The Nrf2-ARE pathway in modulating Parkinson's Disease

Nrf2-ARE 通路调节帕金森病

• 批准号: 7813983
• 负责人: Jeffrey A Johnson
• 金额: $ 45.48万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813983
• 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了抗氧化剂防御机制的能力。氧化应激产生的有害反应性化合物与急性损伤后的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的发展，例如阿尔茨海默氏症，帕金森氏症（PD），亨廷顿和杏仁症的后期层状硬质量。许多神经保护剂II期解毒酶和/或抗氧化剂基因的表达受抗氧化剂反应元件（AS）的控制。依赖性基因表达是由转录因子NRF2诱导的，被认为是一种新颖而重要的途径，该途径将保护与各种氧化应激相关的神经退行性损伤。实验室的长范围目标是评估由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变性中的潜在作用。为了通过激活帕金森氏病来开发针对帕金森氏病的潜在治疗策略，需要将渗透到血脑屏障并强大激活的小分子。我们将使用来自NRF2基因敲除和野生型小鼠的原代皮质培养物作为一种体外系统，以检查它的潜在化学激活剂。我们将测试是否可以识别为有效的化合物是活化剂可以减轻6-羟基二胺（6-OHDA）和MPTP诱导的NRF2 - / - 和野生型小鼠中的帕金森型模型中的Nigrostriatal病变。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病变后，将这些细胞移植到NRF2 - / - 的纹状体中，并将​​这些细胞移植到NRF2 - / - 的纹状体中，从而检查NRF2介导的神经保护作用。该提案的具体目的是：特定目的1。表征NRF2依赖性的特定目的是通过化学激活剂激活并评估其在体外的神经保护势。具体目的2。确定NRF2-ARE途径的化学激活剂允许保护6-OHDA和MPTP诱导的黑质性纹状体病变以及多巴胺能（DA）神经元的丧失。具体目的3。确定过表达神经干细胞和/或星形胶质细胞的移植赋予了免受6-OHDA或MPTP诱导的Nigrostriatal病变的保护以及DA神经元的丧失。

项目成果

Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity.

• DOI: 10.1016/j.neuro.2012.01.015
• 发表时间: 2012-06
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Williamson TP;Johnson DA;Johnson JA
• 通讯作者: Johnson JA

Keap1-Nrf2 activation in the presence and absence of DJ-1.

• DOI: 10.1111/j.1460-9568.2010.07138.x
• 发表时间: 2010-03
• 期刊: The European journal of neuroscience
• 作者: Gan L;Johnson DA;Johnson JA
• 通讯作者: Johnson JA

Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model.

• DOI: 10.1523/jneurosci.3049-12.2012
• 发表时间: 2012-12-05
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Gan L;Vargas MR;Johnson DA;Johnson JA
• 通讯作者: Johnson JA