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：
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
项目类别：
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

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.

项目摘要帕金森氏病（PD）是一种渐进的，令人衰弱的神经退行性疾病，没有已知的治愈方法。尽管 PD的原因是未知的，氧化应激，神经胶质，兴奋性毒性，线粒体功能障碍和蛋白质众所周知，错误折叠都在疾病发病机理中发挥作用。 NRF2途径的激活是一个承诺 PD的治疗方法。不幸的是，基于NRF2的药物已在亲电药团上放松，患者的耐受性不佳。开发基于NRF2的更有效的进展的关键障碍疗法是目前缺乏对可以安全激活该途径的机制的理解。 Bach1是一个反映NRF2基因表达的转录因子。我们的目标是验证bach1抑制作用 PD发病机理的治疗策略，并确定新的靶标进行干预。我们的中心假设是，由于NRF2依赖性和NRF2无关，Bach1抑制在PD中是神经保护性的机制。该假设基于以下知识：遗传缺失和药物抑制小鼠中的Bach1导致神经保护NRF2依赖性以及NRF2独立于NRF2的组成型激活基因，并预防帕金森神经毒素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MPTP神经毒性中的细胞特异性作用，2）描述 Bach1抑制在介导α-核蛋白诱导的PD中的作用，3）区分Bach1-和Nrf2-- 神经保护方面的依赖途径，以及4）身份的治疗干预措施。我们的预期结果包括发现1）遗传缺失和BACH1的药物抑制改善小鼠中的α-突触核病和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-NULL小鼠免受MPTP- 神经毒性； 4）神经保护的Bach1依赖性机制涉及NRF2依赖性的上调AS 以及NRF2独立的神经保护基因，而NRF2依赖性抗氧化剂元件含有的基因对于NRF2依赖性机制至关重要。我们的研究将通过：1）影响该领域提高对信号通路和下游神经保护事件的BACH1调制的理解与PD的临床前模型有关； 2）验证一组新型的非电子Bach1抑制剂作为潜力 PD和突触核酸的治疗剂； 3）确定治疗干预的新目标。目标1：将检验以下假设：遗传缺失和药物抑制Bach1可以预防不同的黑质多巴胺能变性模式。目标2：将检验Bach1抑制的假设在α-突触核疾病的小鼠模型中减弱了疾病的发展。目标3：将检验以下假设 Bach1抑制供词通过NRF2依赖性和NRF2独立的机制神经保护。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

Structure-Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors.

DOI：
10.3390/antiox11020220
发表时间：
2022-01-24
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
0
作者：
Poloznikov AA;Nikulin SV;Hushpulian DM;Khristichenko AY;Osipyants AI;Asachenko AF;Shurupova OV;Savin SS;Lee SH;Gaisina IN;Thatcher GRJ;Narciso A;Chang EP;Kazakov SV;Krucher N;Tishkov VI;Thomas B;Gazaryan IG
通讯作者：
Gazaryan IG