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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.

项目总结