The Nrf2-ARE pathway in modulating Parkinson's Disease

Nrf2-ARE 通路调节帕金森病

• 批准号: 7612032
• 负责人: Jeffrey A Johnson
• 金额: $ 44.6万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612032
• 关键词: 1-Methyl-4-phenylpyridinium; Acids; Acute; Adenoviruses; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Astrocytes; Attenuated; Binding Proteins; Blood - brain barrier anatomy; Brain; Cell Death; Cells; Chemical Models; Chemicals; Chronic; Complex; Corpus striatum structure; Data; Defense Mechanisms; Development; Drug Metabolic Detoxication; Elements; Enzymes; Free Radical Scavenging; Free Radicals; Gene Expression; Gene Expression Profiling; Gene Pool; Genes; Glutamates; Glutathione; Hydrogen Peroxide; In Vitro; Knock-out; Knockout Mice; Laboratories; Lesion; MPTP Poisoning; Malonates; Mediating; Mitochondria; Modeling; Mus; NADP; NF-E2-related factor 2; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Oxidative Stress; Oxidopamine; Parents; Parkinson Disease; Pathogenesis; Pathway interactions; Phase; Play; Prevention; Procedures; Process; Production; Quinones; Regulation; Reporter; Resistance; Rodent; Role; Rotenone; System; Testing; Therapeutic; Transcriptional Activation; Translating; Transplantation; Wild Type Mouse; base; cis acting element; design; dopaminergic neuron; falls; in vivo; inhibitor/antagonist; nerve stem cell; neuron loss; neuroprotection; neurotoxicity; novel; overexpression; small molecule

DESCRIPTION (provided by applicant): Oxidative stress is an imbalance in which free radicals and their products exceed the capacity of antioxidant defense mechanisms. The harmful reactive compounds generated by oxidative stress are associated with neuronal cell death following acute insults and are also believed to be a principle factor in the development of many chronic neurodegenerative diseases such as Alzheimer's, Parkinson's (PD), Huntington's and Amyotrophic Lateral Sclerosis. The expression of many neuroprotective phase II detoxification enzymes and/or antioxidant genes is governed by the antioxidant responsive element (ARE). ARE-dependent gene expression is induced by the transcriptional factor, Nrf2, and is considered to be a novel and important pathway that confers protection to a variety of oxidative stress-related neurodegenerative insults. The long- range objective of the laboratory is to evaluate the regulation and cell-specific expression of ARE-driven genes and the potential role of these genes in prevention of neurodegeneration. In order to develop potential therapeutic strategies targeting Parkinson's disease through activation of the ARE, small molecules that penetrate the blood-brain barrier and robustly activate ARE will be required. We will use primary cortical cultures from Nrf2 knockout and wild-type mice as an in vitro system to examine potential chemical activators of the ARE. We will test whether compounds identified as potent ARE activators can attenuate nigrostriatal lesions in both 6-hydroxydopamine (6-OHDA) and MPTP induced Parkinson's models in Nrf2-/- and wild-type mice. Finally, we will examine Nrf2-mediated neuroprotection by infecting astrocyte cultures with adenovirus Nrf2 constructs and transplanting those cells into the striata of Nrf2-/- and wildtype mice after 6-OHDA or MPTP lesions. The specific aims of this proposal are: Specific Aim 1. Characterize Nrf2-dependent ARE activation by chemical activators and evaluate their neuroprotective potential in vitro. Specific Aim 2. Determine that chemical activators of the Nrf2-ARE pathway confer protection from the 6-OHDA and MPTP-induced nigrostriatal lesions and loss of dopaminergic (DA) neurons. Specific Aim 3. Determine that transplantation of Nrf2 overexpressing neural stem cells and/or astrocytes confers protection from 6-OHDA or MPTP-induced nigrostriatal lesions and loss of DA neurons.

描述（由申请人提供）：氧化应激是一种不平衡，其中自由基及其产物超过抗氧化防御机制的能力。氧化应激产生的有害反应性化合物与急性损伤后神经元细胞死亡有关，也被认为是许多慢性神经退行性疾病如阿尔茨海默病、帕金森病 (PD)、亨廷顿舞蹈病和肌萎缩侧索硬化症发展的主要因素。许多神经保护性 II 期解毒酶和/或抗氧化基因的表达受抗氧化反应元件 (ARE) 控制。 ARE 依赖性基因表达由转录因子 Nrf2 诱导，被认为是一种新颖且重要的途径，可为各种氧化应激相关的神经退行性损伤提供保护。该实验室的长期目标是评估 ARE 驱动基因的调节和细胞特异性表达以及这些基因在预防神经退行性变中的潜在作用。为了通过激活 ARE 开发针对帕金森病的潜在治疗策略，需要能够穿透血脑屏障并强力激活 ARE 的小分子。我们将使用 Nrf2 敲除小鼠和野生型小鼠的原代皮质培养物作为体外系统来检查 ARE 的潜在化学激活剂。我们将测试被确定为有效 ARE 激活剂的化合物是否可以减轻 6-羟基多巴胺 (6-OHDA) 和 MPTP 诱导的 Nrf2-/- 和野生型小鼠帕金森病模型中的黑质纹状体损伤。最后，我们将通过用腺病毒 Nrf2 构建体感染星形胶质细胞培养物并将这些细胞移植到 6-OHDA 或 MPTP 损伤后的 Nrf2-/- 和野生型小鼠的纹状体中来检查 Nrf2 介导的神经保护作用。该提案的具体目标是： 具体目标 1. 表征化学激活剂对 Nrf2 依赖性 ARE 的激活，并评估其体外神经保护潜力。具体目标 2. 确定 Nrf2-ARE 通路的化学激活剂可提供保护，防止 6-OHDA 和 MPTP 诱导的黑质纹状体损伤和多巴胺能 (DA) 神经元损失。具体目标 3. 确定 Nrf2 过表达神经干细胞和/或星形胶质细胞的移植可提供保护，防止 6-OHDA 或 MPTP 诱导的黑质纹状体损伤和 DA 神经元损失。