创伤性脑损伤后昏迷是困扰临床的重要问题，机制不清。研究表明，食欲素作用于蓝斑神经元OX1R受体在觉醒维持中发挥重要作用。我们预实验显示：蓝斑神经元细胞膜上OX1R受体减少可能是介导创伤性脑损伤后昏迷的重要机制。研究表明：靶蛋白的棕榈酰化参与细胞内蛋白的分选与运输。我们发现：昏迷大鼠蓝斑δ-catenin的棕榈酰化水平及δ-catenin与OX1R的结合均显著下降，而抑制正常大鼠蓝斑δ-catenin的棕榈酰化后细胞膜上OX1R也明显减少。我们还发现：转录因子Pax2与棕榈酰化转移酶DHHC5基因启动子区的结合下调可能是介导δ-catenin棕榈酰化水平改变的机制。本项目将：1）明确蓝斑OX1R受体膜上转运降低在创伤性脑损伤后昏迷中的作用；2）探讨δ-catenin棕榈酰化的改变介导OX1R细胞膜上转运；3）探讨Pax2调控DHHC5转录表达的机制。为治疗创伤性脑损伤后昏迷提供潜在靶点。

Coma after traumatic brain injury is an important clinical problem, but the mechanism remains unclear. Studies have shown that orexin plays an important role in the maintenance of arousal by acting on the OX1R receptor of locus coeruleus neurons. Our preliminary experiments showed that the decrease of OX1R receptor on the cell membrane of locus coeruleus neurons is an important mechanism mediating coma after traumatic brain injury. Studies have shown that palmitoylation of target proteins is involved in the separation and transport of intracellular proteins. We found that the level of palmitoylation of δ-catenin and the binding of δ-catenin to OX1R in locus coeruleus significantly decreased in comatose rats. The level of OX1R on cell membrane decreased significantly after inhibiting the palmitoylation of δ-catenin in locus coeruleus of normal rats. We also found that down-regulation of the binding of transcription factor Pax2 to the promoter region of palmitoyltransferase DHHC5 may be a mechanism mediating the change of δ-catenin palmitoylation level. This project will: (1) clarify the role of decreased transport of OX1R receptor on locus coeruleus in coma after traumatic brain injury; (2) explore the role of δ-catenin palmitoylation in mediating transport of OX1R to cell membrane; and (3) explore the mechanism of Pax2 regulating DHHC5 transcription and expression, to provide potential targets for the treatment of coma after traumatic brain injury.