酸中毒在I/R损伤神经元迟发性死亡(DND)中具有重要意义，钠/碳酸氢根共转运体（NBCs）可通过“pH调控性钠内流”导致“钙稳态”失衡。前期研究发现PIP2可直接激活NBCe1-A(PNAS, 2009), 对NBCe1-B/C则需IP3/[Ca2+]下游某些激酶参与（J Physiol， 2012），最近观察到ITPKA激酶的作用，并确认IP4为激活终产物；同时I/R损伤后CA1神经元NBCe 电流异常增强。IP4可竞争PIP3下调PI3K/AKT活性，抑制细胞抗凋亡/自噬机制，而ITPKA的激活则需要PI3K/AKT参与。我们推测这种交互调控在激活NBCs、引起“钙稳态”失衡并触发细胞死亡中具有重要意义。本申请拟通过研究上述途径及“钙稳态”失衡在I/R损伤中的意义，探讨NBCs抑制剂在预防海马DND中的价值，为预防和治疗缺血性心脑血管疾病寻找新的切入点。

Metabolic acidosis plays a key role in ischemia reperfusion (I/R) induced hippocampus neuron delayed neuronal death (DND), while its detail mechanism remains obscure. We demonstrated that PIP2 activated NBCe-A directly and NBCe-B/C through a IP3/Ca2+ mediated mechanism. Recently we identified that IP4, a 3-position phosphorylated IP3 derivate by IP3-3 Kinase A (ITPKA), was an effective activator of NBCe-C，and I/R augmented NBCe currents in hippocampus CA1 neurons. IP4 negatively regulated PI3K/AKT by competing with PIP3 binding, which reduced the capacities for cell to against apoptosis /autophagy, meanwhile the activation of ITPKA requires PI3K/AKT. We hypothesis that ITPKA/IP4 and PI3K/AKT signal pathways interactively regulating NBCe might contribute to sodium over influx and calcium homeostasis imbalance during brain I/R injury. Blockage of NBCs would protect neuron from I/R injury. The results of the proposed studies will enhance our understanding of NBCs and other NBCBTs in the CNS following ischemia. This knowledge will be beneficial for developing a more effective approach to stroke treatment.