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: 8708080
• 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/8708080
• 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.

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。

项目成果

Assessing asthma in African American children using the Asthma Control Test and the Childhood Asthma Control Test.

使用哮喘控制测试和儿童哮喘控制测试评估非裔美国儿童的哮喘。

• DOI: 10.1016/j.anai.2014.12.019
• 发表时间: 2015
• 期刊: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology
• 作者: Todoric,Krista;Bangdiwala,Shrikant;Vadlamudi,Anusha;Alarcon,Lisa;Hernandez,Michelle
• 通讯作者: Hernandez,Michelle

Body mass index correlates with pollutant-induced interleukin-1β in sputum and blood.

体重指数与痰和血液中污染物诱导的白介素-1β 相关。

• DOI: 10.1016/j.anai.2014.11.010
• 发表时间: 2015
• 期刊: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology
• 作者: Todoric,Krista;Zhou,Haibo;Zhang,Hongtao;Mills,Katherine;Peden,DavidB;Hernandez,MichelleL
• 通讯作者: Hernandez,MichelleL

Environmental determinants of allergy and asthma in early life.

• DOI: 10.1016/j.jaci.2017.05.010
• 发表时间: 2017-07
• 期刊: The Journal of allergy and clinical immunology
• 作者: Burbank AJ;Sood AK;Kesic MJ;Peden DB;Hernandez ML
• 通讯作者: Hernandez ML