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

基本信息

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
项目类别：
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

项目摘要

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）：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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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
影响因子：
0
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.