小胶质细胞过度活化介导的脑水肿和神经元损害是脑创伤(TBI)致死致残的主要原因。研究表明：Nrdp1介导受体酪氨酸激酶降解和小胶质细胞M2型极化。VEGFR1属受体酪氨酸激酶并介导小胶质细胞活性。TNFSF15是新发现的VEGFR1调控因子其受体DR3在小胶质细胞中表达并能激活Akt。本组前期发现：TNFSF15减少TBI小鼠损伤区活化的小胶质细胞数量，VEGFR1表达和水肿体积，保护神经元（见工作基础），但机制不详。本课题拟在前期工作的基础上，通过TNFSF15转基因TBI小鼠及体外细胞模型，探讨TNFSF15调控小胶质细胞过度活化的体内靶点和抑制小胶质细胞活化对体外BBB和神经元的保护作用；研究TNFSF15是否通过DR3激活Akt/USP8提高Nrdp1，调动泛素化-蛋白酶体途径调控VEGFR1表达，同时又通过泛素化-非蛋白酶体途径促进小胶质细胞M2型极化，最终抑制小胶质细胞过度活化

Over-activated microglia-mediated brain edema and neuron damage is the main causes of traumatic brain injury-induced death and disability. Previous data has reported that Nrdp1 mediates degradation of receptor tyrosine kinase and microglia M2 polarization. VEGFR1 is one of the receptor tyrosine kinase and mediates microglia activity. Recently, it’s found that TNFSF15 is a novel VEGFR1 regulator and its receptor DR3 which mediates Akt activation is expressed in microglia. Our pre-experiment found that TNFSF15 decreases the number of activated microglia，VEGFR1 expression and alleviates TBI-induced brain edema and improve neurological function, however, the mechanism of TNFSF15 action on TBI is unclear. In this project, we will utilize SPC-TNFSF15 transgenic TBI mice and cellular model in vitro, to investigate : The targets of TNFSF15 inhibition of microglia activation in vivo, and TNFSF15 protects BBB integrity and neuron damage from affecting microglia activation in vitro; if TNFSF15 activates Akt/USP8/Nrdp1 by DR3 which triggers VEGFR1 degradation in ubiquitin-dependent proteasome pathway and M2 polarization in ubiquitin-independent proteasome pathway leading to TNFSF15 inhibition of microglia activation.