On the Crucial Cerebellar Wound Healing-Related Pathways and Their Cross-Talks after Traumatic Brain Injury in <i>Danio rerio</i>

Upon injury, the direct damage and the subsequent secondary injury in the brain often result in chronic neurological disorders. Due to multifactorial nature of secondary injury and subsequent complex cellular responses, much of the underlying mechanisms are unclear. This study used an adult zebrafish cerebellum injury model to investigate the phenotypes and the secondary injury responses for recovery mechanisms of injured brain. Using the time course microarray analysis, a candidate protein-protein interaction (PPI) network was refined as cerebellar wound healing PPI network by dynamic modeling and big data mining. Pathway enrichment and ontological analysis were incorporated into the refined network to highlight the main molecular scheme of cerebellar wound healing. Several significant pathways, including chemokine, Phosphatidylinositide 3-kinases, and axon guidance signaling pathway and their cross-talks through PI3K, PAK2, and PLXNA3 were identified to coordinate for neurogenesis and angiogenesis, which are essential for the restoration of the injured brain. Our finding provides an insight into the molecular restoration mechanisms after traumatic brain injury, and open up new opportunity to devise the treatment for traumatic brain injury in human.颅脑遭受创伤后，直接损伤与后续引发的继发性损伤往往会导致慢性神经功能障碍。由于继发性损伤具有多因素特性，且伴随复杂的细胞应答过程，其诸多潜在分子机制至今仍未明确。本研究采用成年斑马鱼小脑损伤模型，探究受损大脑的恢复机制相关表型与继发性损伤应答。通过时序基因芯片分析，结合动态建模与大数据挖掘，本研究从候选蛋白质-蛋白质相互作用（protein-protein interaction, PPI）网络中筛选得到小脑伤口愈合PPI网络。将通路富集分析与本体论分析整合至该精修网络中，以揭示小脑伤口愈合的核心分子调控机制。研究鉴定出包括趋化因子通路、磷脂酰肌醇3-激酶通路、轴突导向信号通路在内的多条关键通路，以及它们通过PI3K、PAK2和PLXNA3介导的交叉串扰；这些通路共同协调神经发生与血管生成，而二者是受损大脑修复的关键环节。本研究成果为创伤性脑损伤后的分子修复机制提供了全新认知视角，也为人类创伤性脑损伤的治疗方案开发开辟了新的机遇。