Oligodendrocyte lineage cell plasticity in the spinal cord following peripheral injury

外周损伤后脊髓中少突胶质细胞谱系细胞的可塑性

• 批准号: 9171552
• 负责人: LORI G ISAACSON
• 金额: $ 43.35万
• 依托单位: MIAMI UNIVERSITY OXFORD
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171552
• 关键词: Adult; Amyotrophic Lateral Sclerosis; Axon; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; Cell Communication; Cell Proliferation; Cell Survival; Cells; Cervical; Clinical; Communication; Demyelinating Diseases; Demyelinations; Disease; Foundations; Goals; Individual; Injury; Length; Lentivirus Vector; Life; Microglia; Mitotic; Modeling; Molecular; Mood Disorders; Multiple Sclerosis; Mus; Myelin; Nerve Degeneration; Nervous system structure; Neuraxis; Neuronal Injury; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Oligodendroglia; Peripheral; Peripheral Nervous System; Play; Process; Proliferating; Recovery; Reporter; Role; Signal Transduction; Site; Solid; Spinal Cord; Spinal cord injury; Stem cells; Testing; Therapeutic; Thoracic spinal cord structure; Tissues; Work; axon injury; base; injured; knock-down; nervous system disorder; neuronal cell body; neuronal survival; neurotrophic factor; oligodendrocyte lineage; repaired; response; self-renewal

Project Summary The long term goal of this study is to elucidate the role of retrograde signaling and cell-cell interactions in the central nervous system (CNS) following peripheral axon injury. In particular we will focus on the plasticity that occurs in spinal cord oligodendrocyte (OL) lineage cells following injury of peripherally located sympathetic preganglionic axons. Following the transection of preganglionic axons in the cervical sympathetic trunk (CST), we observe robust region-specific increases in spinal cord oligodendrocyte progenitor cells (OPCs) and OLs that express full length TrkB, the cognate receptor for brain derived neurotrophic factor (BDNF). This plasticity is localized to only the region of the injured preganglionic neurons in the upper thoracic spinal cord. In Aim 1 we will test the hypothesis that the plasticity in OL lineage cells observed following peripheral axon injury is the result of proliferation and differentiation of OPCs. Because microglial cells in the spinal cord, which have been shown to influence the activities of OL lineage cells, show robust activation following the CST transection, we will test the hypothesis in Aim 2 that the presence of activated microglia is a requirement for OL cell plasticity. BDNF, which is increased in the spinal cord following CST transection, is known to regulate OL activities, and we observe an increase in TrkB OLs following CST transection, leading to the hypothesis in Aim 3 that TrkB and/or BDNF is necessary for OL plasticity to occur. We predict that the loss of TrkB signaling and/or BDNF following CST transection will severely impact OL plasticity. The mechanisms that regulate the process of OPC self-renewal and differentiation to become mature OLs are important because alterations in OL lineage cells underlie numerous neurological disorders including demyelinating disease, mood disorders, recovery following spinal cord injury, amyotrophic lateral sclerosis, and multiple sclerosis. Therefore, a better understanding of the many factors that regulate OL lineage cells has broad clinical implications. Use of our unique CST transection model allows for the examination of glial responses to neuronal injury in the absence of the secondary injury cascades initiated by spinal trauma. Only with this solid foundation can strategic therapeutic strategies be devised to augment cell survival and replacement following injury or disease in the adult nervous system.

项目摘要 本研究的长期目标是阐明逆行信号传导和细胞间相互作用的作用。 外周轴突损伤后中枢神经系统（CNS）中的相互作用。特别是 我们将重点关注脊髓少突胶质细胞（OL）谱系细胞的可塑性 周围交感神经节前轴突损伤后。后 切断颈交感神经干（CST）的节前轴突，我们观察到强大的 脊髓少突胶质祖细胞（OPCs）和OLs的区域特异性增加， 表达全长TrkB，其为脑源性神经营养因子（BDNF）的同源受体。这 可塑性仅局限于上胸部受损的节前神经元区域 脊髓在目的1中，我们将检验在OL谱系细胞中观察到的可塑性的假设， OPCs增殖和分化是导致外周轴突损伤的主要原因。因为 脊髓中的小胶质细胞，这已被证明会影响OL的活动 谱系细胞，在CST横切后显示出稳健的激活，我们将在 目的2：激活的小胶质细胞的存在是OL细胞可塑性的必要条件。BDNF， 在脊髓横断后增加，已知其调节OL 活动，我们观察到CST横断后TrkB OL增加，导致 目标3中假设TrkB和/或BDNF是OL可塑性发生所必需的。我们预测 CST横断后TrkB信号传导和/或BDNF的丢失将严重影响OL， 可塑性调节OPC自我更新和分化过程的机制， 成为成熟的OL是重要的，因为OL谱系细胞的改变是许多 神经系统疾病，包括脱髓鞘疾病、情绪障碍、 脊髓损伤、肌萎缩侧索硬化症和多发性硬化症。因此，更好的 对调节OL谱系细胞的许多因子的理解具有广泛的临床意义。 使用我们独特的CST横断模型可以检查胶质细胞对 在没有脊髓创伤引发的继发性损伤级联的情况下的神经元损伤。只 有了这个坚实的基础，就可以设计出战略性的治疗策略来增加细胞存活， 以及在成人神经系统损伤或疾病后的替代。