Role of Bach-1-Mediated Transcriptional Regulation in Neuroprotection

项目摘要 帕金森病（PD）是一种进行性的、使人衰弱的神经退行性疾病，目前尚无治愈方法。而 帕金森病的病因尚不清楚，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 已知错误折叠在疾病发病机制中起作用。Nrf 2通路的激活是一种有希望的 PD的治疗方法不幸的是，基于Nrf 2的药物依赖于亲电药效团， 其在患者中耐受性不好。开发更有效的基于Nrf 2的 目前缺乏对安全激活这一途径的机制的理解。Bach 1是一个 抑制Nrf 2基因表达的转录因子。我们的目标是验证Bach 1抑制作为一种新的 PD发病机制的治疗策略，并确定新的干预靶点。我们的中央 假设Bach 1抑制由于Nrf 2依赖性和Nrf 2非依赖性而在PD中具有神经保护作用 机制等这一假设是基于这样的知识，即基因缺失和药理学抑制 Bach 1在小鼠中导致神经保护性Nrf 2依赖性以及Nrf 2非依赖性的组成性激活 基因，并保护免受帕金森神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）。 我们的目标是：1）确定Bach 1在体内MPTP神经毒性中的细胞特异性作用，2）描述 Bach 1抑制在介导α-synuclein诱导PD中的作用，3）区分Bach 1-和Nrf 2- 神经保护中的依赖性途径，以及4）识别用于治疗性干预的新靶点。我们 预期结果包括发现1）Bach 1的遗传缺失和药理学抑制 改善小鼠α-突触核蛋白病和MPTP神经毒性; 2）Bach 1介导的神经保护作用 机制涉及不同的细胞类型; 3）Bach 1抑制或缺失保护Nrf 2-null小鼠对抗MPTP-1。 神经毒性; 4）Bach 1依赖性神经保护机制涉及上调Nrf 2依赖性， 以及Nrf 2非依赖性神经保护基因，而Nrf 2依赖性抗氧化反应元件 （ARE）基因对Nrf 2依赖性机制至关重要。我们的研究将影响该领域：1） 提高对Bach 1信号通路调节和下游神经保护事件的理解 与PD的临床前模型相关; 2）验证一组新的、非亲电子Bach 1抑制剂作为潜在的 用于PD和突触核蛋白病的治疗剂;和3）鉴定用于治疗性干预的新靶标。 目的1：将测试Bach 1的基因缺失和药理学抑制可防止 黑质纹状体多巴胺能变性的不同模式。目的2：将检验Bach 1抑制 在α-突触核蛋白病的小鼠模型中减弱疾病发展。目标3：将检验假设， Bach 1抑制通过Nrf 2依赖性和Nrf 2非依赖性机制赋予神经保护作用。

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.