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的气流限制，主要归因于吸烟引起的肺气肿和慢性支气管炎（CS）。慢性阻塞性肺病的特征是异常炎症、空气空间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COPD的患病率预计在未来几十年将会增加，因此有必要通过靶向已确定参与COPD发病机制的途径来寻找新的治疗方法来减少COPD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的转录因子，积极调节编码抗氧化剂和外源性解毒酶的基因的表达，并在暴露于香烟烟雾后对肺部的氧化应激和炎症提供细胞保护。Kelch-like ECH-associated protein 1 （Keapl）在正常情况下通过靶向Nrf2进行蛋白酶体降解来负性调节Nrf2活性。然而，在氧化应激（例如暴露于香烟烟雾）中，转录因子与其抑制剂解离，易位到细胞核并激活抗氧化和解毒基因的表达。老鼠体内Nrf2基因的破坏会导致更严重的氧化-抗氧化失衡和炎症，从而导致慢性香烟烟雾导致的更早发病和更严重的肺气肿。因此，我们假设（通过遗传或小分子方法）增强Nrf2活性可以通过上调抗氧化和解毒基因来减少肺中的氧化应激、炎症和凋亡，从而减轻cs诱导的肺气肿。特异性目标1将在小鼠模型中使用遗传方法验证Nrf2活性增强将减少CS诱导的肺气肿进展的假设，通过生成条件敲除小鼠，其中Keapl基因通过他莫昔芬诱导系统被破坏，导致Nrf2活性的整体增加。特异性Aim 2将测试一种有效的Nrf2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。这项转化性研究将为Nrf2通路在COPD发病机制中的作用提供新的见解，并有助于开发一种新的干预COPD的治疗方法。

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.