Glial cell responses promote spinal cord repair in zebrafish

胶质细胞反应促进斑马鱼脊髓修复

• 批准号: 10446788
• 负责人: Mayssa H. Mokalled
• 金额: $ 40.64万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446788
• 关键词: Adult; American; Astrocytes; Automobile Driving; CRISPR screen; Cells; Cellular biology; Chronic; Cicatrix; Environment; Functional Regeneration; Gene Expression; Genes; Genetic; Genetic Transcription; Gliosis; Grant; Human; Impairment; Injury; Intervention; Macrophage Activation; Mammals; Maps; Microglia; Molecular; Motor; Natural regeneration; Neuroglia; Outcome; Paralysed; Pathogenicity; Pathway interactions; Protein Isoforms; Recovery; Recovery of Function; Regenerative Medicine; Regenerative capacity; Regenerative response; Rehabilitation therapy; Reporter; Resolution; Role; Scientist; Sensory; Series; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Structure; Testing; Therapeutic; Tissues; Transcription Repressor; Work; Zebrafish; epithelial to mesenchymal transition; experimental study; extracellular; fascinate; gain of function; gene regulatory network; in vivo; innovation; loss of function; macrophage; mutant; neural repair; overexpression; peptidomimetics; progenitor; programs; psychologic; regeneration model; regenerative; regenerative cell; relating to nervous system; response; response to injury; spinal cord regeneration; spinal cord repair; teleost fish; therapy development; transcription factor; transcriptomics

ABSTRACT 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 transection. Although innate spinal cord repair in zebrafish has fascinated scientists for decades, the contribution of glial cells to this elevated regenerative capacity is vastly understudied. Following SCI, adult zebrafish initiate a glial bridge that reconnects the severed spinal cord and supports functional neural repair. Pro-regenerative glial bridging distinguishes the zebrafish spinal cord and occurs without the detrimental outcomes of reactive gliosis elicited by the mammalian spinal cord. We propose that zebrafish glia orchestrate a series of transient, pro-regenerative responses that enable spinal cord repair. In this proposal, we will 1) determine the early injury responses that initiate glial bridging, 2) identify glial bridging mechanisms that are specific to zebrafish bridging glia and absent in mammalian glia, and 3) uncover the cellular and molecular mechanisms that direct glial bridge disassembly after regeneration is complete. This study will provide a mechanistic understanding of glial cell biology during zebrafish spinal cord regeneration, and will guide approaches for manipulating glial cells to promote spinal cord repair in mammals.

抽象的 每年约有18,000名美国人遭受新的脊髓损伤（SCI）。初级和次要赔偿 由SCI引起的永久性感觉和运动功能，需要长期治疗， 康复和心理干预措施。因此，开发治疗或反向SCI的疗法是一种压力 再生医学的需求。与哺乳动物相反，硬骨鱼自然再生功能神经组织 和完全脊髓横断后的反向瘫痪。虽然斑马鱼的先天脊髓维修 几十年来迷人的科学家，神经胶质细胞对这种升高的再生能力的贡献非常大 研究了。 SCI之后，成年斑马鱼启动了一座神经胶桥，该桥梁重新连接了切断的脊髓和 支持功能性神经修复。亲胶质桥接区分斑马鱼脊髓和 发生哺乳动物脊髓引起的反应性神经胶质病的不利结果。我们建议 斑马鱼的神经胶质策划了一系列瞬态，促进性的反应，以实现脊髓修复。在 该提案，我们将1）确定启动神经胶结桥的早期伤害反应，2）确定神经胶质桥梁 特定于斑马鱼桥接神经胶质和不存在哺乳动物胶质的机制，3）发现细胞 以及在再生后导致神经胶质桥拆卸的分子机制。这项研究会 提供对斑马鱼脊髓再生过程中神经胶质细胞生物学的机械理解，并将引导 操纵神经胶质细胞以促进哺乳动物修复的方法。