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Reprogramming proinflammatory microglia by restoring mitochondrial function

通过恢复线粒体功能重新编程促炎性小胶质细胞

基本信息

批准号：
10661552
负责人：
BRIAN M POLSTER
金额：
$ 54.23万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661552
关键词：
2-oxoglutarate 3-dioxygenase proline Affective Animal Model Antioxidants Attenuated Binding Brain Brain Injuries Cell Fraction Cells Chronic Clinical Cognitive Cognitive deficits Complex Consumption Data Dementia Disease Drug usage Encephalitis Enzymes Exhibits Female Flow Cytometry Fluorescence Gene Expression Genetic Glycolysis Goals HMGB1 gene Histopathology Hydroxylation Hypoxia Immune Impairment In Vitro Incubated Individual Inflammatory Injury Interferons Interleukin-1 beta Interleukins Intervention Knock-out Lysosomes Mechanics Metabolic Methods Microglia Mitochondria Modeling Molecular Monitor Motor Mus Nerve Degeneration Neurologic Neurologic Deficit Nitric Oxide Outcome Oxidative Phosphorylation Oxidative Stress Oxygen Oxygen Consumption Pathogenicity Pathway interactions Pharmaceutical Preparations Phenotype Positron-Emission Tomography Process Production Proline Proteins Proteomics Quality Control Reporter Reporting Research Role Severities Signal Transduction Sorting Source TBI treatment TLR4 gene Testing Traumatic Brain Injury Woman behavior test brain cell clinically relevant controlled cortical impact cytokine disability effective therapy efficacy evaluation experimental study glial activation idebenone in vitro Model in vivo inflammatory marker male men mitochondrial dysfunction mouse model neuroprotection novel novel strategies prevent progressive neurodegeneration response to injury restoration sex translational study

项目摘要

Traumatic brain injury (TBI) is a major source of long-term disability and dementia. Microglia, long-lived immune cells of the brain, activate to multiple reactive states in response to injury. The extent of pro-inflammatory activation correlates with the severity of neurological impairments, suggesting that unresolved activation is pathogenic. The proposed research is highly significant because it will evaluate a clinically safe intervention to ameliorate harmful TBI-induced microglial activation that may contribute to dementia and other chronic neurological deficits following TBI. Our data suggest that a metabolic shift from oxidative phosphorylation to glycolysis during pro-inflammatory activation involves impairment to the lysosomal turnover of damaged mitochondria by mitophagy, which is followed by Complex I subunit degradation. Idebenone restores oxygen consumption by damaged mitochondria and attenuates pro-inflammatory nitric oxide and interleukin-1beta production. The restoration of oxygen consumption by idebenone decreases intracellular oxygen concentration. We found that simply lowering oxygen concentration by incubating cells under hypoxia prevents Complex I degradation and mitophagy impairment. Unexpectedly, antioxidants failed to yield similar rescue, suggesting a role for oxygen that is independent of oxidative stress. Using proteomics, we discovered a marked accumulation of prolyl 3-hydroxylase 2 (P3H2) in a mitochondria/lysosome-enriched cell fraction. P3H2 gene expression within the brain is microglia-specific, and our preliminary data show elevated P3H2 in mouse peri-contusional cortex after TBI. P3H2 enzyme uses oxygen as a substrate for proline hydroxylation of target proteins. Idebenone may suppress the activity of P3H2 by decreasing oxygen availability, preventing P3H2 from post-translationally modifying mitochondria or lysosome proteins involved in quality control. This study will test the central hypothesis that idebenone suppresses TBI-induced microglial activation, chronic neurodegeneration, and cognitive deficits by reversing P3H2-dependent inhibition of mitophagy. The following specific aims employ state-of-the-art mouse models to monitor microglial mitochondrial turnover and include novel methods to sort and study microglia ex vivo based on mitochondrial function. The experiments in Aim 1 will test the prediction that idebenone rescues mitophagy in pro-inflammatory microglial cells by decreasing intracellular oxygen concentration, thereby inhibiting P3H2 activity. Using both male and female mice and considering sex as a variable, the experiments in Aim 2 will test the prediction that idebenone or genetic P3H2 knockout ameliorates TBI-induced pro-inflammatory microglia accumulation and neurological deficits by rescuing microglial mitophagy. Positive outcomes will support translational studies of idebenone to treat TBI-induced dementia, with the potential to help millions of men and women living with the devastating consequences of TBI.

创伤性脑损伤（TBI）是导致长期残疾和痴呆的主要原因。小神经胶质细胞,长寿