# Role of Bach-1-Mediated Transcriptional Regulation in Neuroprotection > **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $401,686 ## Abstract 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 Nrf... ## Key facts - **NIH application ID:** 10176609 - **Project number:** 5R01NS101967-05 - **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA - **Principal Investigator:** Bobby Thomas - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $401,686 - **Award type:** 5 - **Project period:** 2017-05-01 → 2024-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10176609 ## Citation > US National Institutes of Health, RePORTER application 10176609, Role of Bach-1-Mediated Transcriptional Regulation in Neuroprotection (5R01NS101967-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10176609. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*