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：
8531934
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/8531934
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）：该提案概述了为期3年的K23指导的面向患者的研究职业发展奖（K23），旨在完善候选人作为医生科学家的培训，并为多学科的转化研究计划做准备，旨在采用针对气道氧化压力的治疗疗法的开发。该提案的目的是提供支持，药物发现/开发方面的培训以及基于干预的概念研究证明的指导，因为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发展。该组和其他人的最新证据强调了细胞内抗氧化剂酶在加剧O3诱导的气道炎症中的作用。缺乏抗氧化酶的健康志愿者，谷胱甘肽的转移酶MU 1（GSTM1），室内暴露于0.4份百万（PPM）臭氧（O3）后，中性粒细胞气道炎症增加了。 GSTM1和许多其他II期抗氧化剂酶（NQO1，GSTP1，HO-1）受主转录因子NF-E2-相关因子2（NRF2）调节。鼠模型和慢性阻塞性肺疾病患者的研究表明，NRF2中的缺陷与氧化剂介导的肺损伤有关。因此，NRF2是针对无处不在吸入的氧化剂（例如O3）保护气道炎症的强大候选者。 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志愿者。其次，培养的分化分化的鼻皮细胞将使用轻度 - 中度持续过敏性哮喘患者衍生而成，检查SFN对这些上皮细胞的治疗是否会改变O3诱导的炎症反应。候选人将获得药物发现过程的经验，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的氧化应激过程。指导团队由三个在指导年轻科学家和制定转化研究计划方面具有丰富经验的人组成：戴维·佩登（David Peden）博士，一位翻译科学家，具有环境污染，氧化压力和主要导师的专业知识；卫斯理·伯克斯（Wesley Burks）博士，一名转化研究人员，重点是I/II期临床试验干预措施，以针对食物过敏；以及临床药理学研究员Angela Kashuba博士，在UNC临床药理学奖学金中拥有丰富的临床药代动力学和药效学研究经验。