneumotoxic agents can sensitize cells to Fas- mediated cell death via an activation of caspase-8 and downstream caspase cascade. We will determine the functional role of c-FLIP and identify the death signaling pathways in primary lung cells using various molecular biology and biochemical techniques. We will also test the hypothesis that downregulation of c- FLIP through post-translational modifications is a critical regulatory event controlling Fas-mediated cell death and survival via caspase-8 and NF-kB signaling pathway. Because our preliminary findings indicate critical roles of reactive oxygen species (ROS) and ubiquitin-proteasome dependent pathway in c-FLIP degradation and Fas signaling, we will elucidate the underlying mechanisms and identify specific ROS involved and their cellular sources. Furthermore, we will determine specific ubiquitination sites on c-FLIP that target this molecule for degradation using site-directed mutagenesis and gene deletion assays. It is expect that the proposed studies will provide valuable new information on the mechanisms of cell death regulation and associated lung disorders which will be important in risk assessment and therapeutic intervention.
细胞凋亡或程序性细胞死亡调节的缺陷导致许多人类疾病,包括 那些肺部的。最近的证据表明 Fas(CD95) 介导的细胞凋亡在 几种肺部疾病的发病机制。然而我们对所涉及机制的理解 过程中是有限的。不了解这些机制直接限制了效果 预防和治疗工作。本研究的总体目标是为研究提供科学依据 Fas 介导的细胞凋亡及其调控中涉及的分子事件的机制理解 特定的肺细胞。我们的初步研究结果表明,虽然 Fas 可以引发肺细胞凋亡,但 Fas 的表达水平及其由 Fas 配体 (FasL) 的激活与对 Fas 的敏感性不相关 介导细胞死亡,表明细胞凋亡信号通路的调节因子必须存在。在这个项目中 我们将寻求确定控制 Fas 介导的肺细胞细胞死亡的关键调节因子,并阐明它们的作用 机制。该项目将专门测试以下假设:Fas 介导的细胞凋亡的敏感性 和相关的肺病理学可以通过细胞 FLICE 抑制的表达水平来确定 蛋白质(c-FLIP)并且某些肺毒性药物对该蛋白质的改变可以使细胞对 Fas- 敏感。 通过激活 caspase-8 和下游 caspase 级联介导细胞死亡。我们将确定 c-FLIP 的功能作用并使用各种方法鉴定原代肺细胞中的死亡信号通路 分子生物学和生化技术。我们还将检验 c 下调的假设 通过翻译后修饰的 FLIP 是控制 Fas 介导的细胞死亡的关键调控事件 通过 caspase-8 和 NF-kB 信号通路实现生存。因为我们的初步调查结果表明至关重要 活性氧(ROS)和泛素蛋白酶体依赖性途径在c-FLIP降解中的作用 和 Fas 信号传导,我们将阐明潜在机制并确定涉及的特定 ROS 及其 细胞来源。此外,我们将确定 c-FLIP 上针对此的特定泛素化位点 使用定点诱变和基因删除测定来降解分子。预计 拟议的研究将为细胞死亡调节机制提供有价值的新信息 相关的肺部疾病对于风险评估和治疗干预非常重要。

项目成果

期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Effect of fiber length on carbon nanotube-induced fibrogenesis.
  • DOI:
    10.3390/ijms15057444
  • 发表时间:
    2014-04-29
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Manke A;Luanpitpong S;Dong C;Wang L;He X;Battelli L;Derk R;Stueckle TA;Porter DW;Sager T;Gou H;Dinu CZ;Wu N;Mercer RR;Rojanasakul Y
  • 通讯作者:
    Rojanasakul Y
Antioxidant c-FLIP inhibits Fas ligand-induced NF-kappaB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner.
Mitochondrial superoxide mediates doxorubicin-induced keratinocyte apoptosis through oxidative modification of ERK and Bcl-2 ubiquitination.
  • DOI:
    10.1016/j.bcp.2012.03.010
  • 发表时间:
    2012-06-15
  • 期刊:
  • 影响因子:
    5.8
  • 作者:
    Luanpitpong, Sudjit;Chanvorachote, Pithi;Nimmannit, Ubonthip;Leonard, Stephen S.;Stehlik, Christian;Wang, Liying;Rojanasakul, Yon
  • 通讯作者:
    Rojanasakul, Yon
Hydroxyl radical mediates cisplatin-induced apoptosis in human hair follicle dermal papilla cells and keratinocytes through Bcl-2-dependent mechanism.
  • DOI:
    10.1007/s10495-011-0609-x
  • 发表时间:
    2011-08
  • 期刊:
  • 影响因子:
    7.2
  • 作者:
    Luanpitpong, Sudjit;Nimmannit, Ubonthip;Chanvorachote, Pithi;Leonard, Stephen S.;Pongrakhananon, Varisa;Wang, Liying;Rojanasakul, Yon
  • 通讯作者:
    Rojanasakul, Yon
Mechanisms of nanoparticle-induced oxidative stress and toxicity.
  • DOI:
    10.1155/2013/942916
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Manke A;Wang L;Rojanasakul Y
  • 通讯作者:
    Rojanasakul Y
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Yon Rojanasakul其他文献

Yon Rojanasakul的其他文献

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{{ truncateString('Yon Rojanasakul', 18)}}的其他基金

Nanoparticle Fibrogenicity and Fibroblast Stem-Like Cells
纳米颗粒成纤维性和成纤维细胞样细胞
  • 批准号:
    9212809
  • 财政年份:
    2016
  • 资助金额:
    $ 13.65万
  • 项目类别:
Induction of Neoplastic Transformation and Cancer Stem Cells by Carbon Nanotubes
碳纳米管诱导肿瘤转化和癌症干细胞
  • 批准号:
    8846114
  • 财政年份:
    2014
  • 资助金额:
    $ 13.65万
  • 项目类别:
Induction of Neoplastic Transformation and Cancer Stem Cells by Carbon Nanotubes
碳纳米管诱导肿瘤转化和癌症干细胞
  • 批准号:
    8691555
  • 财政年份:
    2014
  • 资助金额:
    $ 13.65万
  • 项目类别:
Induction of Neoplastic Transformation and Cancer Stem Cells by Carbon Nanotubes
碳纳米管诱导肿瘤转化和癌症干细胞
  • 批准号:
    9024527
  • 财政年份:
    2014
  • 资助金额:
    $ 13.65万
  • 项目类别:
Prediction and Mechanism of Carbon Nanotube-Induced Fibrosis
碳纳米管诱导纤维化的预测及机制
  • 批准号:
    8268403
  • 财政年份:
    2010
  • 资助金额:
    $ 13.65万
  • 项目类别:
Prediction and Mechanism of Carbon Nanotube-Induced Fibrosis
碳纳米管诱导纤维化的预测及机制
  • 批准号:
    8463235
  • 财政年份:
    2010
  • 资助金额:
    $ 13.65万
  • 项目类别:
Prediction and Mechanism of Carbon Nanotube-Induced Fibrosis
碳纳米管诱导纤维化的预测及机制
  • 批准号:
    8111227
  • 财政年份:
    2010
  • 资助金额:
    $ 13.65万
  • 项目类别:
Prediction and Mechanism of Carbon Nanotube-Induced Fibrosis
碳纳米管诱导纤维化的预测及机制
  • 批准号:
    7983999
  • 财政年份:
    2010
  • 资助金额:
    $ 13.65万
  • 项目类别:
Regulation of Fas-Mediated Lung Cell Apoptosis
Fas 介导的肺细胞凋亡的调节
  • 批准号:
    7100360
  • 财政年份:
    2006
  • 资助金额:
    $ 13.65万
  • 项目类别:
Regulation of Fas-Mediated Lung Cell Apoptosis
Fas 介导的肺细胞凋亡的调节
  • 批准号:
    7579060
  • 财政年份:
    2006
  • 资助金额:
    $ 13.65万
  • 项目类别:

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α-1 抗胰蛋白酶缺陷型 2 型肺泡上皮细胞的功能获得毒性
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