PHARMACOGENOMIC STUDY OF ANTICONVULSANT THERAPY

描述（改编自申请人摘要）：许多癫痫患者 对标准抗惊厥药物（ACD）治疗有抗性。这项建议 试图阐明影响个体的遗传因素的起源， 通过绘制影响这些基因的基因位置， 小鼠的反应。该提案分为两个阶段。第一阶段涉及 确定最适合解剖遗传影响的小鼠品系 控制对特定ACD的反应。第二阶段是绘制这些基因图谱， 影响基因组的特定区域。在第1阶段，菌株特异性 将表征最大电休克发作阈值（MEST）。菌株 具有相似平均MEST的患者将被视为具有等同的药物敏感性， 这些菌株对将用于随后的抗惊厥药物（ACD） 试验. ACD测试将涉及一组剂量反应研究， 临床相关ACD：苯妥英、卡马西平、丙戊酸和 γ-乙烯基GABA定量终点将是确定的绝对MEST 在药物存在的情况下。将选择菌株的数量性状基因座 (QTL)基于其菌株特异性反应进行分析，以便对 对于给定药物，对MEST表现出最大差异效应的菌株 (the显示最大和最小抗惊厥作用的菌株）将被 用于QTL研究。将在父母中测定ACD的脑水平。 菌株，以解决一个可能的主要共表型与 抗惊厥药MEST反应。在第二阶段，QTL定位研究将在 使用1期表型研究提出的小鼠品系进行。映射 将利用分离的F2（互交）群体用于每个菌株对。 用于作图的定量表型将是个体F2小鼠中的MEST 用特定的ACD预处理。将在F2中测定脑ACD水平 动物并用作作图的第二定量表型。为了 区分ACD反应QTL和癫痫敏感性QTL， 在杂交中，将使用一个平行的QTL对每个ACD进行研究。 在生理盐水而非ACD后检测MEST的独立F2群体 预防措施QTL基因型和作图实验将结合联合收割机的15-20 cM 基因组扫描与全面的统计分析，包括参数 以及非参数单位点和多位点模型。结果将导致 影响小鼠抗惊厥反应的基因的直接定位 未来的发展方向包括鉴定这些基因。的 所描述的研究直接建立在 研究员实验室绘制涉及差异敏感性的小鼠基因座 化学和电诱导癫痫发作，最终将导致 研究遗传因素对 抗惊厥药物在人类癫痫患者中的应用。人类的协会 抗惊厥反应与特定的基因组变异将导致更多的 关于个体患者药物选择的合理决定， 将导致更大的成功，在治疗癫痫疾病的一般。

DESCRIPTION (adapted from applicant's abstract): Many patients with epilepsy are resistant to standard anticonvulsant drug (ACD) treatments. This proposal seeks to elucidate the origin of the genetic factors that affect individual response to ACDs by mapping the location of genes that influence these responses in mice. There are 2 phases to this proposal. Phase 1 involves identifying mouse strains best suited for dissecting the genetic influences which control response to specific ACDs. Phase 2 involves mapping these genetic influences to defined regions of the genome. In phase 1, strain-specific maximal electroshock seizure threshold (MEST) will be characterized. Strains with similar mean MESTs will be considered equivalently seizure-sensitive and such pairs of strains will be used for subesequent anticonvulsant drug (ACD) testing. ACD testing will involve dose-reponse studies with a panel of clinically relevant ACDs: phenytoin, carbamazepine, vaiproic acid and gamma-vinyl GABA. The quantitatve endpoint will be the absolute MEST determined in the presence of drug. Strains will be selected for quantitative trait loci (QTL) analyses based on their strain-specific response such that pairs of strains exhibiting the largest differential effects on MEST for a given drug (the strains showing the largest and smallest anticonvulsant effects) will be used for QTL studies. Brain levels of ACDs will be determined in parental strains in order to address one possible major co-phenotype in correlation with the anticonvulsant MEST response. In phase 2, QTL mapping studies will be conducted using mouse strains suggested by phase 1 phenotype studies. Mapping will utilize segregating F2 (intercross) populations for each strain pair. Quantitative phenotype for mapping will be MEST in individual F2 mice pretreated with a specific ACD. Brain ACD levels will be determined in F2 animals and used as a second quantitative phenotype for mapping. In order to distinguish ACD response QTLs from seizure sensitivity QTLs which may segregate in the cross, a parallel QTL study will be conducted for each ACD using an independent F2 population tested for MEST following saline rather than ACD pretreatement. QTL genotype and mapping experiments will combine a 15-20 cM genome scan with comprehensive statistical analyses including both parametric and non-parametric single and multilocus models. Results will lead to the direct localization of genes that influence anticonvulsant responses in mice with future directions involving the identification of these genes. The described studies build directly from the foundation of work in the investigator's lab on mapping mouse loci involved in differential sensitivity to chemically- and electrically-induced seizures and ultimately will lead to a focused strategy for investigating genetic influences on response to anticonvulsant drugs in humans with epilepsy. The association of human anticonvulsant response with specific genomic variants will lead to more rational decisions regarding the choice of drug for individual patients and will lead to greater success in treating seizures disorders in general.