基质金属蛋白酶9对BBB/BSCB的破坏是肌萎缩侧索硬化症的重要炎性机制

项目名称： 基质金属蛋白酶9对BBB/BSCB的破坏是肌萎缩侧索硬化症的重要炎性机制

项目编号： No.81501030

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张敏

作者单位： 华中科技大学

项目金额： 17.5万元

中文摘要： 肌萎缩侧索硬化症（ALS）是一种具有炎性机制的致死性神经系统变性疾病，目前尚无有效治疗手段。近年来研究发现ALS患者及模型动物中普遍存在血脑屏障（BBB）、血脊髓屏障（BSCB）破坏现象。我们预实验发现具有破坏BBB/BSCB功能的基质金属蛋白酶9（MMP-9）在SOD1-G93A小鼠脑和脊髓组织中增高，主要高表达于小胶质细胞和血管内皮细胞，抑制MMP-9表达可改善症状和BBB/BSCB功能。进一步研究提示，MMP-9在ALS中还高表达于外周骨髓细胞。因此我们设想：ALS中外周骨髓细胞通过高表达MMP-9破坏BBB/BSCB，进入脑和脊髓成为小胶质细胞，释放炎性细胞因子，促发运动神经元凋亡。本项目将进一步揭示小胶质细胞-BBB/BSCB-MMP-9三者间复杂互动的相互关系，深入发现 ALS中的炎症机制，为ALS的治疗提供新的途径。

中文关键词： 基质金属蛋白酶；小胶质细胞；血脑屏障；肌萎缩侧索硬化

英文摘要： Amyotrophic lateral sclerosis(ALS) is a fatal neurodegenerative disease with some inflammatory mechanisms. By now, it has no effective treatments to cure, no methods to relieve symptoms or prolong survival time. Recent studies have found blood-brain barrier(BBB) and blood-spinal cord barrier（BSCB）breakdown in ALS patients and animals. In our preliminary experiments, we found that matrix metalloproteinase 9 (MMP-9), which has the ability of destroying the BBB/BSCB, could be detected in the brain and spinal cord of SOD1-G93A mouse, especially highly expressed in microglials and vascular endothelial cells. We also observed that inhibition of MMP-9 in SOD1-G93A mouse could relieve the symptoms and protect BBB/BSCB. Another researches suggest that in ALS, MMP-9 is also highly expressed in bone marrow cells. So we would assume that in ALS, bone marrow cells may destroy BBB/BSCB by MMP-9, enter the central nervous system and turn into microglia, then promote motor neuron apoptosis by releasing inflammatory cytokines. The project will further reveal the relationships and interactions among microglia-BBB/BSCB-MMP-9, discover some other inflammatory mechanisms in ALS, and offer a new approach for the treatment of ALS.

英文关键词： matrix metal oproteinases;microglia;blood-brain barrier;amyotrophic lateral sclerosis