Regulation and function of HDAC1 in spinal neuron regeneration in zebrafish

脊髓损伤后，损伤部位附近的神经细胞被破坏而不被替换。相比之下，斑马鱼能够完全再生脊髓，神经细胞被替换。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，但不能产生新的神经元。我们想了解斑马鱼的祖细胞如何在损伤后灵活地开启神经细胞的产生。在初步实验中，我们已经确定了一种叫做HDAC1的dna修饰酶，它很重要。我们将在斑马鱼脊髓损伤后使用特异性药物和转基因鱼操纵该酶的活性，以确定HDAC1是否是祖细胞活性所必需的。我们将确定HDAC1如何被损伤部位的炎症事件激活。然后，我们将确定HDAC1介导的基因活性的改变。这将为我们了解脊椎动物系统中新神经元的再生提供重要的见解。了解斑马鱼脊髓祖细胞中允许神经发生的重要因素可能会为未来的治疗提供新的靶点，旨在利用哺乳动物脊髓祖细胞的内源性修复能力。

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.