宫内炎性暴露致早产小鼠脑白质神经血管单元损伤机制及fgl2分子靶向干预

项目名称： 宫内炎性暴露致早产小鼠脑白质神经血管单元损伤机制及fgl2分子靶向干预

项目编号： No.81471519

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 罗小平

作者单位： 华中科技大学

项目金额： 75万元

中文摘要： 宫内感染/炎症所致脑白质损伤是影响早产儿神经系统发育的重要危险因素，可引起癫痫、脑瘫等严重后遗症，甚至直接威胁患儿生命。目前炎症导致脑白质损伤的具体机制尚不明确，对脑白质损伤仍无有效的防治手段。申请者前期研究发现纤维蛋白原样蛋白2凝血酶原酶(fgl2)在LPS刺激的大鼠脑组织中表达增加，并参与小胶质细胞活化相关的炎性反应。本项目拟在建立小鼠宫内炎性暴露致脑白质损伤模型的基础上，利用免疫荧光染色、磁共振弥散张量成像、磁共振波谱和双光子共聚焦等技术观察fgl2在早产鼠脑组织神经血管单元相关组份的表达以及各组份的损伤情况；采用fgl2-/-基因敲除小鼠抑制fgl2的表达，研究其可能的保护作用和相关信号转导通路；通过离体白质损伤实验进一步研究fgl2在LPS诱导的脑血管内皮细胞氧化应激和小胶质细胞炎性反应中的作用。探讨脑白质损伤的发病机制及分子靶向干预，为安全有效的防治早产儿脑白质损伤提供新策略。

中文关键词： 宫内感染；脑白质损伤；神经血管单元；纤维蛋白原样蛋白2；基因敲除

英文摘要： Intrauterine infection/inflammation-induced white matter injury (WMI) is an important risk factor for nervous system development in preterm infants, which may lead to severe neurological sequela such as epilepsies and cerebral palsy, and even cause direct mortality of infants. However, the molecular mechanism by which inflammation leads to WMI remains unclear, and until now there is no effective way to prevent or treat WMI. Our previous researches have found that the expression of fibrinogen-like protein 2 prothrombinase (fgl2) was increased in the LPS-stimulated rat brain, which was involved in the activated microglia-related inflammatory response. In the present study, after establishing a mouse model of intrauterine inflammation-induced WMI, we observe fgl2 expression in the preterm neonatal neurovascular unit and its associated injuries using immunofluorescence staining, DTI, MRS and two-photon confocal microscopy etc.. We then inhibit fgl2 expression by using fgl2 knockout mice to investigate potential protective effects on the components of the neurovascular unit in the white matter as well as the target cells and related signaling pathways. Further more, we try to understand the role of fgl2 in the LPS-induced oxidative stress of cerebrovascular endothelial cells and the inflammatory response of microglia in ex vivo white matter injury model. Studying the pathogenic mechnism and molecule-targeted intervention of WMI, may provide new strategies for a safe and effective therapeutic precept of WMI in preterm infants.

英文关键词： intrauterine infection;cerebral white matter injury;neurovascular unit;fgl2;knockout animal