A novel intervention strategy for emphysema by targeting the Nrf2 pathway

针对Nrf2通路的肺气肿新干预策略

• 批准号: 7545398
• 负责人: David James Blake
• 金额: $ 4.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-07 至 2009-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545398
• 关键词: 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; Affect; Air; Allergens; Alveolar; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Appendix; Asthma; Attenuated; Bronchodilator Agents; C57BL/6 Mouse; Cause of Death; Cell Nucleus; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Condition; Cytoprotection; Cytosol; Development; Diet; Disease; Disease Progression; Disruption; Drug Metabolic Detoxication; End Point; Endopeptidases; Endothelial Cells; Environment; Environmental Exposure; Enzymes; Epithelial; Epithelial Cells; Esters; Exposure to; Extracellular Matrix; Gene Expression; Genes; Genetic; Genetic Recombination; Goals; Immune system; Infection; Inflammation; Inflammatory; Integration Host Factors; Intervention; Knockout Mice; Knowledge; Laboratories; Lead; Longitudinal Studies; Lung; Lung Inflammation; Lung diseases; Measures; Mentors; Mus; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Peptide Hydrolases; Play; Predisposition; Prevalence; Process; Protease Inhibitor; Proteins; Pulmonary Emphysema; Pulmonary function tests; Research; Role; Site; Smoker; Structure; System; Tamoxifen; Testing; Time; Triterpenoid Compound; Xenobiotics; alveolar destruction; cell injury; cigarette smoke-induced; cigarette smoking; cigarette smoking; early onset; inhibitor/antagonist; insight; macrophage; methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate; morphometry; mortality; mouse model; neutrophil; novel; novel strategies; novel therapeutics; nuclear factor-erythroid 2; response; small molecule; transcription factor; translational study

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is currently the fifth leading cause of death and affects more than 210 million people worldwide. This debilitating disease is clinically defined by irreversible airflow limitation in the lung that is primarily attributed to pulmonary emphysema and chronic bronchitis due to cigarette smoke (CS). COPD is characterized by abnormal inflammation, air space enlargement, and the loss of alveolar structure. Current treatments such as anti-inflammatories or bronchodilators are inadequate in treating COPD because they do not alter the underlying disease process and as a result do not reduce the progression of the disease. Because the prevalence of COPD is estimated to increase in the coming decades, it is imperative to identify novel therapeutic approaches to reduce the progression of COPD by targeting pathways identified to be involved in COPD pathogenesis. Our laboratory has discovered that nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), a redox-sensitive transcription factor, positively regulates the expression of genes encoding antioxidants and xenobiotic detoxification enzymes and confers cytoprotection against oxidative stress and inflammation in the lungs after exposure to cigarette smoke. Kelch-like ECH-associated protein 1 (Keapl) negatively regulates Nrf2 activity by targeting Nrf2 for proteasomal degradation under normal conditions. However, during oxidative stress (e.g. exposure to cigarette smoke) the transcription factor dissociates from its inhibitor, translocates to the nucleus and activates the expression of antioxidant and detoxifying genes. Disruption of the Nrf2 gene in mice causes greater oxidant-antioxidant imbalance and inflammation, which results in an earlier onset and more severe emphysema due to chronic cigarette smoke exposure. Therefore, we hypothesize that enhancing Nrf2 activity (by a genetic or small molecule approach) can attenuate CS-induced emphysema by decreasing oxidative stress, inflammation and apoptosis in the lung by up-regulating antioxidant and detoxifying genes. Specific Aim 1will test the hypothesis that enhancement of Nrf2 activity will reduce the progression of CS- induced emphysema using a genetic approach in a mouse model by generating conditional knockout mice in which the Keapl gene is disrupted through a tamoxifen inducible system that will lead to a global increase in Nrf2 activity. Specific Aim 2 will test the efficacy of a potent small molecule activator of Nrf2 (CDDO-Me), which will be used to intervene during the development of CS-induced emphysema in mice. The proposed translational study will provide new insights of Nrf2 pathways in the pathogenesis of COPD and aid in the development of a novel therapeutic approach for intervening in COPD.

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）目前是第五大死亡原因，影响全球超过2.1亿人。这种使人衰弱的疾病在临床上被定义为肺部不可逆转的气流限制，这主要归因于肺气肿和香烟烟雾（CS）引起的慢性支气管炎。COPD的特征在于异常炎症、空气空间扩大和肺泡结构的丧失。目前的治疗如抗炎药或支气管扩张剂不足以治疗COPD，因为它们不改变潜在的疾病过程，因此不减缓疾病的进展。由于COPD的患病率估计在未来几十年将增加，因此必须确定新的治疗方法，通过靶向确定参与COPD发病机制的途径来减少COPD的进展。我们的实验室已经发现，核因子-红细胞2 p45相关因子2（Nrf 2），一种氧化还原敏感的转录因子，积极调节编码抗氧化剂和异生物质解毒酶的基因的表达，并赋予细胞保护作用，防止暴露于香烟烟雾后肺部的氧化应激和炎症。Kelch样ECH相关蛋白1（Keapl）通过在正常条件下靶向Nrf 2用于蛋白酶体降解来负调节Nrf 2活性。然而，在氧化应激期间（例如暴露于香烟烟雾），转录因子与其抑制剂分离，易位到细胞核并激活抗氧化和解毒基因的表达。在小鼠中破坏Nrf 2基因会导致更大的氧化-抗氧化失衡和炎症，这会导致更早的发病和更严重的肺气肿，这是由于慢性香烟烟雾暴露。因此，我们假设增强Nrf 2活性（通过遗传或小分子方法）可以通过上调抗氧化剂和解毒基因减少肺中的氧化应激、炎症和细胞凋亡来减轻CS诱导的肺气肿。具体目标1将通过在小鼠模型中使用遗传方法测试Nrf 2活性增强将减少CS诱导的肺气肿的进展的假设，所述遗传方法通过产生条件性敲除小鼠，其中Keapl基因通过他莫昔芬诱导系统被破坏，这将导致Nrf 2活性的总体增加。具体目标2将测试Nrf 2的有效小分子激活剂（CDDO-Me）的功效，其将用于在小鼠中CS诱导的肺气肿的发展期间进行干预。拟议的翻译研究将提供COPD发病机制中Nrf 2通路的新见解，并有助于开发一种干预COPD的新治疗方法。