多药耐药基因MDR1基因多态性与耐药性癫痫密切相关，但其影响癫痫耐药性的机制尚不清楚。迄今没有明确的动物或体外证据阐明MDR1基因多态性如何影响耐药性癫痫的发生。我们前期在细胞模型中发现MDR1多态性可以影响P-gp（MDR1的产物，能转运多种AED）转运抗癫痫药物（AED）。因此，我们推测MDR1多态性通过改变P-gp的功能影响AED的脑内分布，导致癫痫耐药性。本项目拟利用含有MDR1多态性（1236C>T、2677G>T、3435C>T）的P-gp人源化小鼠，研究正常和癫痫状态下MDR1基因多态性对耐药性癫痫的影响及其机理：检测MDR1多态性对耐药性癫痫发生、AED疗效、AED脑内分布的影响；检测基因多态性对P-gp表达和功能的影响；探索基因多态性影响P-gp表达和功能的分子机制。该研究将阐明MDR1多态性与耐药性癫痫相关联的机理，为临床诊断、个性化用药、新药开发提供理论依据。

Epilepsy is a major neurological disorder, affecting more than 50 million people worldwide. Antiepileptic drugs (AEDs) do not effectively treat 30-40% of patients. Gene polymorphisms of MDR1 1236C>T, 2677G>T and 3435C>T have been associated with drug-resistant epilepsy. However，there is no in vivo or in vitro evidence to demonstrate that these polymorphisms can affect the generation and risk of drug-resistant epilepsy in animal models. We have established an effective cell monolayer model and found that 2677G>T and 3435C>T can improve the transport function of P-gp. Therefore, we hypothesize that MDR1 gene polymorphism can affect the expression or function of P-gp, limit the concentration of AED in brain, and cause the drug-resistant epilepsy. We propose to use P-gp humanized mice containing MDR1 polymorphisms (1236C>T, 2677G>T, and 3435C>T) to investigate: 1) the effect of MDR1 polymorphism on the rate of drug-resistant epilepsy, and the efficacy and brain distribution of AED; 2) the influence of MDR1 polymorphisms on the expression and transport function of P-gp; 3) the molecular mechanisms underlying polymorphism-mediated change of P-gp function. This study may demonstrate the direct effect of polymorphism on drug-resistant epilepsy and provide a molecular explanation of the association between the polymorphisms and pharmacoresistance. This study will clarify the mechanism of the association between MDR1 polymorphism and drug resistance epilepsy, and provide a theoretical basis for clinical diagnosis, personalized medicine and new drug development.