肌萎缩侧索硬化症（Amyotrophic Lateral Sclerosis, ALS）是一种病因不详，缺乏有效治疗手段的严重致死性神经系统变性病。家族性ALS病例为研究其发病机制提供了极其重要的途径。最新发现VAPBP56S基因嵌入ALS小鼠模型成功出现了晚发型ALS的发病过程及病理特点，同时发现神经肌肉接头的形态变化，与临床VAPBP56S患者的疲劳不耐受现象相符。本研究拟通过VAPBP56S基因嵌入ALS小鼠模型，确定神经肌肉接头的形态学与血及肌肉组织中低密度脂蛋白受体相关蛋白4 (Low-Density-Lipoprotein Receptor-Related protein4,LRP4)抗体的关系。有助于寻找更多的ALS发病机制的理论依据和思路，为今后的治疗方向寻求新的靶点。

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with the dysfunction or death of motor neurons. Unfortunately, there is no effective therapy for this disease and its pathogenesis is poorly understood. The existence of inherited ALS cases has provided excellent inroads towards unraveling the molecular pathology of the motor neuron diseases. Recently the VAPB knock-in mice exhibit late-onset motor behavior defects as observed in the patients associated with the P56S VAPB. The VAPB knock-in mice also display many cellular pathological features implicated in ALS，as the changes of neuromuscular joints are coincident with the fatigue intolerance in the VAPBP56S ALS parients. This study propose to determine the relationship with the morphological changes of the neuromuscular junctions and LRP4 antibody. It will help us to find more theoretical basis and thoughts to the pathogenesis of ALS, to seek new targets for the future treatments.

国外发现VAPBP56S基因嵌入ALS小鼠模型成功出现了晚发型ALS的发病过程及病理特点，同时发现神经肌肉接头的形态变化，与临床VAPBP56S患者的疲劳不耐受现象相符。本研究已建立杂合性VAPBP56S 基因嵌入ALS 小鼠模型，因课题时间限制，未发现3月龄杂合性小鼠运动功能异常，继续饲养杂合性小鼠并观察小鼠的运动功能变化。取一只杂合性型小鼠的腓肠肌进行肌肉病理检查，未发现神经肌肉接头形态学数量异常。在此小鼠血中未发现LRP4抗体。