Redox-based Fas signaling in allergic airway disease

过敏性气道疾病中基于氧化还原的 Fas 信号传导

基本信息

批准号：
7822474
负责人：
Yvonne M. W. Janssen-Heininger
金额：
$ 0.8万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
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：
2009-06-01 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7822474
关键词：
Address Allergic Antigens Apoptosis Apoptotic Biological Assay Breeding Bronchoalveolar Lavage Fluid CD95 Antigens Catalase A Cell Death Cells Cessation of life Cysteine Cytolysis Dominant-Negative Mutation Drug Metabolic Detoxication Environment Epithelial Epithelial Cells Epithelium Evaluation Event Family member Funding Generations Generic Drugs Hydrogen Peroxide Immune system Immunization Immunoprecipitation Inflammation Invaded Irrigation Lead Ligands Lung Lung diseases MAPK8 gene Measurement Measures Mediating Mitogen-Activated Protein Kinases Modeling Mus NADPH Oxidase NF-kappa B Organism Outcome Ovalbumin Oxidants Oxidation-Reduction Peroxidases Phosphorylation Physiology Play Production Reactive Oxygen Species Role Shapes Signal Transduction Source Stress Testing Tetracyclines Transgenic Mice Transgenic Organisms Tumor Necrosis Factor Ligand Superfamily Member 6 Tumor Necrosis Factor Receptor Western Blotting airway epithelium airway hyperresponsiveness airway remodeling allergic airway disease allergic airway inflammation base catalase comparative ebselen fluorescence imaging gel electrophoresis glucose oxidase inhibitor/antagonist killings mimetics neutralizing antibody overexpression oxidation primary outcome receptor research study response stress-activated protein kinase 1 transcription factor

项目摘要

DESCRIPTION (provided by applicant): The death receptor Fas is expressed on lung cells where it can transduce signals that mediate diverse outcomes. We recently showed that the oxidant, hydrogen peroxide (H202) promotes clustering of Fas in mouse lung epithelial cells, and that H202 uses Fas to signal to c-Jun-N-terminal kinase, (JNK), a critical signaling module that allows cells to sense and respond to stress. The outcome of Fas signaling is not strictly apoptosis, but also including shape changes, inflammation etc. The pro-survival factor, NF-kB is activated in a prolonged fashion in airways of mice with allergic airway disease, which can counteract the pro-apoptotic effect of Fas activation. During allergic airways inflammation, the redox environment of the lung is changed towards a pro-oxidant state, and H202 is present in lungs of mice with allergic airways disease. Thus, the hypothesis to be tested in this proposal is that H202- mediated activation of JNK in lung epithelium of mice with allergic airways disease contributes airways hyper-responsiveness (AHR) and remodeling, through oxidative activation of Fas. In Specific Aim 1, we will determine whether H202 promotes JNK activation, AHR, and remodeling in mice with allergic airways disease via the use of catalase over-expressing mice, and the use of pharmacologic agents that lower H202. We will also directly administer a source of H202, to determine whether H202 is sufficient to activate JNK, and elicit AHR, and whether this requires functional Fas. In Specific Aim 2, we will determine whether Fas is oxidized and oligomerized in mice with allergic lung disease, and whether this occurs in airway epithelium, and the requirement for H202 herein. In Specific Aim 3, we will determine the requirement of airway epithelial Fas in JNK activation, AHR, and remodeling in the airways of mice with allergic airway disease by using LPR mice, which lack Fas systemically, or via the creation a CC 10-DN-Fas expressing mouse. Lastly, in Specific Aim 4 we will determine the contribution of airway epithelial JNK activation in AHR through the generation of a transgenic mouse expressing a dominant negative version of JNK1 in cells of the conducting airways, in a tetracycline inducible manner. These approaches are crucial in defining critical oxidant targets and epithelial signaling events crucial to the patho-physiology of allergic airways disease.

描述（由申请人提供）：死亡受体 Fas 在肺细胞上表达，可以转导介导不同结果的信号。我们最近表明，氧化剂过氧化氢 (H202) 可促进小鼠肺上皮细胞中 Fas 的聚集，并且 H202 使用 Fas 向 c-Jun-N-末端激酶 (JNK) 发出信号，这是一种关键的信号传导模块，允许细胞感知并应对压力。 Fas信号传导的结果并不严格是细胞凋亡，还包括形状改变、炎症等。促生存因子NF-kB在过敏性气道疾病小鼠的气道中被长时间激活，可以抵消促细胞凋亡Fas 激活的影响。在过敏性气道炎症期间，肺部的氧化还原环境转变为促氧化状态，并且H2O2存在于患有过敏性气道疾病的小鼠的肺部中。因此，本提案要测试的假设是，患有过敏性气道疾病的小鼠肺上皮中 H2O2 介导的 JNK 激活通过 Fas 的氧化激活导致气道高反应性 (AHR) 和重塑。在具体目标 1 中，我们将通过使用过氧化氢酶过度表达的小鼠以及使用降低 H202 的药物来确定 H202 是否促进患有过敏性气道疾病的小鼠的 JNK 激活、AHR 和重塑。我们还将直接施用 H2O2 源，以确定 H2O2 是否足以激活 JNK，并引发 AHR，以及这是否需要功能性 Fas。在具体目标 2 中，我们将确定患有过敏性肺病的小鼠中 Fas 是否被氧化和寡聚，以及这种情况是否发生在气道上皮中，以及本文对 H2O2 的需求。在具体目标 3 中，我们将通过使用全身缺乏 Fas 的 LPR 小鼠或通过创建 CC 10-DN 来确定过敏性气道疾病小鼠的 JNK 激活、AHR 和气道重塑中气道上皮 Fas 的需求-Fas表达小鼠。最后，在具体目标 4 中，我们将通过产生以四环素诱导方式在传导气道细胞中表达 JNK1 显性失活版本的转基因小鼠，确定 AHR 中气道上皮 JNK 激活的贡献。这些方法对于定义对过敏性气道疾病的病理生理学至关重要的关键氧化剂靶标和上皮信号传导事件至关重要。