A novel intervention strategy for emphysema by targeting the Nrf2 pathway

描述（由申请人提供）：慢性阻塞性肺病 (COPD) 目前是第五大死因，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的气流受限，主要归因于香烟烟雾（CS）引起的肺气肿和慢性支气管炎。 COPD 的特征是异常炎症、气腔扩大和肺泡结构丧失。目前的治疗方法，如抗炎药或支气管扩张剂，不足以治疗慢性阻塞性肺病，因为它们不能改变潜在的疾病过程，因此不能减少疾病的进展。由于慢性阻塞性肺病的患病率预计在未来几十年内会增加，因此必须通过针对与慢性阻塞性肺病发病机制有关的途径来确定新的治疗方法，以减少慢性阻塞性肺病的进展。我们的实验室发现，核因子-红细胞2 p45相关因子2 (Nrf2)是一种氧化还原敏感转录因子，可正向调节编码抗氧化剂和异生物质解毒酶的基因的表达，并在暴露于香烟烟雾后赋予细胞保护作用，抵抗肺部的氧化应激和炎症。 Kelch 样 ECH 相关蛋白 1 (Keapl) 在正常条件下通过靶向 Nrf2 进行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）期间，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解毒基因的表达。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，从而导致由于长期接触香烟烟雾而导致更早发病和更严重的肺气肿。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部氧化应激、炎症和细胞凋亡，从而减轻 CS 诱导的肺气肿。具体目标1将测试这样的假设：Nrf2活性的增强将减少CS诱导的肺气肿的进展，在小鼠模型中使用遗传方法，通过产生条件敲除小鼠，其中Keapl基因通过他莫昔芬诱导系统被破坏，这将导致Nrf2活性的整体增加。具体目标 2 将测试 Nrf2 强效小分子激活剂 (CDDO-Me) 的功效，该激活剂将用于干预 CS 诱导的小鼠肺气肿的发展过程。拟议的转化研究将为 COPD 发病机制中的 Nrf2 通路提供新的见解，并有助于开发干预 COPD 的新治疗方法。

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.