PHARMACOGENOMIC STUDY OF ANTICONVULSANT THERAPY

描述(改编自申请者摘要)：许多癫痫患者 对标准抗惊厥药物(ACD)治疗有抵抗力。这项建议 试图阐明影响个体的遗传因素的起源 通过定位影响这些基因的位置来对ACDs作出反应 小鼠的反应。这项提议分为两个阶段。第一阶段涉及 确定最适合解剖遗传影响的小鼠品系 它们控制着对特定ACD的反应。第二阶段涉及对这些基因进行定位 对基因组特定区域的影响。在第一阶段，特定于菌株 将描述最大电击惊厥阈值(MEST)。菌株 具有类似平均值的MEST将被认为等同于癫痫敏感和 这些菌株将用于亚序列抗惊厥药物(ACD)。 测试。ACD测试将涉及与一个小组的剂量反应研究 临床相关ACDs：苯妥英钠、卡马西平、丙戊酸和 伽马-乙烯基氨基丁酸。量化终点将是确定的绝对MEST 在毒品存在的情况下。将选择品系进行数量性状基因座 (QTL)分析基于它们的品系特异性反应 对特定药物的MEST表现出最大差异效应的菌株 (表现出最大和最小抗惊厥作用的菌株)将 用于QTL研究。ACDs的大脑水平将在父母中确定 菌株，以解决一个可能的主要共同表型与 抗惊厥的MEST反应。在第二阶段，QTL作图研究将 使用第一阶段表型研究建议的小鼠品系进行。映射 将对每个品系对使用分离的F2(杂交)群体。 在F2小鼠个体中用于定位的定量表型将是MEST 用一种特定的ACD进行预处理。大脑ACD水平将在F2确定 并作为第二个数量表型用于作图。为了 区分ACD反应QTL和癫痫敏感性QTL 在杂交中，将对每个ACD进行平行的QTL研究，使用 在生理盐水而不是ACD后对独立的F2群体进行MEST测试 前置处理。QTL基因分型和作图实验将结合15-20 cM 基因组扫描和全面的统计分析，包括参数 以及非参数单点和多点模型。结果将导致 影响小鼠抗惊厥反应基因的直接定位 未来的方向涉及到这些基因的识别。这个 所描述的研究直接建立在 研究人员实验室定位与差异敏感性有关的小鼠基因座 导致化学和电诱导的癫痫发作，最终将导致 研究遗传因素对疾病反应影响的重点策略 人类癫痫患者的抗惊厥药物。人类社会的联合 特定基因组变异的抗惊厥反应将导致更多 关于个体患者和患者的药物选择的理性决策 将导致在治疗癫痫障碍方面取得更大的成功。

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.