P-糖蛋白(P-gp)对脑内抗癫痫药物的转运在耐药性癫痫中具有重要作用。其编码基因ABCB1 核苷酸多态性与耐药性癫痫密切相关，被认为可能改变P-gp的转运功能，从而影响抗癫痫药物在脑内的分布，导致耐药性。但该假设一直没有得到确认，至今没有ABCB1多态性影响P-gp转运抗癫痫药物的直接证据。我们拟在该项目中，建立含有ABCB1多态性位点的高灵敏度的细胞模型，利用多种手段研究1236C>T、2677G>T、3435C>T位点对P-gp 转运抗癫痫药物的影响及其分子机理。主要包括：1）检测这三个位点对P-gp转运抗癫痫药物的影响；2）检测SNP对不同抑制剂在抑制P-gp功能方面的影响；3）探索SNP影响P-gp功能的机理。该研究将为确定ABCB1多态性位点与耐药性癫痫的相关性提供直接证据，对揭示耐药性癫痫的机理、预测抗癫痫药物疗效、设计新的抗癫痫药物和P-gp抑制剂具有重要意义。

Export of AEDs by P-glycoprotein (P-gp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier in drug-resistant patients, may be a mechanism for resistance to AEDs. Single nucleotide polymorphisms (SNPs) 1236C>T, 2677G>T and 3435C>T have been associated with drug-resistant epilepsy and were sometimes found to have effects on the activities of P-gp. However，there is no direct evidence showing that polymorphisms affect the transport of AEDs by P-gp. In this project, we propose to use monolayers of cells transfected with the ABCB1 variants to investigate: (1) the effect of ABCB1 polymorphisms (1236C>T, 2677G>T and 3435C>T) on AED transport; (2) the influence of ABCB1 polymorphisms on the response of P-gp to its inhibitors; (3) the molecular mechanisms underlying polymorphisms-mediated change of P-gp function. The effects of ABCB1 polymorphisms on AED transport may demonstrate the direct influence of polymorphisms on P-gp function and provide a molecular explanation of the association between the polymorphisms and pharmacoresistance. This knowledge may help design new AEDs and P-gp inhibitors, develop genetic-based individualized therapy of epilepsy, and guide the clinical usage of AEDs.