Role of Bach-1-Mediated Transcriptional Regulation in Neuroprotection

Bach-1 介导的转录调控在神经保护中的作用

• 批准号: 9933558
• 负责人: Bobby Thomas
• 金额: $ 37.41万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9933558
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acute; Antioxidants; Apoptotic; Astrocytes; Attenuated; BACH1 gene; Behavior; Binding; Biochemical; Cell Death; Cells; Complex; Development; Disease; Disease Progression; Elements; Epigenetic Process; Event; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Transcription; Glial Fibrillary Acidic Protein; Gliosis; Goals; Human; Intervention; Intoxication; Knockout Mice; Knowledge; Measures; Mediating; Metallothionein; Microglia; Mitochondrial Proteins; Motor; Mus; Necrosis; Nerve Degeneration; Neurodegenerative Disorders; Neurotoxins; Onset of illness; Outcome; Oxidative Stress; PPAR gamma; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Play; Pre-Clinical Model; Proteins; Response Elements; Role; Signal Pathway; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Toxic Environmental Substances; Transcriptional Regulation; Treatment Efficacy; Up-Regulation; alpha synuclein; base; cell type; dopaminergic neuron; excitotoxicity; heme oxygenase-1; histone modification; improved; in vivo; inhibitor/antagonist; mitochondrial dysfunction; mouse model; mutant; neuroprotection; neurotoxicity; new therapeutic target; novel; novel therapeutics; nuclear factor-erythroid 2; pharmacophore; promoter; protein misfolding; side effect; synuclein; synucleinopathy; transcription factor

Project Summary Parkinson’s disease (PD) is a progressive, debilitating neurodegenerative disorder with no known cure. While the cause of PD is unknown, oxidative stress, gliosis, excitotoxicity, mitochondrial dysfunction and protein misfolding are all known to play a role in disease pathogenesis. Activation of the Nrf2 pathway is a promising therapeutic approach for PD. Unfortunately, Nrf2-based drugs have relied on electrophilic pharmacophores, which are not tolerated well in patients. A critical barrier to progress in developing more effective Nrf2-based therapies is the current lack of understanding of mechanisms that can safely activate this pathway. Bach1 is a transcription factor that represses Nrf2 gene expression. Our goal is to validate Bach1 inhibition as a novel therapeutic strategy for PD pathogenesis, and to identify new target(s) for intervention. Our central hypothesis is that Bach1 inhibition is neuroprotective in PD due to both Nrf2-dependent and Nrf2-independent mechanisms. This hypothesis is based on the knowledge that genetic deletion and pharmacological inhibition of Bach1 in mice results in constitutive activation of neuroprotective Nrf2-dependent as well as Nrf2-independent genes, and protects against the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our objectives are to 1) determine the cell-specific roles of Bach1 in MPTP neurotoxicity in vivo, 2) delineate the role of Bach1 inhibition in mediating α-synuclein-induced PD, 3) differentiate between Bach1- and Nrf2- dependent pathways in neuroprotection, and 4) identity novel targets for therapeutic intervention. Our expected outcomes include finding that 1) genetic deletion and pharmacological inhibition of Bach1 ameliorates α-synucleinopathy and MPTP-neurotoxicity in mice; 2) Bach1-mediated neuroprotective mechanisms involve distinct cell types; 3) Bach1 inhibition or deletion protects Nrf2-null mice against MPTP- neurotoxicity; 4) Bach1-dependent mechanisms of neuroprotection involve upregulation of Nrf2-dependent as well as Nrf2-independent neuroprotective genes, whereas Nrf2-dependent antioxidant response element (ARE)-containing genes are critical for Nrf2-dependent mechanisms. Our studies will impact the field by: 1) improving understanding of Bach1 modulation of signaling pathways and downstream neuroprotective events relevant to pre-clinical models of PD; 2) validating a set of novel, non-electrophilic Bach1 inhibitors as potential therapeutic agents for PD and synucleinopathies; and 3) identifying novel targets for therapeutic intervention. AIM 1: will test the hypothesis that genetic deletion and pharmacological inhibition of Bach1 protects against different modes of nigrostriatal dopaminergic degeneration. AIM 2: will test the hypothesis that Bach1 inhibition attenuates disease development in a mouse model of α-synucleinopathy. AIM 3: will test the hypothesis that Bach1 inhibition confers neuroprotection via Nrf2-dependent and Nrf2-independent mechanisms.

项目摘要 帕金森氏病(PD)是一种进行性的、衰弱的神经退行性疾病，目前尚无治愈方法。而当 帕金森病的原因尚不清楚，可能是氧化应激、胶质细胞增生症、兴奋性毒性、线粒体功能障碍和蛋白质 错误折叠都是已知在疾病发病机制中起作用的。激活Nrf2通路是一种很有希望的方法 帕金森病的治疗途径。不幸的是，基于NRF2的药物依赖于亲电的药效团， 这是患者不能很好地耐受的。在开发更有效的基于NRF2的技术方面取得进展的关键障碍 目前的治疗方法是缺乏对安全激活这一途径的机制的了解。Bach1是一种 抑制Nrf2基因表达的转录因子。我们的目标是验证Bach1抑制作为一种新的 帕金森病发病机制的治疗策略，并寻找新的干预靶点(S)。我们的中央 假设由于Nrf2依赖和非Nrf2依赖，抑制Bach1对帕金森病具有神经保护作用 机制。这一假说是基于这样一种知识，即基因缺失和药物抑制 Bach1在小鼠体内导致神经保护性Nrf2依赖和非Nrf2依赖的结构性激活 基因，并对帕金森病神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)有保护作用。 我们的目标是1)确定Bach1在体内MPTP神经毒性中的细胞特异性作用，2)描述 Bach1抑制在α-突触核蛋白诱导的帕金森病中的作用；3)区分Bach1-和Nrf2- 神经保护中的依赖途径，以及4)确定治疗干预的新靶点。我们的 预期结果包括发现1)Bach1的基因缺失和药理抑制 改善小鼠α-突触核苷酸病和MPTP神经毒性；2)Bach1介导的神经保护 机制涉及不同的细胞类型；3)抑制或缺失Bach1保护Nrf2基因缺失的小鼠免受MPTP- 神经毒性；4)Bach1依赖的神经保护机制包括上调Nrf2依赖的AS 以及Nrf2依赖的神经保护基因，而Nrf2依赖的抗氧化反应元件 含(ARE)的基因对Nrf2依赖机制至关重要。我们的研究将对该领域产生以下影响：1) 提高对Bach1在信号通路和下游神经保护事件中的调节作用的理解 与PD的临床前模型相关；2)验证一组新的、非亲电的Bach1抑制剂作为潜在的 帕金森病和联体核病的治疗剂；以及3)确定治疗干预的新靶点。 目的1：将检验Bach1的基因缺失和药物抑制对 黑质纹状体多巴胺能变性的不同模式。目标2：将检验Bach1抑制的假设 延缓α-突触核病小鼠模型的疾病发展。目标3：将检验以下假设 Bach1抑制通过Nrf2依赖和Nrf2非依赖机制提供神经保护。