脑缺血引发死亡相关蛋白激酶1（DAPK1）迁移至突触外，与NMDA受体的NR2B亚单位结合，导致神经元死亡，但是其下游信号仍不清楚。先前的研究报道和我们的预实验表明：胞外信号调节激酶（ERK）可能是DAPK1的下游信号。因此，我们提出研究假设：在脑缺血时，DAPK1激活后与ERK结合，抑制ERK核转位，使ERK在胞浆聚集，从而导致神经元死亡。本项目利用我们已有的基因敲除小鼠并结合多种技术手段，拟进行以下研究工作：首先，研究DAPK1与ERK是否发生相互作用。其次，研究DAPK1对脑缺血时ERK核转位的影响。然后，在神经元胞核表达激活型ERK，探讨其对脑缺血所致神经元死亡的影响。最后，在神经元胞浆表达激活型ERK，探讨其对脑缺血所致神经元死亡的影响。本研究将为深入认识脑缺血损伤的发病机制和寻找新的分子靶标提供强有力的理论基础和实验依据。

Cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) in to the N-methyl-D-aspartate (NMDA) receptors NR2B protein complex. However, it is unknown that which is the downstream signaling of DAPK1. According to some previous reports and our preliminary studies, the extracellular regulated protein kinase (ERK) may be the downstream molecular of DAPK1. So, we hypothesize that activation of DAPK1 following the cerebral ischemia insult blocks ERK nuclear translocation, results in cytoplastmic accumulation of ERK and in turn induces neuronal death. By use of two lines of genetically modified mice (DAPK1-/- and cdDAPK1-/-) and other techniques we will carry a series of experiments to answer these following questions. (1) Does DAPK1 interact with ERK? (2) To determine if activation of DAPK1 blocks ERK nuclear translocation. (3) Dose nuclear accumulation of ERK in nuclear reverse the neuron death following the cerebral ischemia insult? (4) Is cytoplastmic accumulation of ERK responsible for ischemic neuronal death? This proposal will help us understand the mechanism of neuronal death following the cerebral ischemia, and find a novel molecular target for ischemic stroke therapy.