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

• 批准号: 10680427
• 负责人: Robert Hill
• 金额: $ 41万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 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/10680427
• 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; Color; Communication; Degenerative Disorder; Demyelinating Diseases; Demyelinations; Detection; Development; Digestion; Event; Excision; Failure; Fluorescence; Functional disorder; Generations; Genetic; Image; Imaging Techniques; Impaired cognition; Injury; Investigation; Knowledge; Label; 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; 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; neural circuit; neuropathology; novel; optical imaging; phosphatidylserine receptor; progenitor; receptor; remyelination; repaired; response; success; tissue repair; tool; transmission process

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.

项目摘要 髓鞘已经进化到加快、微调和增加电信号传输的代谢效率 在大脑中。然而，在许多人类疾病中，髓磷脂退化，最终导致破坏性的 运动和认知障碍。重要的是，为了在髓鞘损伤后进行组织修复， 发生时，构成髓鞘的许多层致密细胞膜必须迅速地， 被大脑中的吞噬细胞有效清除这些碎片的清除工作有缺陷， 与许多退行性疾病有关，包括但不限于多发性硬化和衰老， 我们对控制这些过程的细胞动力学和分子机制知之甚少。为了 研究这些关键的细胞事件，并回答以涉及哪些细胞群为中心的问题， 这些不同的细胞类型扮演着什么样的角色，我们已经开发出先进的成像和操纵技术， 这些离散的事件在活的动物中在从几秒到几个月的广泛的时间尺度上。这些 技术包括基于荧光团的转基因标记的新组合的活体成像， 不同的神经元和神经胶质群体以及对致密髓鞘特异的无标记成像方式。 除了这些强大的标记和光学成像策略，我们还开发了一种新技术， 对于单细胞死亡的靶向诱导，我们最近建立了一个按需模型， 小鼠皮质灰质中的可滴定脱髓鞘。将这些技术结合起来， 在靶向基因操作和动物实验背景下脱髓鞘和髓鞘再生的研究 人类疾病的模型。利用这些强大的工具，该项目将调查三个中心目标。一是 越来越多的证据表明，除了小胶质细胞，大脑的主要吞噬细胞，其他常驻胶质细胞， 星形胶质细胞和NG 2胶质细胞也参与其中，并在吞噬和修复中发挥重要作用 过程我们将确定每种胶质细胞类型在动态检测和清除中的精确贡献 退化的髓鞘碎片接下来，我们和其他人已经证明了磷脂酰丝氨酸受体的重要性， 在不同器官中的垂死神经元和其他细胞的有效检测和清除。我们将确定 有缺陷的吞噬细胞受体和碎片消化信号在动态 NG 2神经胶质细胞对皮质脱髓鞘的反应以及由此产生的髓鞘再生成功和髓鞘形成。 最后，有证据表明，神经元活动和/或感觉经验可以改变髓鞘再生，但很少有证据表明， 已知神经元活动在脱髓鞘背景下对吞噬功能的作用。我们将 确定双向神经元活动变化对吞噬细胞对以下物质的反应的后果： 单细胞脱髓鞘最终，这些研究将揭示哪些细胞参与髓鞘碎片的清除， 主要细胞碎片识别途径在成功清除和修复中的作用，以及神经元活动如何 和感觉经验改变吞噬胶质细胞对脱髓鞘事件的反应。