E3泛素连接酶Triad1促进脊髓损伤后神经功能的恢复及其作用机制

脊髓损伤后神经元突起延伸对神经功能恢复具有重要作用。E3泛素连接酶Triad1间接促进P53介导的神经元细胞突起延伸，内体转运相关蛋白EHD1通过内体系统调节神经元突起的延伸，星形胶质细胞分泌NGF和PTN促进神经元突起延伸，均有利于神经功能恢复。课题组前期发现Triad1与EHD1、PTN均存在相互作用，提出脊髓损伤后Triad1泛素化调节EHD1和PTN，增加TrkA膜向转运及PTN稳定性，促进神经功能恢复的假说。本课题拟研究Triad1是否通过K63位泛素化调节EHD1，促进TrkA膜向循环，提高脊髓损伤后神经元突起延伸的能力。Triad1是否通过K63位泛素化调节PTN，增加星形角质细胞中向外分泌的PTN，激活下游信号通路，促进脊髓损伤后神经元突起的延伸。本研究有助于阐明脊髓损伤早期残存神经元突起延伸的能力与周围环境的改变机制，为脊髓损伤后神经功能恢复提供新的治疗思路。

The neurite outgrowth plays an significant role in the recovery of neurological function after spinal cord injury. The E3 ubiquitin ligase Triad1 indirectly promote neurite outgrowth mediated by P53. The EHD1 protein, an endogenous transporter associated protein, is involved in the regulation of the cell growth and the extension of the neurite. Studies show that astrocytes can secrete endogenous neurotrophic factor NGF and PTN after spinal cord injury, and promote the extension of the neurite, which is beneficial to the recovery of neural function. In our previous research, we found that E3 ubiquitin ligase Triad1 can interact with both EHD1 and PTN in rat spinal cord injury model. Our research group proposes the hypothesis that Triad1 could regulate EHD1 and PTN by ubiquitination, hich increased the stability of both EHD1 and PTN, and then, much more TrkA, a kind of high affinity receptors of NGF, was transported to the cell membrane, meanwhile much more PTN was secreted into the intercellular space, binding to its specific receptors on the membrane of neurons. Our study intends to research whether Triad1 can regulate EHD1 by K63 ubiquitination and promote the transport of TrkA to the membrane of neurons through the endosome system, realizing the recycling of TrkA, and promote the ability of neurite outgrowth after spinal cord injury. Whether Triad1 can regulate PTN by K63 ubiquitination, increaseing the secretion of PTN in astrocytes, and combine with the specific receptors on the neuron membrane, which activate the signaling pathway to promote neurite outgrowth after spinal cord injury. This study is helpful to clarify the changes of the ability and the surrounding environment of the survival neurons in the early stage after spinal cord injury, and provide a new treatment idea for the recovery of neurological function after spinal cord injury.