Nrf2 Dependent Regulation of Oxidative Stress in Asthma

在过去的20年里，哮喘的患病率翻了一番，现在影响到世界10%的人口。 美国的过敏性哮喘的易感性在暴露于过敏原的人群中差异很大。 基因-环境相互作用可能在哮喘的发病机制中起重要作用。我们的长期目标 是为了了解调节过敏原易感性的宿主因素和哮喘的发病机制。 这种理解对于制定新的干预战略至关重要。我们最近报道了一个新的主持人 核因子-红细胞2 p45相关因子2（Nrf2），可能在决定 易患过敏性哮喘。Nrf2是一种碱性亮氨酸拉链转录因子，它决定了 通过调节环境应激反应，包括细胞应激反应， 抗氧化剂小鼠中Nrf2的破坏导致对致敏和激发的严重哮喘反应 各种过敏原如卵清蛋白和豚草提取物。哮喘反应过度 Nrf2破坏的小鼠对过敏原的反应涉及增加的氧化应激和明显的 嗜酸性粒细胞进入肺部，更大的T辅助细胞2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是哮喘发病机制的关键调节因子。 中心假设是Nrf2依赖性补偿转录程序调节环境 应激反应，通过减少气道中的氧化应激来防止过敏原诱导的哮喘 上皮细胞和Th2效应细胞，其又抑制细胞因子和趋化因子表达。相反地， 破坏或次优的Nrf2活性导致增加的氧化应激和哮喘反应。具体目标 1.研究哮喘气道上皮细胞Nrf2活性的调节作用。具体目标2： 研究哮喘通过T效应细胞中Nrf2活性的调节。具体目标3：检验假设 Nrf2及其靶向抗氧化基因的遗传变异与儿童期的易感性有关， 具体目的4：检验增强Nrf2活性可以减弱哮喘和特应性的假设。 该提案将重点研究哮喘发病机制的Nrf2依赖性调节， 通过靶向这种转录因子，努力开发临床前干预策略，以减少哮喘 在人群中的易感个体中。

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.