神经系统编码（胡新天）知识库

缺血性脑中风是中老年常见疾病之一，它由脑局部供血不足引起，造成局部神经元的死亡和相关脑区功能的缺失。缺血性脑中风可导致行为障碍，比如言语困难，运动失调，甚至瘫痪。目前针对脑中风的研究方法有施加神经营养因子，神经干细胞移植和运动复健。但是由于可能出现的免疫排斥和致癌风险，收效甚微。于是我们提出了一种通过利用体内胶质细胞重编程为神经元的新方法来治疗脑中风。缺血性脑中风属于脑损伤的一种。当大脑损伤后，胶质细胞会应激性地增生，在损伤区域周围形成胶质疤痕。已经在小鼠上发现，这一类应激性胶质细胞可以通过施加一个在神经发育过程中的关键转录因子，NeuroD1，重编程为有功能的神经元。所以，我们将使用非人灵长类猕猴作为实验动物，使用血管收缩素ET-1在猕猴运动皮层的手部运动区建立缺血性脑中风模型，再在相同位置使用含有NeuroD1片段的逆转录病毒和腺相关病毒对应激性胶质细胞重编程并修复。结果显示，组织方面，ET-1使得皮层缺损，使应激性胶质细胞增生，神经元死亡，造成了典型的脑损伤现象；行为方面，ET-1造成了猕猴手部精细运动能力和下拉能力短暂的损伤。然后，利用病毒在皮层过表达NeuroD1，可以成功地将应激性胶质细胞转化成了神经元。而且，在感染了NeuroD1的损伤区域周围，胶质细胞应激程度低于对照组，神经元的形态，分布与对照组相比更接近于正常，神经元数量也显著多于对照组。所以，NeuroD1可能对于猕猴的缺血性脑损伤有修复作用。本研究表明，ET-1可以在猕猴组织上造成典型缺血性脑中风现象，行为上短暂地损伤猕猴手部的运动能力。NeuroD1可以将猕猴的应激性胶质细胞转化为神经元，并修复猕猴皮层的缺血性脑中风。由于猕猴与人大脑结构的相似性，本研究表明，在体重编程为未来对人类缺血性脑中风的临床治疗手段提供了新的思路。

Ischemic stroke is one of the most common neurological diseases in aged population. It is caused by insufficient blood supply to meet the metabolic need, leading to neuronal death and then dysfunction of relative brain areas. Stroke can cause behavioral deficits, such as difficulty in speaking, loss of motor coordination, or even paralysis. So far, current therapies including neurotrophic factor treatment, stem cell or neural tissue transplantation, and rehabilitation exercise are not very satisfactory, because these therapies can't work well due to immune rejection, potential tumorigenesis, or insignificant effect. Thus, we developed a novel method to treat stroke by regenerating new neurons with brain internal glial cells. Ischemic stroke belongs to brain injury. When brain gets injured, glia will get reactive and proliferate to form glial scar around the injury zone. We have demonstrated that reactive astrocytes can be in vivo reprogrammed directly into functional neurons inside mouse brains with NeuroD1, a vital transcriptional factor in neural development. Here, we used non-human primate macaque as animal model, and established ischemic stroke in the hand area in motor cortex with ET-1 (endothelin-1). Then, we used retrovirus and adeno-associated virus (AAV) as vectors of NeuroD1, to reprogram reactive glia into neurons and repair ischemic injury. We’ve found that ET-1 caused tissue loss, proliferation of reactive glia, neuronal death, which are the typical phenomenon of brain injury. We also found that ET-1 impaired the motor dexterity and grip force of macaque monkeys transiently. Then we found that NeuroD1 has successfully converted reactive astrocytes into neurons in cortex. Around the injury zone infected with NeuroD1, the reactivity of glia is lower than control group; the morphology and distribution of neurons are closer to normal tissue compared to control group; and the number of neurons is also significantly higher than the control group. Thus, NeuroD1 might repair ischemic brain injury of macaque monkeys. Our research showed that, ET-1 established historically significant ischemic stroke injury and behaviorally transient deficit of manual abilities on macaque monkeys. NeuroD1 can in vivo reprogram reactive glia into neurons and repair ischemic injury in the motor cortex of macaque monkeys. Because of the similarities in brain structure between macaque monkeys and human, Our research suggests that brain repair through direct in vivo reprogramming may lead to a novel clinical treatment for ischemic stroke.