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

• 批准号: 6858086
• 负责人: Yvonne M. W. Janssen-Heininger
• 金额: $ 36.7万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858086
• 关键词: CD95 molecule; JUN kinase; NAD(P)H dehydrogenase; apoptosis; biological signal transduction; catalase; cysteine; enzyme activity; gel electrophoresis; genetically modified animals; glucose oxidase; hydrogen peroxide; hypersensitivity; immunoprecipitation; laboratory mouse; lung imaging /visualization /scanning; oxidation reduction reaction; pathologic process; peroxidation; posttranslational modifications; respiratory airflow disorder; respiratory epithelium; western blottings

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在肺部细胞上表达，它可以传递介导多种结果的信号。我们最近表明，氧化剂过氧化氢（H202）促进了小鼠肺上皮细胞中Fas的聚类，并且H202使用FAS信号向C-Jun-N-末端激酶（JNK）发出信号，这是一个关键的信号传导模块，允许细胞感知和反应应激。 FAS信号传导的结果不是严格的凋亡，而是包括形状变化，炎症等。促生存因子NF-KB在患有过敏性气道疾病的小鼠气道中以延长的方式激活，这可以抵消FAS激活的促凋亡效应。在过敏性气道炎症期间，肺的氧化还原环境变为促氧化剂，H202存在于患有过敏性气道疾病的小鼠的肺中。因此，在该提案中要检验的假设是H202-介导的JNK在具有过敏性气道疾病的小鼠肺上皮中的激活，通过氧化激活Fas促进了气道高反应性（AHR）和重塑。在特定目标1中，我们将确定H202是否通过使用过表达的小鼠以及使用降低H202的药理学剂来促进患有过敏酶疾病的小鼠中的JNK激活，AHR和重塑。 我们还将直接管理H202的来源，以确定H202是否足以激活JNK并激活AHR，以及这是否需要功能性FAS。在特定的目标2中，我们将确定在患有过敏性肺部疾病的小鼠中FAS是否被氧化和寡聚，以及这是否发生在气道上皮中，以及此处对H202的需求。在特定的目标3中，我们将通过使用系统缺乏FAS或通过创建CC 10-DN-FAS表达小鼠的CC 10-DN-FAS的LPR小鼠来确定JNK激活，AHR和重塑气道上皮FA的需求。最后，在特定的目标4中，我们将通过以四环素诱导的方式生成一只转基因小鼠在导电气道细胞中表达jnk1的主要负面版本的转基因小鼠在AHR中的贡献。这些方法对于定义关键氧化剂靶标和上皮信号传导事件至关重要，对过敏气道疾病的病理生理至关重要。