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

基本信息

批准号：
10016863
负责人：
Bobby Thomas
金额：
$ 41.18万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
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/10016863
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Acute Antioxidants Apoptotic Astrocytes Attenuated BACH1 gene 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 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 motor behavior 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

项目摘要

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.

项目概要帕金森病 (PD) 是一种进行性、使人衰弱的神经退行性疾病，目前尚无治愈方法。 PD的病因尚不清楚，氧化应激、神经胶质增生、兴奋性毒性、线粒体功能障碍和蛋白质众所周知，错误折叠在疾病发病机制中发挥着作用，Nrf2 通路的激活是一个有希望的前景。不幸的是，基于 Nrf2 的药物依赖于亲电药效团，患者不能很好地耐受，这是开发更有效的基于 Nrf2 的进展的关键障碍。目前缺乏对能够安全激活该途径的机制的了解。抑制 Nrf2 基因表达的转录因子我们的目标是验证 Bach1 抑制作为一种新型药物。 PD 发病机制的治疗策略，并确定新的干预目标。假设由于 Nrf2 依赖性和 Nrf2 独立性，Bach1 抑制在 PD 中具有神经保护作用该假设基于基因缺失和药理学抑制的知识。小鼠中的 Bach1 导致依赖于 Nrf2 以及不依赖于 Nrf2 的神经保护作用的组成型激活基因，并防止帕金森神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP)。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 抑制在介导 α-突触核蛋白诱导的 PD 中的作用，3) 区分 Bach1- 和 Nrf2- 神经保护中的依赖途径，4) 确定治疗干预的新靶点。预期结果包括发现 1) Bach1 的基因缺失和药理抑制改善小鼠的 α-突触核蛋白病和 MPTP 神经毒性 2) Bach1 介导的神经保护作用；机制涉及不同的细胞类型；3) Bach1 抑制或缺失可保护 Nrf2 缺失小鼠免受 MPTP- 神经毒性；4) Bach1 依赖性神经保护机制涉及 Nrf2 依赖性 as 的上调以及 Nrf2 独立的神经保护基因，而 Nrf2 依赖的抗氧化反应元件含有 (ARE) 的基因对于 Nrf2 依赖性机制至关重要。我们的研究将通过以下方式影响该领域：1) 提高对 Bach1 信号通路调节和下游神经保护事件的理解与 PD 临床前模型相关；2) 验证一组新型非亲电子 Bach1 抑制剂的潜力 PD 和突触核蛋白病的治疗药物；3) 确定治疗干预的新靶点。目标 1：将测试 Bach1 的基因删除和药理抑制可预防的假设黑质纹状体多巴胺能变性的不同模式 AIM 2：将检验 Bach1 抑制的假设。减轻 α-突触核蛋白病小鼠模型中的疾病发展：将检验以下假设： Bach1 抑制通过 Nrf2 依赖和 Nrf2 独立机制提供神经保护。