Nrf2 Dependent Regulation of Oxidative Stress in Asthma

哮喘中氧化应激的 Nrf2 依赖性调节

基本信息

批准号：
8294887
负责人：
Shyam Biswal
金额：
$ 40.19万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294887
关键词：
Adoptive Transfer Affect Air Pollutants Allergens Ambrosia Antibodies Antigens Antioxidants Asthma Attenuated Baltimore Binding CD28 gene CD3 Antigens CD4 Positive T Lymphocytes Cells Child Childhood Asthma Cities Complex Consensus Sequence Data Defect Effector Cell Environment Extrinsic asthma Frequencies Gene Expression Profile Gene Expression Profiling Gene Targeting Genes Genetic Variation Genotype Glutamate-Cysteine Ligase Glutathione Glutathione S-Transferase Heat shock proteins Heme Hyperplasia IgE Imidazole Immune response In Vitro Individual Infiltration Inflammation Inflammatory Integration Host Factors Interferons Interleukin-13 Interleukin-4 Intervention Isothiocyanates Knock-out Laboratories Liquid substance London Lung Measures Mexico Modification Molecular Chaperones Mucous body substance Mus NF-E2-related factor 2 National Institute of Environmental Health Sciences Nuclear Nuclear Protein Ovalbumin Oxidative Stress Oxygenases Parents Particulate Matter Pathogenesis Pathway interactions Play Population Predisposition Prevalence Principal Investigator Proteomics Pulmonary Emphysema Reactive Oxygen Species Regulation Reporting Research Personnel Role Sampling Severities Splenocyte Stress Sulforaphane T-Lymphocyte Testing Therapeutic Thioredoxin Triad Acrylic Resin United States airway epithelium airway hyperresponsiveness airway inflammation atopy bZIP Domain biological adaptation to stress chemokine cytokine design eosinophil gene environment interaction glutathione peroxidase lymph nodes mouse model novel nuclear factor-erythroid 2 pre-clinical programs promoter research study response small molecule trafficking transcription factor

项目摘要

In the last 20 years the prevalence of asthma has doubled and it now affects 10% of the population in the United States. The susceptibility to allergic asthma varies greatly in the population exposed to allergens. Gene-environment interaction may play an important role in pathogenesis of asthma. Our long-term objective is to understand the host factors that regulate susceptibility to allergens and the pathogenesis of asthma. Such an understanding is vital for developing new intervention strategies. We recently reported a novel host factor, nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), that may play a critical role in determining susceptibility to allergic asthma. Nrf2 is a basic leucine zipper transcription factor that determines the severity to asthma in mice models by regulating environmental stress response that includes cellular antioxidants. Disruption of Nrf2 in mice leads to severe asthma in response to sensitization and challenge by variety of allergens such as ovalbumin and ragweed extract. The exaggerated asthmatic response in Nrf2-disrupted mice in response to allergen involves increased oxidative stress and pronounced infiltration of eosinophils into the lungs, greater T helper 2 cells and cytokines (IL-4, IL-13), antigen-specific IgE, mucus cell hyperplasia, airway hyperresponsiveness. Thus, Nrf2 is a critical regulator of asthma pathogenesis.Our central hypothesis is that Nrf2 dependent compensatory transcriptional program regulate the environmental stress response that protects against allergen-induced asthma by decreasing oxidative stress in the airway epithelium and Th2 effector cells that in turn inhibits cytokine and chemokine expression. Conversely, disrupted or suboptimal Nrf2 activity causes increased oxidative stress and asthmatic response. Specific Aim 1: To investigate the regulation of asthma by Nrf2 activity in the airway epithelium. Specific Aim 2: To investigate the regulation of asthma by Nrf2 activity in T effector cells. Specific aim 3: To test the hypothesis that genetic variation in Nrf2 and its target antioxidant genes is associated with susceptibility to childhood asthma and atopy.Specific Aim 4: To test the hypothesis that enhancing Nrf2 activity can attenuate asthma.The proposal will focus on investigating Nrf2 dependent regulation of asthma pathogenesis and strive to develop a preclinical intervention strategy by targeting this transcription factor for decreasing asthma in the susceptible individuals in the population.

在过去的20年中，哮喘的患病率增加了一倍，现在影响了10％的人口美国。过敏性哮喘的敏感性在暴露于过敏原的种群中差异很大。基因环境相互作用可能在哮喘发病机理中起重要作用。我们的长期目标是了解调节过敏原敏感性和哮喘发病机理的宿主因素。这种理解对于制定新的干预策略至关重要。我们最近报道了一个新颖的主人因子，核因子 - 瘤2 P45相关因子2（NRF2），可能在确定中起关键作用对过敏性哮喘的敏感性。 NRF2是一个基本的亮氨酸拉链转录因子，它决定了通过调节包括细胞的环境应力反应，小鼠模型中哮喘的严重程度抗氧化剂。小鼠中NRF2的破坏会导致严重的哮喘，以应对敏感和挑战通过多种过敏原，例如椭圆蛋白和碎屑提取物。夸张的哮喘反应响应过敏原的NRF2破坏小鼠涉及增加的氧化应激和明显的浸润嗜酸性粒细胞进入肺部，更大的T辅助2细胞和细胞因子（IL-4，IL-13），抗原特异性IgE，粘液细胞增生，气道高反应性。因此，NRF2是哮喘发病机理的关键调节剂。中心假设是NRF2依赖的补偿性转录程序调节环境通过减少气道中的氧化应激来预防过敏原诱导哮喘的应力反应上皮和Th2效应细胞又抑制细胞因子和趋化因子表达。反过来，破坏或次优的NRF2活性会导致氧化应激和哮喘反应增加。具体目标 1：研究气道上皮中NRF2活性对哮喘的调节。具体目标2：研究T效应细胞中NRF2活性对哮喘的调节。特定目的3：检验假设 NRF2及其靶抗氧化剂基因的遗传变异与儿童敏感性有关哮喘和特殊目标4：测试增强NRF2活性的假设哮喘。该提案将重点研究哮喘发病机理和努力通过靶向这种转录因子来降低哮喘来制定临床前干预策略在人口中的易感人群中。