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

每年约有18,000名美国人遭受新的脊髓损伤(SCI)。原发和继发损害 脊髓损伤会永久性地损害感觉和运动功能，这需要长期的治疗， 康复和心理干预。因此，开发治疗或逆转脊髓损伤的疗法是当务之急。 需要再生医学。与哺乳动物不同，硬骨鱼可以自然地再生功能神经 脊髓(SC)全横断后的组织和反向瘫痪。在脊髓损伤后，成年斑马鱼启动 一种神经胶质桥，重新连接被切断的SC，并再生有助于SC修复的功能神经元。 促进再生的胶质细胞桥接和有效的成体神经发生将斑马鱼SC与 哺乳动物的SC和能够自然修复损伤后。重要的是，这些促进再生的过程 没有由哺乳动物SC引起的反应性胶质增生症或神经毒性的有害后果。然而， 指导神经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。在这个方案中，我们将1)研究引导神经胶质桥接的信号通路，2)确定一个 神经发生的新调节者，以及3)识别产生桥接神经胶质细胞或再生的祖细胞 脊髓损伤后的神经元。这项研究将提供对神经胶质桥接和神经发生的机制的理解 斑马鱼干细胞再生，并将指导操纵哺乳动物脊髓损伤结果的方法。

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.