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，现在影响着世界上10%的人口 美国。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-环境相互作用在哮喘发病机制中可能起重要作用。我们的长期目标 是为了了解调节变应原易感性的宿主因素和哮喘的发病机制。 这样的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宿主 核因子-红系P45相关因子2(Nrf2)，可能在决定 易患过敏性哮喘。NRF2是一种基本的亮氨酸拉链转录因子，它决定了 通过调节包括细胞在内的环境应激反应在小鼠模型中对哮喘的严重性 抗氧化剂。小鼠对致敏和激发的反应中Nrf2基因的破坏导致严重哮喘 由多种过敏原，如卵清蛋白和豚草提取物。对哮喘的夸大反应 NRF2干扰的小鼠对变应原的反应涉及氧化应激增加和显著的渗透 进入肺部的嗜酸性粒细胞，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 细胞增殖，呼吸道高反应性。因此，Nrf2是哮喘发病的关键调节因子。 中心假设是依赖于Nrf2的补偿性转录程序调节环境 通过减少呼吸道氧化应激来预防过敏原诱导的哮喘的应激反应 上皮细胞和Th2效应细胞，进而抑制细胞因子和趋化因子的表达。相反， 破坏或低于最佳的Nrf2活性会导致氧化应激和哮喘反应增加。特定目标 1.探讨气道上皮细胞中Nrf2活性对哮喘的调节作用。具体目标2： 探讨T效应细胞Nrf2活性对哮喘的调节作用。具体目标3：检验假设 Nrf2及其目标抗氧化剂基因的遗传变异与儿童易感性有关 哮喘和特应性。具体目标4：检验增强Nrf2活性可以减弱的假设 建议将重点放在研究Nrf2对哮喘发病机制的依赖调节和 通过靶向转录因子减少哮喘，努力开发临床前干预策略 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.