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: 10176609
• 负责人: Bobby Thomas
• 金额: $ 40.17万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176609
• 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; MPTP Poisoning; 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; new therapeutic target; novel; novel therapeutic intervention; 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 含有ARE的基因对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。

项目成果

Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs.

• DOI: 10.1016/j.neuint.2021.105148
• 发表时间: 2021-10
• 期刊: Neurochemistry international
• 影响因子: 4.2
• 作者: Gaisina IN;Hushpulian DM;Gaisin AM;Kazakov EH;Ammal Kaidery N;Ahuja M;Poloznikov AA;Gazaryan IG;Thatcher GRJ;Thomas B
• 通讯作者: Thomas B

Current perspective of mitochondrial biology in Parkinson's disease.

• DOI: 10.1016/j.neuint.2018.03.001
• 发表时间: 2018-07
• 期刊: Neurochemistry international
• 影响因子: 4.2
• 作者: Ammal Kaidery N;Thomas B
• 通讯作者: Thomas B

Bach1 derepression is neuroprotective in a mouse model of Parkinson's disease.

• DOI: 10.1073/pnas.2111643118
• 发表时间: 2021-11-09
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Ahuja M;Ammal Kaidery N;Attucks OC;McDade E;Hushpulian DM;Gaisin A;Gaisina I;Ahn YH;Nikulin S;Poloznikov A;Gazaryan I;Yamamoto M;Matsumoto M;Igarashi K;Sharma SM;Thomas B
• 通讯作者: Thomas B

Excess homocysteine upregulates the NRF2-antioxidant pathway in retinal Müller glial cells.

• DOI: 10.1016/j.exer.2018.03.022
• 发表时间: 2019-01
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Navneet S;Cui X;Zhao J;Wang J;Kaidery NA;Thomas B;Bollinger KE;Yoon Y;Smith SB
• 通讯作者: Smith SB

BACH1-Hemoxygenase-1 axis regulates cellular energetics and survival following sepsis.

• DOI: 10.1016/j.freeradbiomed.2022.06.005
• 发表时间: 2022-08-01
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Cai, Lun;Arbab, Ali S.;Lee, Tae Jin;Sharma, Ashok;Thomas, Bobby;Igarashi, Kazuhiko;Raju, Raghavan Pillai
• 通讯作者: Raju, Raghavan Pillai