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Glial mechanisms governing the removal and repair of degenerating myelin

控制退化髓磷脂去除和修复的神经胶质机制

基本信息

批准号：
10276003
负责人：
Robert Hill
金额：
$ 41万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10276003
关键词：
Ablation Aging Animal Model Animals Apoptotic Astrocytes Axon Brain CSPG4 gene Cell Death Cell Surface Extensions Cell membrane Cells Cellular Structures Cessation of life Communication Degenerative Disorder Demyelinating Diseases Demyelinations Detection Development Digestion Event Excision Failure Fluorescence Functional disorder Generations Image Imaging Techniques Impaired cognition Injury Investigation Knowledge Label Lead Lipids Maintenance Metabolic Metabolism Methodology Methods Microglia Modeling Molecular Multiple Sclerosis Mus Mutant Strains Mice Mutation Myelin Myelin Sheath Nerve Neurodegenerative Disorders Neuroglia Neurons Oligodendroglia Organ Pathway interactions Pattern Phagocytes Phagocytosis Play Population Process Receptor Signaling Reporter Resolution Rest Role Sensory Signal Transduction Specific qualifier value Speed Stereotyping TREM2 gene Techniques Testing Time Tissues Transgenic Organisms base cell type experience experimental study fluorophore genetic manipulation gray matter human disease human model imaging modality in vivo in vivo imaging intravital imaging motor impairment myelin degeneration neural circuit neuropathology novel optical imaging phosphatidylserine receptor progenitor receptor relating to nervous system remyelination repaired response success tissue repair tool transmission process

项目摘要

PROJECT SUMMARY Myelin has evolved to speed up, finely tune, and increase the metabolic efficiency of electrical signal transmission in the brain. In numerous human diseases however, myelin degenerates, ultimately resulting in devastating motor and cognitive impairment. Importantly, in order for tissue repair to proceed after myelin damage has occurred, the many layers of compacted cell membrane that constitute the myelin sheath must be rapidly and efficiently removed by resident phagocytic cells in the brain. Defective removal of these debris has been implicated in a number of degenerative conditions, including but not limited to, multiple sclerosis and aging, yet we know little about the cellular dynamics and molecular mechanisms governing these processes. In order to study these critical cellular events and answer questions centered on which cell populations are involved and what roles these different cell types play, we have developed advanced techniques for imaging and manipulating these discrete events in the live animal over a wide range of temporal scales from seconds to months. These techniques include intravital imaging of new combinations of fluorophore-based multicolor transgenic labels of distinct populations of neurons and glia together with label-free imaging modalities specific for compact myelin. In addition to these powerful labeling and optical imaging strategies, we have also developed a new technique for targeted induction of single-cell death, which we have recently established as a model of on-demand and titratable demyelination in the mouse cortical gray matter. Combining these techniques now allows dynamic investigation of demyelination and remyelination in the context of targeted genetic manipulations and animal models of human disease. Using these powerful tools this project will investigate three central aims. First, there is increasing evidence that in addition to microglia, the primary phagocytes of the brain, other resident glial cell types, namely astrocytes and NG2 glia, are also involved and play important roles in the phagocytosis and repair process. We will determine the precise contribution of each glial cell type in the dynamic detection and clearance of degenerating myelin debris. Next, we and others have shown the importance of phosphatidylserine receptors in the efficient detection and clearance of dying neurons and other cells in different organs. We will determine the role and consequences of both defective phagocytic receptors and debris digestion signaling on the dynamic response by NG2 glia to cortical demyelination and the resulting remyelination success and myelin patterning. Finally, there is evidence that neuronal activity and/or sensory experience can modify remyelination, but less is known about the roles of neuronal activity on phagocytic function in the context of demyelination. We will determine the consequences of bidirectional neuronal activity changes on the response by phagocytic cells to single-cell demyelination. Ultimately, these studies will reveal which cells are involved in myelin debris clearance, the role of major cell debris recognition pathways in successful clearance and repair, and how neuronal activity and sensory experience modify the response of phagocytic glia to a demyelinating event.

项目总结