miR-129-2-3p通过调控GABRA1通路参与FCD相关难治性癫痫发生机制研究

Epilepsy remains one of the most common clinical neurological disorders, and focal cortical dysplasia (FCD) is one of its most common cause. Currently, the precise early diagnosis and prediction of FCD related refractory epilepsy remains difficult. In previous experiments, we found the expression of miR-129-2-3p was up-regulated in cortex and plasma of the patients with refractory epilepsy caused by FCD compared with the control group, and the result was further verified by plasma experiments. Through bioinformatic prediction, the target gene of miR-129-2-3p is GABRA1. Current research demonstrated that, GABRA1 participates in the mechanism of epileptogenesis, and the increase of GABRA1 in the cortex could reduce the occurrence of epilepsy. However, these is less feasible and effective method to increase the expression level of GABRA1. We therefore plan to use an in vitro and in vivo model, apply various methods in molecular biology to investigate the regulatory relation between miR-129-2-3p and GABRA1, and the involvement of this signaling pathway in epileptogenesis. We aim at further applying miR-129-2-3p to target GABRA1 to further regulate epilepsy. Meanwhile, further detection of the plasma sample of epilepsy patient, and make sure that miR-129-2-3p could be a potential biomarker for the early diagnosis and prognostic evaluation, have promising clinical application and future.

难治性癫痫是目前临床难题，而局灶性皮质发育不良（FCD）是其主要病因之一。但早期准确诊断、预测FCD相关难治性癫痫仍然困难。我们前期通过基因芯片筛查发现，miR-129-2-3p在FCD患者的致痫皮质中特异性升高，并在血浆中得到验证。生物信息学预测发现，miR-129-2-3p的靶基因为GABRA1。目前研究证实，GABRA1参与癫痫的发生机制。增加皮质中GABRA1的表达水平，可减少癫痫的发作，但缺乏高效可行的手段上调GABRA1。据此，本研究利用癫痫的动物及细胞模型，采用多种分子生物学方法，论证miR-129-2-3p/GABRA1的调控关系及其信号通路参与癫痫的形成机制，探索应用miR-129-2-3p靶向调控GABRA1控制癫痫；同时，进一步检测癫痫患者的血浆样本，明确miR-129-2-3p可成为FCD相关难治性癫痫早期诊断和预后评价的生物学标记物，具有良好的临床应用价值和前景。

难治性癫痫是目前临床难题，而局灶性皮质发育不良（FCD）是其主要病因之一。准确诊断、预测FCD相关难治性癫痫仍然困难。研究证实GABRA1参与癫痫的发生机制。增加皮质中GABRA1的表达水平，可减少癫痫的发作。但缺乏高效可行的手段上调GABRA1。miRNA能有效调控转录后基因的表达，其作为一种调节手段已被广泛应用于临床。我们前期通过基因芯片筛查发现，miR-129-2-3p在FCD患者的致痫皮质中特异性升高，并在血浆中得到验证。生物信息学预测发现，miR-129-2-3p的靶基因为GABRA1。我们以此为基础，通过构建荧光素酶报告基因，建立难治性癫痫动物及细胞模型，采用多种分子生物学方法，明确了 miR-129-2-3p 通过直接靶向调控 GABRA1 参与FCD 相关难治性癫痫的发生。并且进一步在动物模型中证明，通过下调miR-129-2-3p 表达能有效上调GABRA1，在脑电图监测中能有效减少放电频率及强度，可作为潜在治疗癫痫的新途径。基于以上研究结果，miR-129-2-3p有可能成为FCD相关难治性癫痫早期诊断和预后评价的生物学标记物，具有良好的临床应用价值和前景。