Down-regulation of oxidant-induced airway inflammation though modulation of NRF2

描述（由申请人提供）：该提案概述了为期3年的K23指导的以患者为导向的研究职业发展奖（K23），旨在完善候选人作为医生科学家的培训，并为专注于开发气道氧化应激疗法的多学科转化研究计划做准备。该提案的目标是提供药物发现/开发方面的支持，培训以及基于干预的概念验证研究的指导，因为候选人将基础科学和临床研究的经验应用于独立转化研究项目的开发。最近的证据，从这个小组和其他人强调的作用，细胞内的抗氧化酶在O3诱导的气道炎症恶化。缺乏抗氧化酶Glucose S Transferase Mu 1（GSTM 1）的健康志愿者在暴露于0.4 ppm臭氧（O3）后，嗜酸性气道炎症增加。GSTM 1和许多其他II相抗氧化酶（NQO 1、GSTP 1、HO-1）由主转录因子NF-E2相关因子2（NRF 2）调节。小鼠模型和慢性阻塞性肺疾病患者的研究表明，NRF 2的缺陷与氧化剂介导的肺损伤有关。因此，NRF 2是一个强有力的候选人，以调节对气道炎症引起的普遍吸入的氧化剂，如O3的保护。本文的目的是使用萝卜硫素（SFN），一种来自专门培育的花椰菜的抗氧化剂化合物，发现其上调NRF 2和NRF 2调节的II期酶（GSTM 1，GSTP 1，HO 1和NQO 1）的表达，以检查口服SFN补充剂的NRF 2诱导是否会减少正常志愿者中O3诱导的气道炎症。其次，培养的分化的鼻上皮细胞来自轻中度持续过敏性哮喘将被用来检查SFN治疗这些上皮细胞修改O3诱导的炎症反应。候选人将获得药物发现过程中的药理学试剂的经验，可以通过拟议的教学课程以及在指导团队的协助下完成这些目标来靶向氧化应激过程。指导团队由三位在指导年轻科学家和开发转化研究项目方面具有丰富经验的人士组成：大卫佩登博士，一位在环境污染、氧化应激方面具有专业知识的转化科学家，也是首席导师;韦斯利伯克斯博士，一位专注于针对食物过敏的I/II期临床试验干预措施的转化研究员;和Angela Kashuba博士，临床药理学研究中心主任，在临床药代动力学和药效学研究方面具有丰富的经验。 公共卫生相关性：由O3引起的呼吸系统并发症是美国和世界范围内的重大公共卫生负担。尽管有令人信服的证据表明肺氧化损伤导致全身有害的健康结果，但环境诱导的氧化应激的治疗选择有限，并且在改善易感人群（如儿童，老年人和过敏性哮喘患者）的健康方面没有显著变化。这项研究有可能确定一种途径，可以通过预防或治疗易感个体吸入环境氧化剂引起的呼吸道炎症来靶向。考虑到哮喘等呼吸道疾病的重大公共卫生负担以及缺乏针对氧化剂诱导的气道炎症的靶向治疗方法，潜在影响很大。

DESCRIPTION (provided by applicant): This proposal outlines a 3 year K23 Mentored Patient-Oriented Research Career Development Award (K23) designed to refine the candidate's training as a physician scientist and to prepare for a multidisciplinary, translational research program focused on the development of therapies against airway oxidative stress. The goal of this proposal is to provide support, training in drug discovery/development, and guidance in intervention-based proof of concept studies as the candidate applies experience in basic science and clinical research to the development of an independent translational research project. Recent evidence from this group and others has emphasized the role of intracellular antioxidant enzymes in exacerbation of O3-induced airway inflammation. Healthy volunteers lacking the antioxidant enzyme, Glutathione S Transferase Mu 1 (GSTM1), suffered from increased neutrophilic airway inflammation after chamber exposure to 0.4 parts per million (ppm) ozone (O3). GSTM1 and numerous other phase II antioxidant enzymes (NQO1, GSTP1, HO-1) are regulated by the master transcription factor NF-E2- related factor 2 (NRF2). Murine models and studies of patients with chronic obstructive pulmonary disease suggest that defects in NRF2 are associated with oxidant-mediated lung injury. Therefore, NRF2 is a strong candidate to modulate in protection against airway inflammation caused by ubiquitous inhaled oxidants such as O3. The intent here is to use sulforaphane (SFN), an antioxidant compound derived from specially bred broccoli that was found to upregulate expression of NRF2 and NRF2-regulated Phase II enzymes (GSTM1, GSTP1, HO1, and NQO1), to examine if NRF2 induction with oral SFN supplementation will reduce O3-induced airway inflammation in normal volunteers. Second, cultured differentiated nasal epithelial cells derived from mild-moderate persistent allergic asthmatics will be used to examine if SFN treatment of these epithelial cells modifies O3-induced inflammatory responses. The candidate will acquire experience in the drug discovery process of pharmacologic agents that can target oxidative stress processes through the proposed didactic coursework as well as with the completion of these aims with the assistance of the mentoring team. The mentoring team consists of three individuals with extensive experience in mentoring young scientists and in developing translational research programs: Dr. David Peden, a translational scientist with expertise on environmental pollution, oxidative stress, and lead mentor; Dr. Wesley Burks, a translational researcher focused on phase I/II clinical trial interventions against food allergy; and Dr. Angela Kashuba, the director f the clinical pharmacology fellowship at UNC with extensive experience in clinical pharmacokinetic and pharmacodynamic studies. PUBLIC HEALTH RELEVANCE: Respiratory complications caused by O3 represent a significant public health burden in the United States and worldwide. Despite compelling evidence that pulmonary oxidative insults lead to systemic deleterious health outcomes, treatment options for environmentally-induced oxidative stress are limited and no significant changes have been made in improving the health of susceptible populations such as children, the elderly and allergic asthmatics. This research has the potential to identify a pathway that could be targeted by prevention or treatment of respiratory inflammation caused by exposure to inhaled environmental oxidants in susceptible individuals. Given the significant public health burden of respiratory diseases such as asthma and the lack of targeted therapeutics for oxidant-induced airway inflammation, the potential impact is great.