CSF1通过CSF1R/PLCG2/ERK/Nrf2信号通路减轻缺血缺氧性脑病后氧化应激及神经元损伤的作用机制研究

氧化应激诱导神经元损伤是缺血缺氧性脑病（HIE）后神经功能缺损的重要病理过程。我们前期研究发现集落刺激因子-1（CSF1）通过CSF1受体（CSF1R）介导减轻HIE后氧化应激损伤，PLCG2作为CSF1R下游基因，在HIE后发生表达变化，然而其具体分子生物学机制不清。据此我们推测，CSF1可能通过CSF1R/PLCG2/ERK/Nrf2信号通路减轻HIE后氧化应激损伤。为验证这一假说，本项目首先建立缺糖缺氧（OGD）神经元损伤模型，给予重组CSF1干预该模型，通过检测线粒体结构、功能及氧化应激的相关指标，观察CSF1减轻OGD诱导神经元损伤的作用机制。再建立HIE动物模型，应用基因沉默技术调控目标基因，观察CSF1干预后HIE模型的脑梗死面积及神经行为学变化，氧化应激及神经元损伤的程度。本研究将阐述CSF1在HIE后发挥神经保护作用的分子生物学机制，为HIE治疗提供新思路和理论依据。

Oxidative stress-induced neuronal injury plays important roles in the pathogenesis of neurological deficits after hypoxic-ischemic encephalopathy (HIE). Our preliminary study found that colony stimulating factor -1 (CSF1) mediated by CSF1 receptor (CSF1R) alleviates oxidative stress damage after HIE, and PLCG2, as a downstream molecule of CSF1R, was expressed after HIE. However, the specific molecular biological mechanism remains unclear. Therefore, we speculate that CSF1 can attenuate oxidative stress damage after HIE via the CSF1R/PLCG2/ERK/Nrf2 signaling pathway. In order to verify this hypothesis, a model of oxygen and glucose deprivation (OGD) neuronal injury will be firstly constructed in this project and the administration of recombinant CSF1 will be given to interfere with this model. We will observe the underlying mechanism of CSF1 reduces OGD-induced neuronal injury by assessing the relevant indicators of mitochondrial structure, function and oxidative stress. Secondly, in an animal model of HIE, we will assess cerebral infarction area, neurobehavioral changes, neuronal damage, and oxidative stress after CSF1 intervention by using the method of gene silencing regulating the target gene. This study will elucidate the molecular biological mechanism of the neuroprotective effect of CSF1 after HIE, which provides new idea and preclinical basis for improving the prognosis of HIE.