ET-1介导的Jagged1/Notch1通路激活在肌萎缩侧索硬化中的作用和机制研究

胶质细胞在肌萎缩侧索硬化（ALS）神经元变性过程中起重要作用。研究表明反应性星形胶质细胞表达endothelin-1（ET-1）增多，并可能与Jagged1-Notch1通路激活有关，但其在ALS中的作用尚不明确。我们前期研究表明，ALS小鼠脊髓ET-1表达显著升高，同时伴Jagged1高表达及Notch1激活。更为重要的是，我们创新性地发现Jagged1表达主要位于小胶质细胞（而非星形胶质细胞），提示小胶质细胞可能在ET-1介导的Notch1通路激活中起关键作用。本课题拟通过AAV介导的在体转基因干预及细胞特异性Jagged1失活等手段，研究星形胶质细胞ET-1在ALS发病中的作用，及其通过小胶质细胞Jagged1介导Notch1通路激活，导致少突胶质前体细胞分化异常及髓鞘再生障碍、星形胶质细胞增生、神经元变性的分子机制，为深入揭示ALS新型发病机制并寻找潜在干预靶点提供理论依据。

Glial cells play a pivotal role in neuron degeneration of ALS. It was reported that endothelin-1 expression was increased in reactive astrocytes and might be related to the activation of Jagged1-Notch1 pathway. However, the role of astrocytic endothelin-1 in ALS is unknown. Our prophase studies showed that ET-1 expression was dramatically increased in the spinal cord of ALS mice, accompanied by high expression of Jagged1 and activation of Notch1. More importantly, we innovatively discovered that Jagged1 was mainly expressed in microglia, not astrocytes, indicating that microglia may play a vital role in the ET-1 mediated Notch1 pathway activation. This project will use adeno-associated virus mediated in vivo transgene intervention, cell-specific Jagged1 ablation to clarify the role of astrocytic ET-1 in ALS and its molecular mechanisms of causing oligodendrocytic differentiation and remyelination disorders, astrocytic proliferation, and neurodegeneration through microglial Jagged1 activated Notch1 pathway. The implementation of this project will provide theoretical basis for the reveal of novel ALS mechanisms and potential intervention targets.