NeuroD1/Dlx2调控猕猴星形胶质细胞转分化对脑出血损伤的修复作用

神经元在受损后不能自发再生，其损伤修复十分有限。这极大地限制了脑出血患者的康复治疗。过表达转录因子NeuroD1和Dlx2可将小鼠纹状体星形胶质细胞（Ast）转分化为GABA能神经元。此技术能否应用于灵长类动物尤为关键。我们的预实验结果表明：在猕猴纹状体Ast中过表达NeuroD1和Dlx2可将其转化为神经元。然而，转化神经元的亚型未知，其对神经功能的恢复作用也尚不明确。本研究利用胶原酶构建猕猴纹状体出血模型，随后在Ast中过表达NeuroD1和Dlx2，进一步结合免疫组化、核磁共振影像和行为学测试，研究转化神经元的亚型、血肿体积、组织缺损大小、免疫炎症反应变化以及猕猴运动功能表现。最终回答两个科学问题：1.NeuroD1和Dlx2可将猕猴纹状体Ast高效转分化为哪类亚型的神经元？ 2.转分化能否修复脑出血继发性脑损伤，并进一步改善神经功能？本研究有望为脑出血患者的康复治疗提供新策略。

Neurons cannot regenerate spontaneously after injury, so the repair of injury is very limited. This greatly limits the rehabilitation of patients with brain injury. Overexpression of transcription factors NeuroD1 and Dlx2 can transdifferentiate mouse striatum astrocytes (Ast) into GABAergic neurons. Whether this technique can be applied to primates is particularly critical. Our preliminary experiments show that overexpression of NeuroD1 and Dlx2 in rhesus monkey striatum Ast can convert it into neurons. However, the subtype of these neurons is unknown, and its effect on the recovery of neural function is not clear. In this study, the model of striatal hemorrhage in rhesus monkeys was established by collagenase, and then NeuroD1 and Dlx2 were overexpressed in Ast. Combined with immunohistochemistry, magnetic resonance imaging and behavioral tests, the subtypes of transformed neurons, hematoma volume, tissue defect size, immune response changes and upper limb motor performance of rhesus monkeys were studied. Finally, we will answer two scientific questions: 1. which subtypes of neurons can NeuroD1 and Dlx2 convert striatal Ast of rhesus monkey into？2. Can transdifferentiation repair secondary brain injury after intracerebral hemorrhage and further improve neurological function? This study is expected to provide a new strategy for the rehabilitation of patients with cerebral hemorrhage.