Mechanisms of glial bridging and neurogenesis during spinal cord regeneration in zebrafish

斑马鱼脊髓再生过程中胶质桥接和神经发生的机制

• 批准号: 10228737
• 负责人: Mayssa H. Mokalled
• 金额: $ 38.84万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228737
• 关键词: Adult; American; Astrocytes; Cells; Cicatrix; Coupled; Data; Dorsal; GDF8 gene; Gene Expression Profile; Genes; Genetic; Gliosis; Growth; Human; Impairment; In Situ Hybridization; Inflammatory; Injury; Intervention; Mammals; Modeling; Molecular; Molecular Genetics; Motor; Muscle; Natural regeneration; Nervous system structure; Neuroglia; Neurons; Outcome; Paralysed; Pharmacology; Process; Publishing; Radial; Recovery; Recovery of Function; Regenerative Medicine; Regenerative capacity; Regulatory Element; Rehabilitation therapy; Sensory; Signal Pathway; Signal Transduction; Spinal Cord; Spinal Cord Lesions; Spinal Cord transection injury; Spinal cord damage; Spinal cord injury; Supporting Cell; Testing; Therapeutic; Tissues; Transgenic Organisms; Work; Zebrafish; adult neurogenesis; connective tissue growth factor; deep sequencing; defined contribution; extracellular; factor A; functional disability; innovation; loss of function; member; mutant; neurogenesis; neuron loss; neurotoxic; neurotoxicity; premature; psychologic; regeneration function; regenerative; relating to nervous system; repaired; response; self-renewal; severe injury; spinal cord regeneration; spinal cord repair; stem cells; teleost fish; therapy development

Around 18,000 Americans suffer new spinal cord injuries (SCI) each year. Primary and secondary damages caused by SCI permanently impair sensory and motor functions, which require long-term therapeutic, rehabilitative, and psychological interventions. Thus, developing therapies to treat or reverse SCI is a pressing need in regenerative medicine. In contrast to mammals, teleost fish naturally regenerate functional neural tissue and reverse paralysis after complete spinal cord (SC) transection. Following SCI, adult zebrafish initiate a glial bridge that reconnects the severed SC, and regenerate functional neurons that contribute to SC repair. Pro-regenerative glial bridging and efficient adult neurogenesis distinguish the zebrafish SC from the mammalian SC and enable natural repair post-injury. Importantly, these pro-regenerative processes occur without the detrimental outcomes of reactive gliosis or neurotoxicity elicited by the mammalian SC. However, little is known about the cellular and molecular mechanisms that direct glial bridging or neurogenesis in zebrafish. In this proposal, we will 1) investigate the signaling pathways that direct glial bridging, 2) identify a new regulator of neurogenesis, and 3) identify the progenitor cells that give rise to bridging glia or regenerating neurons after SCI. This study will provide mechanistic understanding of glial bridging and neurogenesis during zebrafish SC regeneration, and will guide approaches for manipulating SCI outcomes in mammals.

每年约有18，000名美国人遭受新的脊髓损伤（SCI）。原发性和继发性损害 脊髓损伤引起的永久性损害感觉和运动功能，需要长期治疗， 康复和心理干预。因此，开发治疗或逆转SCI的疗法是一项紧迫的任务。 再生医学的需要。与哺乳动物相比，硬骨鱼自然地再生功能性神经元。 组织和扭转瘫痪后完全脊髓（SC）横断。脊髓损伤后，成年斑马鱼开始 神经胶质桥重新连接切断的SC，并再生有助于SC修复的功能性神经元。 促再生胶质桥接和有效的成体神经发生将斑马鱼SC与神经干细胞区分开来。 哺乳动物SC和使自然修复损伤后。重要的是，这些促进再生的过程 而没有由哺乳动物SC引起的反应性神经胶质增生或神经毒性的有害结果。然而， 关于在神经元中指导胶质细胞桥接或神经发生的细胞和分子机制知之甚少。 斑马鱼在这个提议中，我们将1）研究直接神经胶质桥接的信号通路，2）确定一个 新的神经发生调节因子，以及3）鉴定产生桥接胶质细胞或再生的祖细胞 SCI后神经元这项研究将提供机制的理解，胶质桥接和神经发生过程中， 斑马鱼SC再生，并将指导在哺乳动物中操纵SCI结果的方法。