Age-Induced Disruptions in Remyelination After Spinal Cord Injury

脊髓损伤后年龄引起的髓鞘再生破坏

• 批准号: 10160653
• 负责人: Nicole Pukos
• 金额: $ 1.37万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2021-08-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160653
• 关键词: Adult; Affect; Age; Aging; Anatomy; Autophagocytosis; Axon; CSPG4 gene; Cell Aging; Cell Cycle Arrest; Cell Differentiation process; Cell Lineage; Cell Maturation; Cell Proliferation; Cell physiology; Cells; Chemicals; Chronic; Clinical; Data; Demyelinations; Designer Drugs; Down-Regulation; Elderly; Environment; FRAP1 gene; Frequencies; Genes; Glutamates; Goals; Human; Impairment; Incidence; Individual; Injury; Knock-out; Knowledge; Lesion; Locomotor Recovery; Longevity; Mitotic; Modeling; Motor; Mus; Myelin; Neuroglia; Neurons; Oligodendroglia; Paralysed; Pathway interactions; Prevalence; Proliferating; Publishing; Quality of life; Recovery; Recovery of Function; Recycling; Red nucleus structure; Regulation; Running; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Source; Spinal cord injury; Spinal cord injury patients; Testing; Therapeutic Intervention; Time; Transgenic Mice; Transplantation; Trauma; United States; Viral Vector; Work; age related; aged; aging population; axon injury; axonal degeneration; cell injury; cell motility; experimental study; extracellular; falls; functional improvement; gain of function; glutamatergic signaling; improved; injured; insight; loss of function; myelin biogenesis; myelination; neurotransmission; new therapeutic target; novel; oligodendrocyte lineage; oligodendrocyte myelination; overexpression; receptor; recruit; remyelination; repaired; response; self-renewal; single-cell RNA sequencing; stem cells; young adult

PROJECT SUMMARY/ABSTRACT Spinal cord injury (SCI) is a devastating trauma that affects over 17,000 individuals in the United States per year, resulting in permanent paralysis for which there are no clinical therapies. These functional deficits are largely attributed to axon degeneration and extensive demyelination. Since surviving oligodendrocytes (OLs) cannot self-renew to remyelinate axons, the primary source of new myelin originates from proliferating NG2 progenitor cells. After SCI, it well-characterized that NG2 cells migrate and differentiate into new myelinating OLs along demyelinated axons. However, preliminary and published data suggest that NG2 cell differentiation and myelin biogenesis slow with advancing age. The frequency of SCI in the aging population is markedly increasing, yet the mechanism behind this impaired remyelination remains unknown. Here, we will use loss-of- function and gain-of-function experiments to investigate signaling pathways that contribute to the age- dependent decline in NG2 cell function, remyelination, and functional recovery after SCI. In particular, we will study two signals that regulate oligodendrogenesis: the mammalian target of rapamycin (mTOR) and glutamate. In Aim 1 we will genetically inhibit mTOR in aged mice to determine if mTOR downregulation reverses age-related impairments in CNS repair. Single cell RNA sequencing from young and aged mice will be run to further characterize changes in OL function and mTOR signaling. Then, in Aim 2 we will use viral vectors to test if overexpressing glutamate is sufficient to promote neuron-glia crosstalk and remyelination in aged-SCI mice. Collectively, these experiments aim to provide novel insight into how NG2 cells and myelination are regulated in the aging injured environment. If successful, data from this proposal will be one of the first to show that specific signaling molecules are responsible for anatomical and functional improvements in aged-SCI mice. This knowledge will aid in identifying new targets for therapeutic intervention to improve the quality of life of elderly SCI patients.

项目摘要/摘要 脊髓损伤(SCI)是一种毁灭性的创伤，每年影响美国超过17,000人 一年，导致永久性瘫痪，没有临床治疗方法。这些功能缺陷是 主要归因于轴突变性和广泛的脱髓鞘。由于存活的少突胶质细胞(OL) 不能自我更新以再生髓鞘轴突，新髓鞘的主要来源来自增殖的NG2 祖细胞。脊髓损伤后，ng2细胞迁移和分化为新的髓鞘具有良好的特征。 沿着脱髓鞘轴突的狼疮样改变。然而，初步和公布的数据表明，NG2细胞分化 髓鞘的生物发生随着年龄的增长而减慢。脊髓损伤在老龄化人口中的发生率显著增加。 然而，这种受损的再髓鞘形成背后的机制仍不清楚。在这里，我们将使用损失- 功能和功能增益实验，以研究有助于年龄的信号通路- 脊髓损伤后NG2细胞功能、重新髓鞘形成和功能恢复的依赖性下降。特别是，我们将 研究调节少突胶质细胞发生的两个信号：哺乳动物雷帕霉素靶点(MTOR)和 谷氨酸。在目标1中，我们将从基因上抑制衰老小鼠的mTOR，以确定mTOR是否下调 逆转中枢神经系统修复中与年龄相关的损害。来自年轻和老年小鼠的单细胞RNA测序将 以进一步表征OL功能和mTOR信号的变化。然后，在《目标2》中，我们将使用病毒 载体测试过表达谷氨酸是否足以促进神经元-神经胶质细胞串扰和再髓鞘形成 老龄脊髓损伤小鼠。总的来说，这些实验旨在提供新的洞察力，了解NG2细胞和 髓鞘形成在老化损伤的环境中受到调节。如果成功，来自该提案的数据将是 第一个表明特定的信号分子对解剖和功能的改善负责 在老年脊髓损伤小鼠中。这一知识将有助于确定新的治疗干预目标，以改善 老年脊髓损伤患者的生活质量研究