NRF2/ARE PATHWAY AS A THERAPEUTIC TARGET FOR AMYOTROPHIC LATERAL SCLEROSIS

NRF2/ARE 通路作为肌萎缩侧索硬化症的治疗靶点

• 批准号: 7770782
• 负责人: Mahmoud Kiaei
• 金额: $ 13.24万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770782
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3-nitropropionic acid; Abbreviations; Acids; Adult; Age; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Astrocytes; Avidin; Binding; Biogenesis; Biological Availability; Biotin; Body Weight decreased; Cell Nucleus; Cessation of life; Code; Complex; Copper; Cuprozinc Superoxide Dismutase; Cysteine; Cytoplasm; DNA Nucleotidylexotransferase; Development; Disease; Dopamine; Drug Kinetics; Drug Metabolic Detoxication; ERR1 protein; Enzymes; Event; Familial Amyotrophic Lateral Sclerosis; Fibroblast Growth Factor 1; Foundations; Gene Expression; Gene Targeting; Genes; Genetic Programming; Genetic Transcription; Glial Fibrillary Acidic Protein; Glutathione S-Transferase; Goals; Hydrogen Peroxide; Impairment; Incidence; Inflammation; Inflammatory; Inherited; Inhibitory Concentration 50; Label; Lead; Longevity; Mediating; Methods; Missense Mutation; Mitochondria; Modeling; Molecular; Motor; Motor Neurons; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NADP; NF-E2-related factor 2; NF-kappa B; NQO1 gene; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Nuclear; Onset of illness; Oral Administration; PPAR gamma; PTGS2 gene; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase; Proteins; Rattus; Reactive Oxygen Species; Reduced Glutathione; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Spinal Cord; Staging; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Transgenic Mice; Tumor Necrosis Factor Ligand Superfamily Member 6; Tumor Necrosis Factor-alpha; Up-Regulation; Uridine; Zinc; cyclooxygenase 2; cytochrome c oxidase; drug candidate; excitotoxicity; heme oxygenase-1; human NOS2A protein; in vivo; intraperitoneal; mitochondrial dysfunction; motor deficit; mouse model; multicatalytic endopeptidase complex; mutant; neuroinflammation; neuron loss; neurotoxicity; nuclear respiratory factor; oxidation; oxidative damage; prevent; protein misfolding; public health relevance; research study; response; superoxide dismutase 1; therapeutic target; tool

DESCRIPTION (provided by applicant): Pathological activation of oxidative damage, neuroinflammation, and mitochondrial dysfunction are implicated in pathogenesis of Amyotrophic lateral sclerosis (ALS). These pathophysiolgical aspects are tightly regulated by Nrf2/ARE (NF-E2 related factor 2/antioxidant response element) signaling, the impairment of which triggers detrimental signaling events leading to motor neuron death in ALS. Due to this, the Nrf2/ARE pathway is considered important and has great promise to be explored for neurotherapeutics in neurodegenerative diseases such as ALS. The Nrf2 has been identified as a key regulatory factor in the coordinated induction of ARE driven "battery" of neuroprotective genes; e.g. antioxidant and anti-inflammatory proteins. The Nrf2 system is regulated by the cytosolic protein Keap1 (Kelch like ECH associated protein 1) that binds to Nrf2 and prevents its translocation to the nucleus. Oxidation of a critical cysteine in Keap 1 allows Nrf2 to translocate into the nucleus, where it activates transcription of a large number of genes encoding phase II detoxification enzymes. Our synthetic triterpenoids, are structurally modified to achieve increased bioavailability in central nervous system and are potent activators of Nrf2/ARE pathway. Oral administration of these Nrf2/ARE activators in ALS mice resulted in translocation of Nrf2 from cytoplasm to nucleus and upregulated expression of genes involved in antioxidant response and mitochondrial biogenesis while pro-inflammatory genes were downregulated in ALS mice. In pilot experiments in G93A SOD1 mice, treatment with these triterpenoids resulted in decrease in weight loss, improvement in motor performance and most importantly a significant increase in survival. We hypothesize that Nrf2/ARE signaling pathway is impaired in ALS and synthetic triterpenoids possess great potential as therapeutic candidates in preventing motor neuron death. Two specific aims are proposed to test our hypothesis. In aim 1, we will examine the efficacy of triterpenoid drugs CDDO (2-cyano-3, 12- dioxooleana-1,9-dien-28-oic acid) ethylamide, and CDDO-trifluoroethylamide in blocking motor deficits, neuronal loss, oxidative damage and inflammation in a mouse model of ALS when triterpenoids are administered during symptomatic and presymptomatic stages. This will enable us to validate and identify the most potent triterpenoid in preventing ALS-like disease in mice. In aim 2, we will determine the targets downstream of the Nrf2/ARE modulated by the most potent triterpenoid drug in an effort to identify the precise neuroprotective mechanism of action in a mouse model of ALS. Unraveling the neuroprotective mechanisms modulated by these synthetic triterpenoids through activation of Nrf2/ARE signaling pathway will enable us to develop these compounds into potential therapeutic drugs to retard the death of motor neurons in ALS. PUBLIC HEALTH RELEVANCE: This study proposes to examine the role of Nrf2/ARE pathway in Amyotrophic Lateral Sclerosis (ALS). The long-term goal is to understand the role of Nrf2/ARE genetic program in ALS and to determine the neuroprotective efficacy of synthetic triterpenoids that activate the neuroprotective Nrf2/ARE signaling pathway in motor neurons in the mouse model of ALS. The study will enable us to characterize Nrf2/ARE pathway and to determine the best synthetic triterpenoid as a potential drug candidate for the development of an effective therapeutic strategy for ALS.

DESCRIPTION (provided by applicant): Pathological activation of oxidative damage, neuroinflammation, and mitochondrial dysfunction are implicated in pathogenesis of Amyotrophic lateral sclerosis (ALS).这些病理生理学方面受到 Nrf2/ARE（NF-E2 相关因子 2/抗氧化反应元件）信号传导的严格调节，其损伤会触发有害的信号传导事件，导致 ALS 中的运动神经元死亡。因此，Nrf2/ARE 通路被认为很重要，并且有望在 ALS 等神经退行性疾病的神经治疗中得到探索。 The Nrf2 has been identified as a key regulatory factor in the coordinated induction of ARE driven "battery" of neuroprotective genes;例如抗氧化剂和抗炎蛋白。 Nrf2 系统由胞质蛋白 Keap1（Kelch 样 ECH 相关蛋白 1）调节，Keap1 与 Nrf2 结合并防止其易位至细胞核。 Keap 1 中关键半胱氨酸的氧化使 Nrf2 易位到细胞核中，在细胞核中激活大量编码 II 相解毒酶的基因的转录。 Our synthetic triterpenoids, are structurally modified to achieve increased bioavailability in central nervous system and are potent activators of Nrf2/ARE pathway. ALS 小鼠口服这些 Nrf2/ARE 激活剂会导致 Nrf2 从细胞质易位到细胞核，并上调参与抗氧化反应和线粒体生物合成的基因表达，而促炎基因在 ALS 小鼠中下调。在 G93A SOD1 小鼠的初步实验中，使用这些三萜类化合物治疗可减少体重减轻，改善运动性能，最重要的是显着提高生存率。我们假设 Nrf2/ARE 信号通路在 ALS 中受损，而合成三萜类化合物在预防运动神经元死亡方面具有作为治疗候选者的巨大潜力。 Two specific aims are proposed to test our hypothesis. In aim 1, we will examine the efficacy of triterpenoid drugs CDDO (2-cyano-3, 12- dioxooleana-1,9-dien-28-oic acid) ethylamide, and CDDO-trifluoroethylamide in blocking motor deficits, neuronal loss, oxidative damage and inflammation in a mouse model of ALS when triterpenoids are administered during symptomatic and presymptomatic 阶段。 This will enable us to validate and identify the most potent triterpenoid in preventing ALS-like disease in mice.在目标 2 中，我们将确定由最有效的三萜类药物调节的 Nrf2/ARE 下游的靶标，以努力确定 ALS 小鼠模型中精确的神经保护作用机制。 Unraveling the neuroprotective mechanisms modulated by these synthetic triterpenoids through activation of Nrf2/ARE signaling pathway will enable us to develop these compounds into potential therapeutic drugs to retard the death of motor neurons in ALS. PUBLIC HEALTH RELEVANCE: This study proposes to examine the role of Nrf2/ARE pathway in Amyotrophic Lateral Sclerosis (ALS). The long-term goal is to understand the role of Nrf2/ARE genetic program in ALS and to determine the neuroprotective efficacy of synthetic triterpenoids that activate the neuroprotective Nrf2/ARE signaling pathway in motor neurons in the mouse model of ALS. The study will enable us to characterize Nrf2/ARE pathway and to determine the best synthetic triterpenoid as a potential drug candidate for the development of an effective therapeutic strategy for ALS.