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

通过调节 NRF2 下调氧化剂诱导的气道炎症

• 批准号: 8353647
• 负责人: Michelle Hernandez
• 金额: $ 20.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-16 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353647
• 关键词: Acute; Address; Adrenal Cortex Hormones; Air; Alfalfa; Allergic; Antioxidants; Ascorbic Acid; Asthma; Award; Basic Science; Biology; Biopsy; Breathing; Breeding; Broccoli - dietary; Cell Line; Cells; Child; Chronic Obstructive Airway Disease; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Cross-Over Studies; Data; Defect; Development; Dinoprostone; Down-Regulation; Drug Kinetics; Elderly; Environmental Pollution; Enzymes; Epithelial Cells; Exposure to; Fellowship; Food Hypersensitivity; GSTP1 gene; Gene Expression; Genetic Transcription; Goals; Health; Hospitalization; Hour; Human; IL8 gene; Immunosuppression; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Ingestion; Interleukin-6; Intervention; Laboratories; Lead; Learning; Link; Lipids; Liquid substance; Literature; Lung; Lung diseases; Measurement; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Modeling; Morbidity - disease rate; Mus; NF-E2-related factor 2; NQO1 gene; Neutrophil Infiltration; Nose; Oral; Oxidants; Oxidative Stress; Ozone; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physicians; Placebo Control; Placebos; Population; Prevention; Process; Production; Public Health; Publishing; Randomized; Research; Research Personnel; Research Project Grants; Respiratory System; Respiratory physiology; Respiratory tract structure; Role; Scientist; Sputum; Study models; Sulforaphane; Supplementation; Testing; Training; Training Support; Translational Research; Treatment outcome; United States; Up-Regulation; Visit; Vitamin E; Water; airway epithelium; airway inflammation; allergic airway inflammation; base; cytokine; design; drug discovery; experience; glutathione S-transferase M1; healthy volunteer; heme oxygenase-1; improved; lung injury; multidisciplinary; neutrophil; novel; oxidative damage; programs; respiratory; therapeutic target; therapy development; transcription factor; treatment effect; volunteer

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.

描述（由申请人提供）：本提案概述了为期 3 年的 K23 指导性患者导向研究职业发展奖 (K23)，旨在完善候选人作为医师科学家的培训，并为专注于开发对抗气道氧化应激的疗法。该提案的目标是在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时，为药物发现/开发提供支持和培训，并为基于干预的概念验证研究提供指导。该小组和其他人的最新证据强调了细胞内抗氧化酶在 O3 诱导的气道炎症恶化中的作用。缺乏抗氧化酶谷胱甘肽 S 转移酶 Mu 1 (GSTM1) 的健康志愿者在腔室暴露于百万分之 0.4 (ppm) 臭氧 (O3) 后，中性粒细胞气道炎症增加。 GSTM1 和许多其他 II 相抗氧化酶（NQO1、GSTP1、HO-1）受主转录因子 NF-E2 相关因子 2 (NRF2) 调节。小鼠模型和慢性阻塞性肺病患者的研究表明，NRF2 缺陷与氧化剂介导的肺损伤有关。因此，NRF2 是调节保护免受普遍存在的吸入氧化剂（例如 O3）引起的气道炎症的有力候选者。这里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剂化合物，被发现可以上调 NRF2 和 NRF2 调节的 II 期酶（GSTM1、GSTP1、HO1 和 NQO1）的表达，以检查 NRF2 诱导是否口服 SFN 补充剂将减少正常志愿者中 O3 引起的气道炎症。其次，培养的源自轻度至中度持续性过敏性哮喘的分化鼻上皮细胞将用于检查 SFN 治疗这些上皮细胞是否可以改变 O3 诱导的炎症反应。候选人将通过拟议的教学课程获得针对氧化应激过程的药物发现过程的经验，并在指导团队的帮助下完成这些目标。导师团队由三名在指导年轻科学家和开发转化研究项目方面拥有丰富经验的人士组成：David Peden 博士，一位在环境污染、氧化应激方面拥有专业知识的转化科学家，也是首席导师； Wesley Burks 博士，专注于针对食物过敏的 I/II 期临床试验干预的转化研究员；安吉拉·卡舒巴 (Angela Kashuba) 博士是北卡罗来纳大学临床药理学研究员，在临床药代动力学和药效学研究方面拥有丰富的经验。 公共卫生相关性：O3 引起的呼吸系统并发症是美国和全世界的重大公共卫生负担。尽管有令人信服的证据表明肺部氧化损伤会导致全身有害的健康结果，但针对环境引起的氧化应激的治疗选择有限，并且在改善儿童、老年人和过敏性哮喘等易感人群的健康方面没有取得重大改变。这项研究有可能确定一种途径，可用于预防或治疗易感人群因暴露于吸入环境氧化剂而引起的呼吸道炎症。鉴于哮喘等呼吸系统疾病给公共卫生带来巨大负担，并且缺乏针对氧化剂引起的气道炎症的靶向治疗方法，潜在影响是巨大的。