p38α介导巨噬细胞自噬缺陷诱导神经-肌肉接头炎性蜕变的分子机制

Amyotrophic lateral sclerosis (ALS) is a deadly progressive neurodegenerative disorder. Neuromuscular junction disassembly is the early step during the pathogenesis of ALS, and abnomal inflammation initiates this devastating event. Our recently studies identified that autophagy inhibition mediated by p38α polarized immune cells to M1 activation. Activation of p38α is significantly elevated in macraphages of ALS mouse model and ALS patients, and which is accompanied with autophagy impairment. Based on all of the above, we hypothesize that abmormal macrophage activation induced by p38α-mediated autophagy inhibtion leads to the degeneration of neuromuscular junction, which is very possibly a early step in ALS pathogenesis. We propose to investigate the roles of p38α inhibion or silence in modulation of the function of macrophage and protection of neuromuscular junction in both cellular and animal models of ALS. A positive outcome of this project will significantly advance our knowledge of the basic regulatory mechanism during early stage of ALS pathogenesis, identify useful biomarker for efficient diagnosis, and discover new therapeutic target.

肌萎缩侧索硬化症（ALS）为致命性神经退行性疾病，神经-肌肉接头蜕变是其始因，而异常免疫炎性反应是神经-肌肉接头蜕变的直接导火索。我们前期研究发现p38α介导的自噬抑制驱动免疫细胞炎性（M1）极化，ALS小鼠和病人巨噬细胞内p38α活化程度明显升高且伴随自噬缺陷。因此，我们推测p38α介导的自噬抑制诱导巨噬细胞异常炎性激活从而引起了神经-肌肉接头蜕变，该通路可能是导致ALS发生的早期原因。本研究拟采用ALS细胞和动物模型，通过p38α特异性抑制或增强，检测细胞和组织内自噬水平、自噬流和ROS产生，测定炎症小体的活化度与巨噬细胞的激活状态（M1/M2）。并通过神经元轴突变性、神经-肌肉接头蜕变的检测和模型小鼠运动功能评价，探讨p38α特异性抑制或沉默对巨噬细胞的调节和对神经-肌肉接头的保护作用，为ALS的临床治疗提供有效靶点。

肌萎缩侧索硬化症（ALS）为致命性神经退行性疾病，神经-肌肉接头蜕变是其始因，而异常免疫炎性反应是神经-肌肉接头蜕变的直接导火索。我们的研究发现p38α介导的自噬抑制驱动免疫细胞炎性（M1）极化，ALS小鼠和病人巨噬细胞内p38α活化程度明显升高且伴随自噬缺陷。我们进一步发现p38α介导的自噬抑制诱导巨噬细胞异常炎性激活从而引起了神经-肌肉接头蜕变，该通路是导致ALS发生的早期原因。本研究用ALS细胞和动物模型，通过p38α特异性抑制或增强，检测细胞和组织内自噬水平、自噬流和ROS产生，测定炎症小体的活化度与巨噬细胞的激活状态（M1/M2）。并通过神经元轴突变性、神经-肌肉接头蜕变的检测和模型小鼠运动功能评价，证实p38α特异性抑制或沉默对巨噬细胞的调节和对神经-肌肉接头的保护作用，为ALS的临床治疗提供了新的有效靶点。