“RPS6-HSP90-RIP3”在冰毒/高热致大鼠皮质神经元程序性坏死中的调控研究

冰毒是全球泛滥的合成类毒品之一，冰毒使用者体温常快速升高。冰毒/高温协同作用对人体神经系统的危害巨大。冰毒除致瘾外，还能导致皮质神经元死亡，但具体机制不清楚。我们前期研究显示冰毒/高热诱导大鼠皮质神经元出现程序性坏死，可能与RIP3有密切关系，但其具体作用和更为上游的调控机制还值得深入探索。最新研究显示RPS6可能调控HSP90发挥稳定RIP3在程序性坏死的作用，我们前期研究也显示皮质神经元在冰毒/高热诱导下，RPS6和HSP90显著上调，且两者之间存在结合关系，因此我们推测“RPS6-HSP90-RIP3”通路在冰毒/高热致大鼠皮质神经元程序性坏死中发挥重要的调控作用。本项目拟通过形态学、分子生物学和细胞生物学等手段，利用体内/外两个层面来验证以上实验假设。本项目对揭示冰毒导致皮质神经元程序性坏死的机理以及如何挽救冰毒中毒（伴高热）者大脑皮质神经元程序性坏死的策略选择具有重要科学意义。

Methamphetamine is one of the synthetic drugs abused globe-widely, the temperature of methamphetamine abuser usually rises rapidly. Methamphetamine/hyperthermia synergistically cause a huge damage to human’s nervous system. Except from addiction, methamphetamine can lead to cortical neurons’ death, but the specific mechanism is still largely unclear. Our previous study showed that methamphetamine/hyperthermia can induce necroptosis, it may have a close relationship with RIP3, but its specific effect and upstream regulation mechanism worth exploring further. The latest study reported that RPS6 can stabilize HSP90 to make RIP3 exert its effect on necroptosis. Our previous study showed that the expression of RPS6 and HSP90 in rat cortical neurons induced by methamphetamine/hyperthermia increased significantly, and there existed interaction relationship between the two molecules using computerize simulation, therefore we speculate that “RPS6-HSP90-RIP3” pathway plays an important role in cortical neurons’ necroptosis induced by methamphetamine/hyperthermia. We plan to prove the hypothesis in the project by morphology, molecular biology and cellular biology using both in vivo and vitro experiment models. The project has important scientific significance to discover the mechanism of cortical neurons’ necroptosis and direct to save neurons’ necroptosis induced by methamphetamine/hyperthermia.