GIP/GIPR促进周围神经损伤修复的效应及机制研究

神经损伤造成局部缺血缺氧微环境，神经细胞如何调节代谢状态，适应损伤微环境并提高再生能力是一个未受到足够重视的重要科学问题。抑胃肽GIP是葡萄糖依赖的调节胰岛素分泌的肠肽，近年研究表明GIP及受体GIPR同样也表达于神经系统，并且GIPR敲除小鼠神经损伤修复能力受损，但其机制不明。我们前期发现GIP显著促进轴突生长，且明显增强了细胞糖酵解。因此推测：神经损伤因素可以激活GIP/GIPR信号通路，调整细胞代谢状态，适应微环境并促进再生。本研究将探讨：①坐骨神经损伤后神经元及施万细胞中GIP/GIPR的时空表达模式以及对神经损伤修复的效应；②GIP/GIPR对施万细胞代谢状态的影响和机制，以及对轴突再生的效应；③GIP是如何被诱导的，重点研究损伤诱导的施万细胞来源的SHH如何调节GIP/GIPR通路并适应代谢微环境的机制。本研究将为周围神经损伤修复提供代谢调节和代谢微环境角度的新机制

The nerve injury results in hypoxic and ischemic microenvironment. How neural cells adapt the metabolic challenge and improve the regenerative capacity is an important issue that has not been well addressed. Gastric inhibitory peptide (GIP) is synthesized in and secreted from K cells in the intestinal epithelium, which stimulates insulin secretion in glucose dependent manner. Recent studies revealed that GIP/GIPR presented in nervous system as well, and GIPR knockout mice showed impaired ability for repair of nerve injury. However, the underlying mechanism is elusive yet. In our previous study, we found that GIP increased axonal growth and augmented glycolysis significantly. Therefore, we proposed that GIP/GIPR could modulate metabolic state of neural cells to adapt injury microenvironment and facilitate regeneration. In this study, we first investigate temporal and spatial expression pattern of GIP/GIPR in sciatic nerve injury model, and elicit the effect of GIP/GIPR augment or attenuation on repair of periphery nerve injury. Then, we investigate how GIP/GIPR modulate metabolic state of Schwann cell and how GIP/GIPR improve axon regeneration. Finally, we aim to address whether and how Schwann cell derived sonic hedgehog (SHH) regulate GIP/GIPR signal axis and adopt microenvironment challenge during periphery injury. This study will provide a mechanistic insight of nerve regeneration on the view of metabolic regulation.