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Mitochondrial Structural and Functional Remodeling in Microglial Activation

小胶质细胞激活中的线粒体结构和功能重塑

基本信息

批准号：
9093229
负责人：
BRIAN M POLSTER
金额：
$ 23.1万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9093229
关键词：
Acute Affect Agonist Alzheimer&apos s Disease Animal Model Belief Bioenergetics Blinded Blood - brain barrier anatomy Brain Brain Injuries Cardiac Cells Chronic Complex Data Electron Microscopy Equilibrium Figs - dietary Flow Cytometry Genus Hippocampus Glycolysis Goals Heart Arrest Human Hydrogen Peroxide ITGAM gene Individual Injection of therapeutic agent Injury Interferon Type II Interferons Knock-out Knockout Mice Label Link Lipopolysaccharides Measures Microglia Mitochondria Modeling Morphology Mus NADPH Oxidase Nerve Degeneration Neurodegenerative Disorders Neurons Nitric Oxide Oxidative Phosphorylation PTPRC gene Parkinson Disease Pathology Pharmaceutical Preparations Population Pre-Clinical Model Production Proteins Quality Control Reactive Oxygen Species Respiration Reverse Transcriptase Polymerase Chain Reaction Role Secondary to Signal Transduction Staining method Stains Stroke TLR4 gene TNF gene Testing The Jackson Laboratory Thinking Time Traumatic Brain Injury brain cell brain tissue catalase cellular imaging cytokine in vivo in vivo Model inhibitor/antagonist mouse model neuroinflammation neuropathology novel novel therapeutics public health relevance research study response small molecule inhibitor targeted treatment trafficking

项目摘要

DESCRIPTION (provided by applicant): The mitochondrial fission-promoting protein Drp1 is linked to neuropathology in acute and chronic neurodegenerative disorders. Mdivi-1, a blood-brain barrier permeable drug thought to inhibit Drp1, protects the brain in preclinical models of stroke, cardiac arrest, and Parkinson's disease. While major efforts are underway to test whether targeting the mitochondrial fission-fusion balance in neurons can modify neurodisease, the implications of targeting mitochondrial fission in non-neuronal brain cells are almost entirely unexplored. We see a mitochondrial structural remodeling consistent with Drp1-dependent fission in microglia when they enter a proinflammatory activation state termed M1. A bioenergetic shift from oxidative phosphorylation to glycolysis promotes M1 activation, and activation is marked by production of nitric oxide (NO) and proinflammatory cytokines. Resembling the neuroinflammatory state seen in human brain injury, M1 activation can persist for months to years and result in additional pathology. A better understanding of the mechanisms contributing to M1 activation will help discover novel therapeutics that block the deleterious consequences of M1 microglial activation. We find that the Drp1 inhibitor mdivi-1 suppresses microglial NO and TNF-α production in response to lipopolysaccharide (LPS) ± interferon-γ. We also find that mdivi-1 can inhibit reactive oxygen species (ROS) production by mitochondrial complex I in a Drp1-independent fashion. It is important to determine whether one or both of the known mdivi-1 targets, Drp1 and ROS, contribute to M1 microglial activation in vivo, and thus represent bona fide targets for therapy. This study will test the central hypothesis that in vivo, Drp1 activity but not mitochondrial ROS is required for microglial activation and the accompanying shift in cellular bioenergetics. Microglial activation will be induced in mice by intracerebroventricular administration of LPS. To investigate the role of Drp1, a novel microglia-specific inducible knockout mouse model will be developed. In addition, the existing MCAT mouse ectopically expressing matrix-targeted, H2O2-detoxifying catalase will be used to evaluate a specific requirement for mitochondrial ROS independent of other ROS. In Aim 1, we will determine whether Drp1 is necessary for the bioenergetic shift and microglial M1 activation induced by LPS in vivo. In Aim 2, we will determine whether mitochondrial ROS are required for the bioenergetic shift and microglial M1 activation induced by in vivo LPS injection. Our studies will take a crucial step toward determining whether microglial mitochondria can be targeted for therapy. Since normal Drp1-dependent fission is required for mitochondrial trafficking and quality control in neurons, a strategy specifically targeting Drp1 in microglia may ultimately be more desirable than global inhibition of mitochondrial fission. Our long-term goal is to target mitochondrial mechanisms of microglial activation in models of ischemic and traumatic brain injury, with the ultimate hope of developing a protective therapy for humans.