SULT4a1, a novel neuroprotective protein in stroke

SULT4a1，一种新型中风神经保护蛋白

• 批准号: 10096888
• 负责人: Shaida A. Andrabi
• 金额: $ 38.48万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10096888
• 关键词: Age; Back; Biological Assay; Biotin; Brain; Cause of Death; Cell Death; Cell Death Signaling Process; Cell Survival; Cells; Cessation of life; Co-Immunoprecipitations; Coagulation Process; Complex; Cytosol; Data; Disease; Drug Metabolic Detoxication; Electron Microscope; Enzymes; Evaluation; Experimental Models; Exposure to; Family; Functional disorder; Gene Targeting; Genus Hippocampus; Glucose; Homeostasis; Hydrogen Peroxide; Image; In Vitro; Inflammatory Response; Knockout Mice; Knowledge; Lead; Ligation; Literature; MG132; Magnetic Resonance Imaging; Mechanics; Mediating; Mediator of activation protein; Middle Cerebral Artery Occlusion; Mitochondria; Modeling; Morbidity - disease rate; Mus; Neurons; Oxidation-Reduction; Oxides; Oxygen; Pathway interactions; Pattern; Peroxides; Pharmacology; Phenotype; Play; Process; Proteins; Proteomics; Regulation; Role; Secondary to; Stains; Stroke; System; TXN gene; Therapeutic Intervention; Thrombectomy; Ubiquitin; Vertebrates; Viral; brain tissue; cell injury; deprivation; disability; in vivo; knock-down; live cell imaging; member; microscopic imaging; mitochondrial dysfunction; neuroprotection; new therapeutic target; novel; novel strategies; peroxiredoxin; peroxiredoxin I; post stroke; relating to nervous system; small hairpin RNA; stroke model; sulfotransferase; targeted treatment; therapeutic target; therapeutically effective; ubiquitin-protein ligase

Stroke remains a leading cause of death and morbidity in the USA and lacks effective therapeutic interventions. Redox imbalance and mitochondrial dysfunction are considered as leading causes of cell death in stroke. Identification of novel therapeutic targets that restore redox homeostasis, mitochondrial function, and cell survival is a critical need. Deregulation in peroxiredoxins (PRDXs) is one of the mechanisms leading to redox imbalance and mitochondrial dysfunction. PRDXs act as double-edged swards that the highly neuroprotective when inside the cells in reduced forms. However, when oxidized and released from damaged/dead cells, PRDXs can lead to secondary cell death signaling via inflammatory responses. Therefore, the regulation of PRDXs in stroke is a vital neuroprotective strategy. We identified that regulation of PRDXs by SULT4a1 (relatively less studies neuronal protein) is a critical neuroprotective function of SULT4a1 and may have a vital neuroprotective role in stroke. Loss of SULT4a1 in mouse neurons leads to the accumulation of oxidized PRDXs with subsequent redox imbalance, mitochondrial dysfunction, and cell death. SULT4a1 can interact with PRDX1, PRDX2, PRDX3, and PRDX5. These PRDXS (cytosolic-PRDX1 and PRDX2, and mitochondrial-PRDX3 and PRDX5) are crucial for cytosolic and mitochondrial redox homeostasis via detoxification of peroxides. During this process, PRDXs are oxidized and must be recycled back to reduced forms. Expression of SULT4a1 increases the levels of reduced PRDXs in peroxide-treated cells. SULT4a1 protein levels decrease in stroke via the ubiquitin proteasomal system. However, the role of SULT4a1 in stroke or the mediators that lead to loss of SULT4a1 in stroke are not known. We will use oxygen- glucose deprivation in mouse cortical neurons and a middle cerebral artery occlusion (MCAO) model of stroke in mice to identify the neuroprotective roles of SULT4a1 in stroke. We propose the following four aims to study the role of SULT4a1 in stroke: Specific Aim #1: Can SULT4a1 maintain redox homeostasis via PRDXs in stroke? Specific Aim #2: Can SULT4a1 rescue mitochondrial function in stroke? Specific Aim #3: Is SULT4a1 neuroprotective in stroke? Specific Aim #4: Identify the mechanisms leading to loss of SULT4a1 in stroke Our supporting data strongly favor our hypothesis and the proposed aims. Combining viral-mediated expression of SULT4a1 with Seahorse Flux analysis, electron microscope imaging, proximity ligation assays, proximity-dependent biotin identification, live-cell imaging, and MRI imaging in experimental models of stroke represents a novel approaches to identify the neuroprotection by SULT4a1 in stroke. These studies will reveal essential knowledge about the role of the novel SULT4a1-dependent pathways in stroke, and determine whether SULT4a1 can represent a credible target for therapeutic intervention in stroke.

中风仍然是美国死亡和发病的主要原因，缺乏有效的治疗方法