Secreted Factors for Zebrafish Spinal Cord Regeneration

斑马鱼脊髓再生的分泌因子

• 批准号: 10338234
• 负责人: KENNETH D POSS
• 金额: $ 20.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-21 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338234
• 关键词: Adopted; Affect; Area; Axon; Behavior; Behavioral; Binding Sites; Bioinformatics; Biomedical Engineering; Cell Survival; Cells; Central cord canal structure; Chromatin; Cicatrix; DTR gene; Data; Data Analyses; Data Set; Distal; EGF gene; Engineering; Environment; Ependymal Cell; Epidermal Growth Factor; Event; Genes; Genetic Enhancer Element; Genetic Transcription; Gliosis; Growth; Heparin Binding; Human; Impairment; In Situ Hybridization; Injury; Instruction; Mammalian Cell; Mammals; Molecular; Molecular Genetics; Motor; Mus; Mutation; Natural regeneration; Nerve; Neuroglia; Neurons; Outcome; Paralysed; Population; Production; Proliferating; Promoter Regions; Proteins; Reagent; Recombinants; Recovery; Regenerative Medicine; Regenerative capacity; Regulation; Reporter; Research; Resistance; Role; Sensory; Sequence Analysis; Signal Transduction; Site; Spinal Cord; Spinal Cord transection injury; Spinal cord damage; Spinal cord injury; Supporting Cell; Swimming; Testing; Time; Tissues; Transgenes; Transgenic Organisms; Work; Zebrafish; axon growth; base; differential expression; experimental study; extracellular; factor A; injured; insight; mutant; neuron loss; paralogous gene; regeneration potential; regenerative; response to injury; spinal cord regeneration; spinal cord repair; teleost; teleost fish; therapy development; transcription factor; transcriptome; wound

Primary and secondary tissue damage from spinal cord injury permanently impairs sensory and motor functions, causing irreversible paralysis. Developing therapies to treat and reverse spinal cord injury is an urgent need in regenerative medicine and remains an enormous research challenge. The path to an effective cure requires a combination of molecular, cellular, electrostimulatory, and engineering approaches, and must be guided by a deeper understanding of the inherent regenerative capacity of spinal cord tissue. Following spinal cord injury, nerve cell death and scar formation inhibit regeneration. To date, attempts to alleviate the negative effects of scarring and to support cell survival and nerve regrowth after injury have not overcome the challenges of mammalian spinal cord regeneration. By contrast with mammals, teleost zebrafish can form new neurons, regrow axons, and recover the ability to swim just 6 to 8 weeks after a paralyzing injury that completely severs the spinal cord. Importantly, these regenerative events proceed without massive scarring. Instead, following injury, specialized non-neural glia and other cells build a tissue bridge to connect the two severed ends, allowing axons to grow across the wound and reestablish crucial connections. Encouraging key mammalian cells to adopt this bridging behavior would shift the mammalian spinal cord injury response from scarring to regeneration, potentially to an extent sufficient to save tissue function. This highly desirable outcome requires an extensive understanding of the molecular signals that enable innate spinal cord regeneration. We have bioinformatically assessed datasets of transcriptome changes after spinal cord injury in zebrafish and mice, with the idea that factors preferentially induced in a successful context of regeneration would be instructive for such events. Based on the preliminary data from analysis of several new mutant and transgenic zebrafish strains, we propose to: 1) elucidate the roles of an induced and secreted factor in the regulation of spinal cord regeneration in zebrafish; and 2) define the molecular regulation and targets of this factor after spinal cord injury. Our work will provide an in-depth understanding of a key factor during spinal cord regeneration and reveal insights into its regulatory mechanisms. These discoveries will guide approaches for comprehending, and potentially manipulating, the capacity for human spinal cord regeneration.

脊髓损伤造成的原发和继发性组织损伤会永久性地损害感觉和运动功能， 导致不可逆转的瘫痪。开发治疗和逆转脊髓损伤的疗法是当务之急 再生医学，仍然是一个巨大的研究挑战。通往有效治愈之路需要 分子、细胞、电刺激和工程方法的组合，必须由 对脊髓组织固有的再生能力有更深入的了解。在脊髓损伤后， 神经细胞死亡和疤痕形成会抑制再生。到目前为止，试图减轻 创伤后形成疤痕并支持细胞存活和神经再生尚未克服 哺乳动物的脊髓再生。与哺乳动物相比，硬骨斑马鱼可以形成新的神经元，再生 轴突，并在完全切断脊椎的瘫痪损伤后仅6至8周恢复游泳能力 电源线。重要的是，这些再生过程不会留下巨大的疤痕。相反，在受伤后， 特化的非神经胶质细胞和其他细胞建立一个组织桥来连接两个切断的末端，从而允许轴突 在伤口上生长并重新建立至关重要的连接。鼓励关键的哺乳动物细胞采用这种方法 桥接行为会将哺乳动物脊髓损伤的反应从疤痕转移到再生， 潜在地达到足以挽救组织功能的程度。这一非常理想的结果需要广泛的 了解使脊髓先天再生的分子信号。我们有生物信息 评估了斑马鱼和小鼠脊髓损伤后转录组变化的数据集，其想法是 在成功的再生背景下优先诱导的因素将对此类事件具有指导意义。基座 根据对几个新的突变和转基因斑马鱼品系的初步分析数据，我们建议：1) 阐明诱导和分泌因子在斑马鱼脊髓再生调节中的作用； 2)明确脊髓损伤后该因子的分子调控及其靶点。我们的工作将提供一个 深入了解脊髓再生过程中的一个关键因素并揭示其调控机制 机制。这些发现将指导理解和潜在地操纵 人类脊髓再生的能力。