内质网应激（ERS）相关性钙离子紊乱和细胞程序性坏死参与了缺血/缺氧性脑病（HIE）的发生，但目前尚不清楚ERS相关性细胞内钙紊乱是否通过调节细胞程序性坏死途径参与HIE。本课题组前期研究发现：HIE后给予内质网钙离子受体RyR抑制剂能降低HIE鼠脑内程序性坏死相关蛋白的表达并改善神经功能；氦气预处理（HePC）具有类似的生物学效应，即接受HePC的动物脑内磷酸化RyR表达及胞浆Ca2+显著下降。基于以上研究，我们推测HePC可能通过影响内质网钙平衡从而抑制神经元程序性坏死达到神经保护作用。为了验证此假说，本课题拟针对内质网钙受体（IP3R和RyR）以及钙信号关键分子CaMKII，从整体、细胞和分子水平研究ERS相关性细胞内钙变化对HIE神经元程序性坏死的调节作用；并进一步探讨HePC是否通过调节内质网钙平衡来抑制细胞程序性坏死从而保护神经。本研究将为HePC神经保护提供理论基础和依据。

Necroptosis, cytoplasmic calcium imbalance and endoplasmic reticulum stress (ERS) are involved in the pathogenesis of hypoxic-ischemic encephalopathy (HIE). Our previous studies have confirmed the neuroprotective effects of helium pre-conditioning (HePC) on HIE in a neonatal rat model. It is still unclear that whether ERS induced intracellular calcium imbalance may regulate necroptosis and whether the neuroprotective effects of HePC are ascribed to the regulation of endoplasmic reticulum related calcium balance and necroptosis. Our pilot study showed HePC or treatment with ryanodine receptor (RyR) after HIE can reduce the expression of necroptosis related key proteins in the brain of HIE rats and improve the neurofunction; HePC can reduce the expression of phosphorylated RyR and intracellular calcium in the brain. This study aimed to investigate (1) whether and how the change in ERS related intracellular calcium regulates neuronal necroptosis at cellular level; (2) whether HePC is able to regulate the endoplasmic reticulum related calcium balance and then inhibit neuronal necroptosis to exert neuroprotective effects by focusing two key proteins (inositol 1,4,5-trisphosphate receptor [IP3R] and RyR) related to the regulation of calcium release in endoplasmic reticulum and a protein in calcium signaling pathway (Ca2+/calmodulin-dependent protein kinase II [CaMKII]). Our findings will further elucidate the mechanism underlying the neuroprotective effects of HePC, and provide a new target for the treatment of HIE.