Regulation and function of HDAC1 in spinal neuron regeneration in zebrafish

HDAC1在斑马鱼脊髓神经元再生中的调控及功能

• 批准号: BB/R003742/1
• 负责人: Thomas Becker
• 金额: $ 55.56万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR003742%2F1
• 关键词: Regulation; function; HDAC1; spinal; neuron

After spinal cord injury, nerve cells in the vicinity of the injury site are destroyed and not replaced. In contrast, in zebrafish, which are capable of full spinal cord regeneration, nerve cells are replaced. The source for new nerve cells are special progenitor cells. These progenitor cells also exist in the spinal cord of mammals, but fail to generate new neurons. We want to understand how progenitor cells in zebrafish can flexibly switch on the production of nerve cells after injury. In preliminary experiments we have identified a DNA-modifying enzyme, called HDAC1, as important. We will manipulate the activity of this enzyme after spinal cord injury in zebrafish using specific drugs and transgenic fish to determine whether HDAC1 is necessary for progenitor cell activity. We will determine how HDAC1 is activated by inflammatory events at the injury site. Then we will identify alterations in gene activity mediated by HDAC1. This will give us important insights into regeneration of new neurons in a vertebrate system. Understanding the important factors in the spinal progenitor cells that allow for neurogenesis in zebrafish may lead to new targets for future therapeutic aiming to harness the endogenous repair capacity of spinal progenitor cells in mammals.

脊髓损伤后，损伤部位附近的神经细胞被破坏并未替换。相反，在能够全脊髓再生的斑马鱼中，神经细胞被取代。新神经细胞的来源是特殊的祖细胞。这些祖细胞也存在于哺乳动物的脊髓中，但无法产生新的神经元。我们想了解斑马鱼中的祖细胞如何在受伤后灵活地打开神经细胞的产生。在初步实验中，我们已经确定了一种称为HDAC1的DNA修饰酶，这很重要。我们将使用特定的药物和转基因鱼类在斑马鱼中脊髓损伤后操纵该酶的活性，以确定HDAC1是否对于祖细胞活性是必需的。我们将确定HDAC1如何通过伤害部位激活HDAC1。然后，我们将确定由HDAC1介导的基因活性的改变。这将使我们对脊椎动物系统中新神经元的再生的重要见解。了解允许在斑马鱼中神经发生的脊柱祖细胞中的重要因素可能会导致未来治疗的新靶标，以利用哺乳动物中脊髓祖细胞的内源性修复能力。

项目成果

Axon Regeneration - Methods and Protocols

轴突再生 - 方法和方案

• DOI: 10.1007/978-1-0716-3012-9_15
• 发表时间: 2023
• 作者: Drake L

Regenerative neurogenesis: the integration of developmental, physiological and immune signals.

• DOI: 10.1242/dev.199907
• 发表时间: 2022-04-15
• 期刊: Development (Cambridge, England)

CRISPR gRNA phenotypic screening in zebrafish reveals pro-regenerative genes in spinal cord injury.

• DOI: 10.1371/journal.pgen.1009515
• 发表时间: 2021-04
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Keatinge M;Tsarouchas TM;Munir T;Porter NJ;Larraz J;Gianni D;Tsai HH;Becker CG;Lyons DA;Becker T
• 通讯作者: Becker T

Phenotypic screening using synthetic CRISPR gRNAs reveals pro-regenerative genes in spinal cord injury

• DOI: 10.1101/2020.04.03.023119
• 发表时间: 2020-04
• 期刊: bioRxiv
• 作者: Marcus Keatinge;Themistoklis M Tsarouchas;Tahimina Munir;J. Larraz;Davide Gianni;Hui-hsin Tsai;C. G. Becker;D. Lyons;T. Becker

Dynamic cell interactions allow spinal cord regeneration in zebrafish

• DOI: 10.1016/j.cophys.2020.01.009
• 发表时间: 2020-04-01
• 期刊: CURRENT OPINION IN PHYSIOLOGY
• 影响因子: 2.5
• 作者: Becker, Thomas;Becker, Catherina G.
• 通讯作者: Becker, Catherina G.