Dysregulation of Nrf2 in CF epithelia

CF 上皮细胞中 Nrf2 的失调

• 批准号: 8466363
• 负责人: ASSEM G ZIADY
• 金额: $ 34.85万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466363
• 关键词: Adverse effects; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Asthma; Biological Models; Birth; Cardiac; Cell Line; Cell Nucleus; Cells; Cessation of life; Characteristics; Chloride Ion; Chlorides; Chronic Obstructive Airway Disease; Collaborations; Complex; Cyclic AMP; Cystic Fibrosis Transmembrane Conductance Regulator; Cytoplasm; Data; Deterioration; Disease; Disease Progression; Epithelial Cells; Epithelium; Equilibrium; Exhibits; Failure; Foam Cells; Functional disorder; Future; Gases; Genetic Transcription; Glutathione; Goals; Hydrogen Peroxide; IL8 gene; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Lead; Link; Lung; Lung diseases; Mediating; Neurologic; Niemann-Pick Diseases; Nose; Oxidants; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Patients; Peroxides; Pharmaceutical Preparations; Phenotype; Production; Pulmonary Cystic Fibrosis; Regulation; Reporting; Resolution; Respiratory Failure; Response Elements; Signal Transduction; Site; Stimulus; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; airway epithelium; arm; cystic fibrosis mouse; cystic fibrosis patients; cytokine; early onset; efficacy testing; in vivo Model; mortality; mouse model; mutant; mutant mouse model; new therapeutic target; response; success; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Inflammation in the CF lung has been shown to be excessive, and slow to resolve. Typically this leads to lung damage, eventual lung failure and is the lead cause of mortality. A number of studies have reported that CF cells, especially airway epithelia produce abnormal levels of inflammatory cytokines in response to inflammatory stimuli. Anti-inflammatory therapy that controls inflammatory signaling has been shown to be beneficial, slowing lung deterioration in patients, and is perhaps one of the best therapies for CF. Therefore, delineating the mechanisms of inflammation in CF, which can yield targets for anti-inflammatory therapy, is an important and worthwhile effort. Furthermore, it is logical to suspect that downstream mechanisms that contribute to inflammation in the CF lung are also present in other inflammatory lung diseases, such COPD and Asthma, increasing the significance of studying aberrant inflammatory signaling in CF. However, neither the mechanisms that promote nor those that limit inflammatory responses are well understood. Recent studies by us have elucidated a dysregulation of the antioxidant response element (ARE) transcription factor, Nrf2, in multiple in vitro and in vivo models of CF. Although CF cells exhibit oxidative stress, Nrf2 protective cascades are not activated and are in fact decreased. This results in the accumulation of intracellular oxidants, which significantly increases inflammatory cytokine production and reduces the activity of pathways that resolve inflammation. This is an important finding as Nrf2 has been implicated in a number of inflammatory lung diseases and can be safely and specifically activated, and is therefore a viable therapeutic target. Rescue of Nrf2 dysfunction in CF epithelial cells reduces inflammatory responses to normal levels, but does not inhibit normal responses, which would be deleterious in the context of CF. In this application we propose to examine the regulation of Nrf2 activity in CF primary epithelial cells, CF animal models, and tissues from CF patients. We plan to: 1) To determine the step or steps in the Nrf2 activation cascade that are dysfunctional in CF; 2) To examine the mechanism by which CFTR dysfunction results in the dysregulation of Nrf2; and 3) To test pharmacological agents which activate Nrf2 by different mechanisms to elucidate potential therapies for Nrf2 dysfunction. These studies have the potential to delineate the link between CFTR dysfunction and inflammation in CF, and define novel therapeutic targets. Furthermore, our studies extend to mechanisms of inflammation and disease observed in cardiac (foam cell formation and arthrosclerosis), pulmonary (chronic obstructive pulmonary disease and asthma), and neurological (Niemann-Pick and Parkinson's disease) disorders. Therefore, our findings may illuminate mechanisms relevant to a wide range of disorders.

描述（由申请人提供）：CF肺中的炎症已被证明过度且解决缓慢。通常，这会导致肺部损伤，最终导致肺部衰竭，并且是死亡率的主要原因。许多研究报告说，CF细胞，尤其是气道上皮响应于炎症刺激而产生异常水平的炎性细胞因子。控制炎症信号传导的抗炎疗法已被证明是有益的，在患者中降低了肺恶化，也许是CF的最佳疗法之一。因此，描述CF中炎症的机制（可以产生抗炎疗法的靶标）是一项重要且有价值的努力。此外，怀疑有助于CF肺部炎症的下游机制在其他炎症性肺部疾病中也存在，这是合乎逻辑的，例如COPD和哮喘，增加了研究CF中炎性信号的重要性。但是，促进的机制和限制炎症反应的机制都不良好。我们最近的研究阐明了在多个体外和体内模型中的抗氧化反应元件（IS）转录因子NRF2的失调。尽管CF细胞表现出氧化应激，但NRF2保护性级联反应未被激活，实际上正在减少。这会导致细胞内氧化剂的积累，从而显着增加炎症细胞因子的产生并降低解决炎症的途径的活性。这是一个重要的发现，因为NRF2已与许多炎症性肺部疾病有关，并且可以安全，专门激活，因此是可行的治疗靶标。 CF上皮细胞中NRF2功能障碍的营救可降低对正常水平的炎症反应，但不会抑制正常反应，在CF的背景下，这将是有害的。在此应用中，我们建议检查CF原发性上皮细胞，CF动物模型和CF患者组织中NRF2活性的调节。我们计划：1）确定CF中功能失调的NRF2激活级联的步骤或步骤； 2）检查CFTR功能障碍导致NRF2失调的机制； 3）测试通过不同机制激活NRF2的药理学剂，以阐明NRF2功能障碍的潜在疗法。这些研究有可能描述CFTR功能障碍与CF炎症之间的联系，并定义新的治疗靶标。此外，我们的研究扩展到心脏（泡沫细胞形成和关节炎），肺部（慢性阻塞性肺部疾病和哮喘）以及神经学（Niemann-Pick和Parkinson病）疾病中观察到的炎症和疾病机制。因此，我们的发现可能会阐明与多种疾病有关的机制。