星型胶质细胞上调基因-1（AEG-1）在肌萎缩侧索硬化（ALS）星型胶质细胞中的作用及其相关机制研究

肌萎缩侧索硬化（ALS）是一种涉及多重病理机制的神经退行性疾病，尚无有效治疗方法。星型胶质细胞在ALS神经元死亡中发挥重要作用，其中，神经炎性反应与兴奋性氨基酸毒性是其介导神经元死亡的重要途径。星型胶质细胞上调基因-1（AEG-1）恰与上述两个途径密切相关，但其在ALS中所发挥的作用尚不清楚。本课题组前期工作发现ALS运动神经元中AEG-1低表达与其退行性死亡密切相关，进一步研究提示ALS星型胶质细胞中AEG-1表达水平上调。因此我们以hSOD1G93A转基因小鼠及原代星型胶质细胞为实验对象，研究AEG-1在ALS星型胶质细胞介导的炎性反应及兴奋性毒性的作用，通过神经元-星型胶质细胞共培养探究其对神经元存活的影响，并靶向沉默ALS小鼠星型胶质细胞中AEG-1，研究其对ALS小鼠的影响。对阐明AEG-1在ALS星型胶质细胞介导的神经毒性机制有重要意义，并可能为ALS的干预提供新的靶点。

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease currently without effective therapy. The mechanisms of ALS are complicated. Astrocytes-mediated neuroinflammation and excitotoxicity play critical roles in triggering and sustaining the pathogenses of ALS. Astrocyte elevated gene-1(AEG-1) has been reported to be closely related to the above pathological processes. However, the exact role of AEG-1 in ALS is still unclear. In our previous work, we found that AEG-1 was crucial for the survival of motor neurons in the presence of mutant SOD1. We also found that AEG-1 was upregulated in the astrocytes of ALS mouse model. Based on these findings, we aim to investigate the role of AEG-1 in regulating the activation of astrocytes and gliosis and the abnormality of glutamate transportation in astrocytes by using hSOD1G93A transgenic mice and cultured astrocytes from the transgenic mice. Neuron-astrocyte co-culture, targeted gene silencing and overexpression in vitro and in vivo will be applied in our study to explore the inflammatory and excitotoxic role of AEG-1 in ALS. We hope that this study will provide new therapeutic target for ALS.