LncRNA PVT1-miRNA-186调控ABC转运体介导颞叶癫痫耐药机制研究

Multidrug resistance of epilepsy is very complicated. Previous study found that ATP binding cassette(ABC) transporters were higher expression level in drug-resistant epileptic patients, which implied ABC transporters play important roles in drug resistant. However, the regulation mechanisms of ABC transporters in drug resistant epilepsy are unknown. Previously, our team carried out the miRNA chips and lncRNA-expression microarray with the brain tissues of temporal lobe drug resistant epileptic patients and found the expressions of ABC transporters ABCB1(MDR1), ABCC1(MRP1) and ABCC2(MRP2) were up-regulated; lncRNA PVT1 and miR-186 expression were significantly different compared with controls. Bioinformatics and preliminary experiments implied lncRNA PVT1 and miR-186 were related with the regulation of MDR1, MRP1 and MRP2. In this project, based on preliminary studies, we aim to explore the regulatory network of MDR1, MRP1 and MRP2 transporters regulated by lncRNA PVT1 and miR-186 on the molecules, cells, animals models and clinical patients levels. Furthermore, we aim to clarify the new mechanism of lncRNA PVT1-miRNA-186 regulated ABC transporters mediated temporal lobe epilepsy drug resistance, and provide a theoretical basis and experimental evidence for the clinical treatment of resistant epilepsy.

癫痫多药耐药十分复杂,研究发现三磷酸腺苷结合盒(ATP binding cassette,ABC)转运体在耐药癫痫患者高表达提示其在耐药中起重要作用。ABC转运体在癫痫耐药中的表达调控机制不明。本项目组在前期颞叶耐药癫痫脑组织miRNA, lncRNA及表达谱芯片研究中发现ABC转运体ABCB1(MDR1)、ABCC1(MRP1)及ABCC2(MRP2)表达上调，lncRNA PVT1及miR-186表达差异显著。生物信息学及预实验提示lncRNA PVT1及miR-186与MDR1、MRP1及MRP2表达调控相关。本研究拟在前期研究基础上从分子细胞、动物和临床层面探讨lncRNA PVT1、miR-186参与MDR1、MRP1及MRP2转运体的调控网络，阐明lncRNA PVT1-miR-186调控ABC转运体介导癫痫耐药的新机制，为耐药性癫痫的临床治疗提供理论基础和实验依据。

癫痫多药耐药十分复杂,研究发现三磷酸腺苷结合盒(ATP binding cassette,ABC)转运体在耐药癫痫患者高表达提示其在耐药中起重要作用。ABC转运体在癫痫耐药中的表达调控机制不明。本项目组发现颞叶耐药癫痫脑组织miRNA, lncRNA及表达谱芯片研究中发现ABC转运体ABCB1(MDR1)、ABCC1(MRP1)及ABCC2(MRP2)表达上调，lncRNA PVT1及miR-186表达差异显著。对10 例颞叶癫痫耐药患者脑组织及配对的对照组进行miRNA 芯片、lncRNA 及表达谱芯片进行数据分析生物信息学及实验提示lncRNA PVT1及miR-186与MDR1、MRP1及MRP2表达调控相关。用qRT-PCR 对33 例颞叶癫痫耐药患者脑组织及21 例脑外伤对照的MDR1、MRP1、MRP2、lncRNA PVT1、miR-186 的mRNA 表达量进行分析，发现MDR1、MRP1、MRP2 mRNA 在耐药癫痫患者表达高，lncRNA PVT1 也表达高于对照组, 且lncRNA PVT1 表达量与miR-186 表达量呈负相关。本研究发现lncRNA PVT1、miR-186参与MDR1、MRP1及MRP2转运体的调控网络，阐明lncRNA PVT1-miR-186调控ABC转运体介导癫痫耐药的新机制，为耐药性癫痫的临床治疗提供理论基础和实验依据。