激活内源性神经发生构建功能性神经网络修复猴脊髓损伤机制研究

Spinal cord is the important hub linking brain and the peripheral nervous system. The networks in the spinal cord are composed of ascending and descending fiber tracks and inter-neurons, and they are mainly involved in the modulation of body sensory and motor functions. Now, the difficult point of the restoration after spinal cord injury (SCI) is the fact that the injured micro-environment is hostile and unfavorable for neuronal regeneration and axonal extending. Our group report for the first time in the world that bioactive material scaffold can active endogenous neural stem cells (NSCs) of adult rat, and promote migration, proliferation and differentiation into functional mature neurons, and finally integrate in the host neural circuits and improve the behavior recovery after SCI. This finding provides the novel strategy for SCI treatment. For the further advance of clinical application and improvement of regeneration quantity, we intend to modify and optimize the biomaterial scaffold to bridge the long-distance lesion (20mm) gap of thoracic cord in the rhesus monkey. Meanwhile, we will investigate the mechanism of newly regenerated networks in the injured area, including the origin and types of newly-born neurons, the connection with the specific brain nuclei and corticospinal tracts and so on. Reveal the key gene expression and molecular regulation pathways during the spinal cord regeneration induced by biomaterials, clarify the molecular mechanism on endogenous neurogenesis.of adult monkey induced by biomaterials. This will provide the theoretical basis for the application of biomaterial scaffold to activate endogenous neurogenesis and rebuild the neural network after the adult monkey SCI. Bring the new method for the clinical treatment.

脊髓是联络大脑和周围神经系统的重要枢纽。脊髓神经网络由上下行走的神经束和中间神经元构成，主要参与调控机体的多种运动和感觉功能。脊髓损伤修复的难点在于损伤局部的微环境不利于神经元再生和轴突的延伸。本团队在国际上首次报道生物材料支架可激活成年大鼠内源性神经干细胞迁移至损伤区、增殖分化为成熟神经元且整合到宿主的神经环路中，功能得到部分恢复，为脊髓损伤的治疗提供了新的思路。为推进临床应用，进一步提高再生质量，拟对支架材料进行修饰与优化，移植修复猴胸髓长距离（20mm）缺损；深入剖析损伤局部新生神经网络形成，包括新生神经元的来源、类型、与大脑特定核团及皮质脊髓束等之间的功能联系；揭示材料诱导脊髓再生过程中关键基因表达及分子调控通路，阐明材料诱导成年猴内源性神经发生的分子机理。为生物材料支架激活内源性神经发生重建神经网络修复成年猴脊髓损伤提供理论依据,为临床治疗脊髓损伤开创新的方法。

本项目在前期研究的基础上，将自主研发的生物活性材料修复移植至脊髓损伤区内，通过向损伤局部缓慢且长久释放营养因子，改善损伤局部微环境，诱导内源性神经干细胞分化为神经元，新生神经元和宿主脊髓组织建立起功能性神经网络。.生物活性材料可促进成年恒河猴脊髓损伤后损伤区内新生神经元的产生及皮质脊髓束轴突的长距离再生，再生的轴突跨越损伤区到达损伤区的远端；大体电生理、fMRI和步态分析结果共同显示生物活性材料可以促进脊髓损伤后感觉和运动功能的恢复。.本项目深入地探究了新生神经元的来源，并系统地鉴定了损伤部位新生神经元的神经元亚型，确定了新生神经元可以接收来自大脑多个区域的突触连接，揭示了损伤部位局部脊髓神经环路的重建情况，并证明了损伤平面下方的神经环路仍具有可塑性。.首次证明生物活性材料可通过诱导内源性新生神经元产生，重建脊髓上排尿反射神经环路，使下尿路重获脊髓上控制；其诱导的新生神经元可整合到排尿反射神经环路中，重连控制下尿路的脊髓低级中枢和脊髓上脑高级中枢；同时证明了新生神经元在膀胱功能恢复中的重要作用。.同时我们的研究表明：生物活性材料是通过抑制损伤局部的炎症反应、促神经发生和促血管形成的细胞分子机制达到修复脊髓损伤的目的。.本项目的研究成果为脊髓损伤开创了全新的方法，为患者的临床治疗带来了希望。