Regulation of 3D genome organisation and function in axonal regeneration

中枢神经系统(CNS)损伤，如脊髓损伤(SCI)，由于损伤轴突的再生和再连接失败，导致严重的神经功能损害和恢复不良。到目前为止，仍不清楚为什么大脑或脊髓中的神经在受伤后不能再生。虽然已知许多支持神经生长的基因在损伤后无法激活，但失败的原因仍不清楚。最近由其他人和我们积累的证据表明，控制再生程序的基因的可及性的变化可能会促进例如脊髓损伤后的修复和再生。了解再生程序是如何调节的，对于改善神经再生和受神经和脊髓损伤影响的人的功能恢复非常重要。基因表达的调节受到包含我们遗传信息的染色质的3D结构的影响。例如，染色质的动态3D变化对于胚胎的正常发育是必不可少的，最近被认为与癌症有关。这项提议将首次在小鼠的神经和脊髓损伤模型中研究染色质状态如何受到神经损伤的影响，以及这如何影响再生基因的表达。我们不仅将尝试确定重要的机制，还将尝试重塑染色质结构以促进神经再生。我们的研究将使用小鼠坐骨神经和脊神经损伤模型，结合分子技术和生物信息学分析，将有助于阐明损伤后基因表达和染色质结构的变化。综上所述，我们的研究将为神经再生的染色质依赖调控提供新的理解，并将为促进神经和脊髓损伤后的修复提供新的途径。

Injury in the central nervous system (CNS) such as spinal cord injury (SCI) results in severe neurological functional impairment and poor recovery due to failure in regeneration and re-connectivity of injured axons. To date, it is still unclear why nerves in the brain or spinal cord cannot regrow after injury. While it is known that many genes that could support the growth of nerves cannot be activated after injury, the reasons for this failure remain obscure. Recent accumulating evidence by others and us suggests that changes in the accessibility of genes that control the regeneration programme may facilitate repair and regeneration after spinal injury for example. Understanding how the regeneration programme is regulated could be very important to improve regeneration of nerves and recovery of function in people affected by nerve and spinal injuries.The regulation of gene expression is affected by the 3D structure of the chromatin that contains our genetic information. Dynamic 3D changes in chromatin are essential for proper embryonic development for example and have been recently implicated in cancer.This proposal will investigate for the first time how chromatin state is affected by nerve injury and how this affects regenerative gene expression in models of nerve and spinal injury in mice. We will not only try to identify important mechanisms but we will also attempt to reshape chromatin structure to promote nerve regeneration.Our studies will use sciatic and spinal nerve injury models in the mouse combined with state of the molecular techniques and bioinformatics analysis that will allow to clarify how gene expression and chromatin structure change after injuryIn summary, our studies will provide a novel understanding of chromatin-dependent regulation of nerve regeneration and will also propose novel avenues to foster repair after nerve and spinal injury.