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

描述（由申请人提供）：该提案概述了一个为期3年的K23指导患者导向研究职业发展奖（K23），旨在完善候选人作为内科科学家的培训，并为多学科，转化研究项目做好准备，重点是开发针对气道氧化应激的治疗方法。该提案的目标是在候选人将基础科学和临床研究经验应用于独立转化研究项目的开发时，提供药物发现/开发方面的支持、培训和基于干预的概念验证研究方面的指导。最近来自这个小组和其他人的证据强调了细胞内抗氧化酶在臭氧诱导的气道炎症加重中的作用。缺乏抗氧化酶谷胱甘肽S转移酶Mu 1 （GSTM1）的健康志愿者在室内暴露于百万分之0.4 （ppm）的臭氧（O3）后，中性粒细胞气道炎症增加。GSTM1和许多其他II期抗氧化酶（NQO1、GSTP1、HO-1）受主转录因子NF-E2相关因子2 （NRF2）调控。小鼠模型和慢性阻塞性肺疾病患者的研究表明NRF2缺陷与氧化介导的肺损伤有关。因此，NRF2是一个强有力的候选调节，以防止由吸入的无处不在的氧化剂如O3引起的气道炎症。本文的目的是使用萝卜硫素（SFN），一种从特殊培育的西兰花中提取的抗氧化化合物，被发现可以上调NRF2和NRF2调节的II期酶（GSTM1, GSTP1， HO1和NQO1）的表达，来检测口服SFN诱导NRF2是否会减少正常志愿者中o3诱导的气道炎症。其次，培养分化的鼻上皮细胞来源于轻度至中度持续性过敏性哮喘患者，将用于检测SFN治疗这些上皮细胞是否会改变o3诱导的炎症反应。候选人将通过建议的教学课程以及在指导团队的帮助下完成这些目标，获得针对氧化应激过程的药物制剂的药物发现过程的经验。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个人组成：David Peden博士，一位在环境污染、氧化应激方面具有专长的转化科学家，也是首席导师；Wesley Burks博士，他是一名专注于I/II期临床试验干预食物过敏的转化研究员；Angela Kashuba博士，北卡罗来纳大学临床药理学奖学金主任，在临床药代动力学和药效学研究方面拥有丰富的经验。

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.