4E-BP1介导的翻译异常在局灶性皮质发育不良及相关癫痫中的作用和机制研究

Focal Cortical Dysplasia (FCD) is a congenital abnormality of brain development and is highly associated with medically intractable epilepsy. Neuronal dysmorphogenesis and migration deficit are considered as the cellular abnormalities of FCD. However, the pathogenesis remains to be defined, although hyperactive mTOR signaling has been implicated in mediating cellular and molecular changes of FCD. Our previous studies revealed that focally increasing mTOR activity led to accelerated axon growth, which can be prevented by decreasing cap-dependent translation through 4E-BP1. Therefore, we infer that overactive cap-dependent translation through 4E-BP1 may be an important molecular mechanism of FCD. This project has developed a new FCD epilepsy model and we have noticed that convulsive seizures of this model were rescued by inhibiting translation through 4E-BP1. Next we will explore the pathological mechanism of FCD; furthermore, by using the novel translating ribosome affinity purification (TRAP) methodology with sequential Microarray technology, this project will uncover the translation profile and identify specific molecular targets of FCD. In conclusion, this project will provide a powerful resource for understanding the molecular program driving FCD and offer additional molecular targets for FCD and epilepsy treatment.

局灶性皮质发育不良（FCD）是一种先天性大脑皮质发育畸形，是难治性癫痫的重要病因。其病理基础是皮质神经元形态异常和迁移障碍。目前认为这可能与mTOR信号通路的异常活化有关，但具体调控机制尚不清楚。我们的前期研究发现在小鼠皮质mTOR异常活化的神经元中轴突出现加速生长，且通过抑制4E-BP1蛋白介导的翻译异常能使轴突生长恢复正常。据此我们推断4E-BP1介导的翻译异常可能为FCD的重要发病机制。本项目已建立FCD小鼠癫痫模型，并已初步验证抑制4E-BP1介导的翻译异常能缓解FCD小鼠癫痫发作。拟探讨4E-BP1导致FCD及相关癫痫的病理机制；同时运用翻译核糖体亲和纯化技术（TRAP）提取FCD皮质神经元特异性的mRNA，结合Microarray，建立mRNA翻译图谱，揭示4E-BP1导致FCD及相关癫痫的分子机制。本项目将为FCD及相关癫痫的研究提供理论依据，为药物治疗提供新的靶点。