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）目前是死亡​​的第五大原因，影响了全球超过2.1亿人。这种使人衰弱的疾病在肺中的不可逆气流限制在临床上定义，这主要归因于肺部肺气肿和慢性支气管炎，这是由于香烟烟雾（CS）。 COPD的特征是异常的炎症，空气空间增大和肺泡结构的丧失。目前的治疗方法（例如抗炎或支气管扩张剂）在治疗COPD方面不足，因为它们不会改变潜在的疾病过程，因此不会降低疾病的进展。由于估计COPD的患病率在未来几十年中会增加，因此必须通过靶向被确定涉及COPD发病机理的途径来识别新型治疗方法以降低COPD的进展。我们的实验室发现，核因子 - 磷灰2 p45相关因子2（NRF2）是一种对氧化还原敏感的转录因子，积极调节编码抗氧化剂的基因表达，抗氧化剂和异种生物学解毒酶的基因表达，并在抗氧化应力和炎症中染色体抗氧化应激和炎症的表达。暴露于香烟。 Kelch样ECH相关蛋白1（KEAPL）通过靶向NRF2在正常条件下靶向蛋白酶体降解来负调节NRF2活性。然而，在氧化应激（例如暴露于香烟烟雾的情况下）转录因子与其抑制剂分离，易位到细胞核并激活抗氧化剂和毒基因的表达。小鼠NRF2基因的破坏会导致更大的氧化剂抗氧化剂失衡和炎症，从而导致由于慢性香烟烟雾暴露而引起的早期发作和更严重的肺气肿。因此，我们假设增强NRF2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来减少肺中CS诱导的肺气肿。特定目标1Will检验以下假设，即通过产生有条件的敲除小鼠，使用小鼠模型中的遗传方法，使用遗传方法来减少CS诱导的肺气肿的进展，在该小鼠中，Keapl基因通过他莫克西莫克斯型诱导型系统而破坏了，这将导致tamoxifen诱导的系统。 NRF2活动的全球增加。特定的目标2将测试有效的NRF2（CDDO-ME）的有效的小分子激活剂的功效，该分子将在小鼠中CS诱导的肺气肿的发展过程中进行干预。拟议的翻译研究将为COPD发病机理提供NRF2途径的新见解，并有助于开发一种新型的治疗方法，以介入COPD。