脑卒中严重危害人民身体健康，药物研发失败的重要原因之一是病理机制未被充分阐明。课题组前期研究显示，抑制糖酵解关键酶己糖激酶2（hexokinase 2, HK2）可有效减轻急性缺血性脑卒中模型的脑损伤，小胶质细胞激活依赖于HK2上调表达，HK2介导了IL-1β表观调节，证明小胶质细胞HK2导致了炎性脑损伤。并不清楚HK2是否对神经元也产生直接损伤作用，这对于回答“被激动的糖酵解关键酶是否通过代谢以外的功能，参与了缺血性脑卒中脑损伤过程”这一问题非常重要。预实验发现缺氧引起HK2选择性神经元核分布，本项目拟选择性在神经元敲除HK2，并应用体内外脑卒中模型，确证HK2对神经元的直接损伤作用，并探讨缺氧等病理因素诱导HK2核分布、和hnRNP K相互作用，激活促神经元凋亡转录因子EGR-1的分子机制。项目有望阐明HK2以转录调节为特征的神经元损伤新效应，为研发靶向HK2的脑卒中治疗药物提供依据。

The cerebral stroke is harming the health of the people seriously, and its not fully illustrated pathological mechanism is one of reasons for the failure in the drug research and development. In our previous study, we found that the inhibition of hexokinase 2 (HK2), a glycolytic key enzyme whose upregulation dependently was required by activation of microglia, efficiently attenuated the brain injury caused by acute ischemic stroke in rat model via an epigenetic regulation for IL-1β, indicating the vital role of specific microglial HK2 in neuroinflammatory damage of brain. Currently it’s not fully demonstrated that if HK2 cause the injury to neurons directly, which is required to answer the question of that if the activated glycolytic key enzymes during the stroke is involved in cerebral damage via a pathway other than their metabolic functions. Basing on our previous study of selective the nuclear redistribution of HK2 in neuron induced by hypoxia, we aim to illustrated the direct damage effects of HK2 in neurons by a specific neuronal HK2 knockout using in vitro and in vivo model of ischemic stroke, and explore the possible mechanism of activating the pro-apoptosis transcript factor of Egr-1 by the nuclear redistribution of HK2 and its interaction with hnRNP K induced by pathological factors including hypoxia. Our study hope to uncover the novel role of HK2 in neuronal injury via a pathway characterized by transcriptional regulation, which providing the experimental data for the research and development of drug targeting HK2 for cerebral stroke.