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Extracellular mitochondria transfer in gray and white matter for ameliorating sensorimotor and cognitive deficits after stroke

灰质和白质中的细胞外线粒体转移可改善中风后的感觉运动和认知缺陷

基本信息

批准号：
10415616
负责人：
Kazuhide Hayakawa
金额：
$ 50.5万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415616
关键词：
Aging Allografting Animals Astrocytes Blood - brain barrier anatomy Blood Vessels Brain CRISPR/Cas technology Cell Nucleus Cell Survival Cells Cerebral Ischemia Cognitive Cognitive deficits Confocal Microscopy Cyclic ADP-Ribose Data Dementia Electrophysiology (science)Elements Endothelial Cells Endothelium Energy Supply Etiology Female Glucose Golgi Apparatus Homeostasis Human In Vitro Infarction Integrins Ischemia Knowledge Label Mammalian Cell Maps Mass Spectrum Analysis Mediating Metabolism Methods Mitochondria Mitochondrial Proteins Modification Molecular Mus Neuraxis Neurologic Neuronal Plasticity Neurons Oligodendroglia Oligonucleotides Outcome Oxygen PARK7 gene PECAM1 gene Pathway interactions Pattern Pharmacology Plasmids Play Post-Translational Protein Processing Process Property Protein Inhibition Publishing Rattus Recombinants Recovery Recovery of Function Role Sensorimotor functions Signal Pathway Signal Transduction Site-Directed Mutagenesis Small Interfering RNA Small Nuclear RNA Specific qualifier value Stroke Testing Therapeutic Tissues Western Blotting angiogenesis base behavioral outcome brain endothelial cell cognitive function cognitive recovery cognitive testing deprivation experimental study extracellular functional improvement glycation gray matter improved in vivo in vivo imaging inhibitor loss of function male neural growth neurogenesis neurological recovery neurovascular neutralizing antibody novel novel strategies novel therapeutic intervention oligodendrocyte precursor optical imaging post stroke post stroke dementia potential biomarker precursor cell prevent remyelination repaired response spatiotemporal tool trafficking transcriptome transcriptome sequencing white matter

项目摘要

Extracellular mitochondria transfer in gray and white matter for ameliorating sensorimotor and cognitive deficits after stroke Mitochondrial function is essential for maintaining cellular homeostasis in the central nervous system (CNS). It is now recognized that mitochondria are surprisingly released and transferred between cells. However, the underlying mechanisms remain poorly understood. In this proposal, we will investigate post-translational modification by O-GlcNAc as a critical element for extracellular mitochondrial functionality and the transfer- mediated blood-brain barrier recovery, oligodendrocyte protection and neural plasticity after stroke. Our pilot data suggest that (i) ER-Golgi trafficking may regulate mitochondrial protein O-GlcNAcylation, (ii) transfer of O-GlcNAcylated mitochondria may protect neurons, oligodendrocyte precursors and endothelial cells against oxygen-glucose deprivation, (iii) blockade of DJ1 O-GlcNAcylation may increase mitochondrial glycation and degradation, thus reducing the protective capacity of extracellular mitochondria, (iv) levels of mitochondrial O-GlcNAc-DJ1 may be positively correlated with functional recovery after stroke and negatively correlated with aging, (v) methods to dissect these mechanisms (molecular tools, optical imaging, electrophysiology, snRNA-seq etc) are feasible in our collaborating labs. Based on our pilot data, we hypothesize that damage associated molecular pattern (DAMP) or CD31 signals upregulate CD38 in reactive astrocytes, and CD38-driven post-translational modification by O-GlcNAc supports extracellular mitochondrial functionality that accelerates viable mitochondrial transfer-mediated neurovascular remodeling and remyelination, thus ameliorating sensorimotor deficits and post-stroke dementia after stroke. We have 3 specific aims. In Aim 1, we will dissect mechanisms of O-GlcNAc-modified mitochondrial release and transfer between astrocytes and neurons or brain endothelial cells or OPCs/oligodendrocytes. In Aim 2, we will investigate O-GlcNAcylated mitochondrial transfer in gray matter and white matter in young, older, male or female mice after focal ischemia. In Aim 3, we will use gain- and loss-of-function experiments to modify mitochondrial protein O-GlcNAcylation, and assess sensorimotor and cognitive outcomes in vivo. Our experiments will utilize molecular tools including a combination of pharmacologic activators/inhibitors, site- directed mutagenesis, and AAV-induced mitochondrial labeling to assess astrocyte-specific mitochondria transfer. Single-nuclei RNA seq will be performed to fully map transcriptomes in gray and white matter post- stroke. Translational relevance will be assessed with in vivo imaging, electrophysiology and long-term outcomes post-stroke. This project should define a novel mechanism of mitochondrial transfer in both gray and white matter, and hopefully provide new approaches to accelerate sensorimotor recovery and ameliorate post- stroke vascular-related dementia.

灰质和白质细胞外线粒体转移改善感觉运动和