Jagged1-Notch/Akt信号通路调控星形胶质细胞和内皮细胞相互作用影响颞叶癫痫发生的机制研究

颞叶癫痫（TLE)极易发展成为药物难治性癫痫，深入阐明其发病机制是改善其预后的关键。反应性星形胶质细胞介导的血脑屏障功能失调是TLE发生和发作的重要原因。本课题组前期在KA诱导的TLE模型中证实，星形胶质细胞与内皮细胞间的Jagged-Notch1通路激活并参与调控病理性血管增生。此外，Notch1下游PI3K-Akt的激活可能与该调控过程密切相关。由此，我们推测在颞叶癫痫进程中，星形胶质细胞与内皮细胞间的Jagged1-Notch/Akt通路激活，触发病理性血管增生，导致血脑屏障功能失调，神经元微环境破坏，从而引起癫痫反复发作逐步形成耐药癫痫。本项目拟采用特异性基因敲除、腺病毒RNA干扰等分子生物学方法，在体内和体外探讨阻断Jagged1-Notch/Akt通路对血管新生和血脑屏障完整性改变的影响，及下游靶基因表达，进一步阐明癫痫发生的机机制，为实现癫痫的针对性防治提供新靶点。

Temporal lobe epilepsy is likely to develop into drug-refractory epilepsy. Further elucidation of the pathogenesis is essential to improve the prognosis of epilepsy. Reactive astrocyte-mediated dysfunction of the blood-brain barrier is an important cause of epileptogenesis and seizures. Our pre-study found that the Jagged1-Notch1 pathway is activated and regulates pathological angiogenesis during temporal lobe epilepsy in a TLE model induced by Kaicic Acid. Furthermore, activation of PI3K-Akt downstream of Notch1 may be closely related to this regulatory process. On this basis, we put forward the hypothesis: In the process of temporal lobe epilepsy, the Jagged1-Notch/Akt pathway is activated between astrocytes and endothelial cells, triggering pathological vascular proliferation, leading to dysfunction of the blood-brain barrier and destruction of neuronal microenvironment, leading to recurrent seizures. Forming drug-resistant epilepsy. Using gene Targeted knock-out ，RNA interfering technology,we will further study the effects of blocking the Jagged1-Notch/Akt signaling pathway on astrocyte proliferation, angiogenesis ,BBB integrity, activation levels of the Akt signaling pathway and its key regulatory molecules both in vitro and in vivo. Further elucidating the mechanism of epileptogenesis provides new targets and new strategies for targeted prevention and treatment of epilepsy.