肌萎缩侧索硬化症(ALS)是一种运动神经元变性疾病，确切发病机制尚不清楚，无有效治疗方法。课题组前期发现，ALS转基因鼠发病中经典Wnt信号通路与运动神经元退变密切相关。经典与非经典Wnt通路构成复杂的信号网络，Wnt5a是联系两者的关键分子。预实验发现，沉默Wnt5a可抑制经典Wnt信号通路，降低运动神经元活力。Wnt5a调控Wnt信号网络参与运动神经元变性的机制尚不明确。本项目选取SOD1-G93A突变型ALS转基因鼠及NSC34细胞模型，探讨Wnt5a对经典及非经典Wnt信号通路的调控；体外干预Wnt5a，探讨其介导的Wnt信号网络对运动神经元变性的影响，明确其与不同Wnt受体的相互作用；体外阻断相应受体，阐明Wnt5a介导的Wnt信号网络在运动神经元变性中的分子机制；靶向调控Wnt5a及其受体，延缓ALS鼠运动神经元变性，增强对运动神经元的保护作用，为寻求ALS有效治疗提供新思路。

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motorneuron degeneration. The pathogenesis is unclear, and there is no effective treatment. Our previous data showed that activation of canonical Wnt signaling pathway was associated with ALS process. Wnt5a plays a regulatory role in the crosstalk between canonical and non-canonical Wnt signaling pathway. We found that knocking down of Wnt5a could inhibit the expression of canonical signaling molecules in ALS cell model and attenuate motorneuron survival. However, the mechanism of such role still remain unknown. In this project, firstly, we will investigate the regulation of Wnt5a in the interaction of canonical and non-canonical Wnt signaling pathway by using SOD1G93A transgenic ALS mice and SOD1G93A mutation NSC34 cell model. Secondly, we will determine the influence of Wnt5a-mediated Wnt signaling on motorneuron degeneration by interfering with the expression of Wnt5a in ALS cell model. Thirdly, we will detect the interaction of Wnt5a with different receptors in vivo and in vitro, and clarify the molecular mechanism of Wnt5a in the neural degeneration by blocking the receptors. Finally, we will examine whether or not targeted-regulation of Wnt5a and its receptors delay the neural degeneration in ALS mice, whereby protecting the motorneurons, which may provide new therapies for ALS.