A novel role of NF-kB in viral-induced airway oxidative stress

NF-kB 在病毒诱导的气道氧化应激中的新作用

基本信息

批准号：
8638667
负责人：
Antonella Casola
金额：
$ 23.19万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-11 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638667
关键词：
Acetylation Acetylesterase Acute Admission activity Affect Animals Antioxidants Asthma Bronchiolitis Cells Cessation of life Child Chronic Obstructive Airway Disease Chronic lung disease Clinical Complement Factor B Data Development Disease Elderly Enzyme Gene Enzymes Epidemic Epithelial Cells Gene Expression Generations Genes Genetic Transcription Histones Hospitals In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Intervention Lead Link Lower Respiratory Tract Infection Lung Lung Inflammation Lung diseases Mediator of activation protein Molecular Morbidity - disease rate Mus NF-E2-related factor 2 Nuclear Outcome Measure Oxidative Stress Pathogenesis Pathway interactions Play Pneumonia Post-Translational Protein Processing Process Production Public Health Publishing Reactive Oxygen Species Recruitment Activity Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Vaccines Respiratory Tract Infections Respiratory syncytial virus Role Severities Site Syndrome Testing Transcription Coactivator Ubiquitination Vaccines Viral Virus airway hyperresponsiveness chemokine effective therapy experience flu in vivo inhibitor/antagonist leukocyte activation lung injury migration mortality mouse model multicatalytic endopeptidase complex novel novel therapeutics oxidative damage prevent promoter public health relevance research study respiratory respiratory virus response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the most common cause of epidemic respiratory disease in children, responsible for 100,000 hospital admissions annually in the US alone, for which no vaccine or effective treatment is currently available. In the past years, we have shown that RSV infection leads to activation of the transcription factor Nuclear Factor (NF)-kB, as well as to the rapid generation of reactive oxygen species (ROS), both of which are involved in the expression of chemokines, proinflammatory mediators that regulate the migration and activation of leukocytes to the site of infection. In addition, RSV-induced ROS generation is associated with oxidative stress and lung damage both in vitro and in vivo, due to an imbalance between ROS production and antioxidant cellular defenses. Preliminary experiments revealed a new and fundamental role of NF-kB in modulating AOE gene expression in response to RSV infection, by inhibiting activation of NF-E2- related factor 2 (Nrf2), which regulates basal and inducible expression of AOE genes. In this project we will pursue the hypothesis that NF-¿B plays a key role in RSV-induced lung disease as it antagonizes Nrf2- dependent gene expression, leading to inhibition of airway antioxidant defenses and subsequent oxidative lung damage. We will test our hypothesis by pursuing the following Specific Aims: Aim 1. To determine the mechanism(s) by which NF-kB activation leads to inhibition of Nrf2 activation. We will investigate whether NF- kB affects Nrf2 activation by affecting its acetylation, through the recruitment of histone deacetylases and competition of transcriptional coactivators, and by promoting Nrf2 ubiquitination and degradation. Aim 2. To investigate whether modulation of RSV-induced NF-kB activation in vivo leads to decreased lung oxidative stress and disease. We will pharmacologically inhibit NF-kB activation in a mouse model of RSV infection and assess markers of oxidative injury, AOE expression and clinical disease. Our results will help elucidate an important and novel molecular pathway by which respiratory viruses induce lung disease, with strong implications for developing novel therapeutic strategies not only against viral-induced lower respiratory tract infections (LRTI) but also other acute and chronic lung diseases where inflammation and oxidative stress play an important pathogenic role, such as asthma and chronic obstructive pulmonary disease.

描述（由应用提供）：呼吸道合胞病毒（RSV）是儿童流行呼吸道疾病的最常见原因，仅在美国，每年在美国就有100,000次住院治疗，目前没有疫苗或有效治疗。在过去的几年中，我们已经表明，RSV感染导致转录因子核因子（NF）-KB的激活以及活性氧种（ROS）的快速产生，它们都参与趋化因子的表达，促炎介质，这些介质介质调节了对感染部位的迁移和活化。此外，由于ROS产生和抗氧化剂细胞防御能力不平衡，RSV诱导的ROS的产生与体外和体内的氧化应激和肺损伤有关。初步实验揭示了NF-KB通过抑制NF-E2-相关因子2（NRF2）的激活来调节AOE基因表达对RSV感染的反应，从而调节AOE基因的碱性和诱导表达。在该项目中，我们将提出以下假设：NF-€b在RSV诱导的肺部疾病中起关键作用，因为它拮抗了NRF2依赖的基因表达，从而导致抑制气道抗氧化剂防御剂，并随后氧化肺损伤。我们将通过追求以下特定目的来检验我们的假设：目的1。确定NF-KB激活导致抑制NRF2激活的机制。我们将通过通过募集组蛋白脱乙酰基酶和转录共激活剂的竞争以及促进NRF2泛素化和降解来研究NF-KB是否通过影响NRF2激活来影响NRF2激活。目的2。研究RSV诱导的NF-KB活化的调节是否导致肺氧化应激和疾病的改善。我们将在RSV感染的小鼠模型和氧化损伤，AOE表达和临床疾病的评估标记中物理抑制NF-KB激活。我们的结果将有助于阐明一种重要且新颖的分子途径，呼吸道病毒诱导肺部疾病，对制定新型治疗策略的影响不仅对病毒引起的下呼吸道感染（LRTI），而且还具有很大的影响。还有其他急性和慢性肺疾病，其中感染和氧化应激起具有重要的致病作用，例如哮喘和慢性阻塞性肺部疾病。