Neuropilin-2在癫痫发生中的作用及其分子机制的研究

作为神经系统最常见的疾病之一，癫痫有着复杂的发病机制，中枢神经系统兴奋与抑制间的不平衡是影响癫痫发生的重要因素之一。神经元轴突导向分子受体Npn-2在神经系统发育、成熟过程中起重要作用。在成熟的神经元中，Npn-2蛋白表达在兴奋型神经元突触后部位，参与突触可塑性的调节，在维持神经元兴奋和抑制间的平衡中起关键作用。小鼠模型中，Npn-2的缺失可以导致自发癫痫的发生，然而这个过程的机制尚不明确。本研究项目提出Npn-2通过对成熟神经元的调节来影响癫痫发生的假说，将使用遗传学加上动物癫痫模型的方法对这个假说进行验证。在使用组织特异性敲除来确定Npn-2起作用的组织后，还将在成年鼠中应用药物诱导的特异性敲除来进一步明确Npn-2影响癫痫发生的作用时间。最后，本项目还将探索Npn-2在癫痫中作用的信号传导通路，用以阐明这个过程的分子机制。本研究的结果将为癫痫发病机制带来新的认识，提供可能的治疗靶点。

Epilepsy is a chronic neurological disease with complex underlying mechanisms. The neuronal network excitation and inhibition imbalance is one of the major factors in epilepsy formation. Axon guidance receptor Npn-2 is essential for the development and maturation of the nervous system. Npn-2 knockout mice show spontaneous occurrence of epilepsy. Our previous study found that Npn-2 is expressed at postsynaptic density in excitatory neurons and plays key role in regulating homeostatic plasticity while controlling the balance between neuronal excitation and inhibition. Here we propose that the prone to epilepsy in Npn-2 knockout mice is due to its function in regulation of homeostatic synaptic plasticity at mature neurons. To this end, we will use tissue specific-inducible CRE to remove Npn-2 in tissue and developmental stage specific manners. In addition, we will conduct RNAseq and proteomic screens to explore signaling pathways downstream of Npn-2. Our proposed research will provide insight into underlying mechanisms of epilepsy and possibly discover new therapeutic targets.