PHARMACOGENOMIC STUDY OF ANTICONVULSANT THERAPY

抗惊厥治疗的药物基因组学研究

• 批准号: 6263261
• 负责人: THOMAS N FERRARO
• 金额: $ 30.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-29 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6263261
• 关键词: anticonvulsants; brain disorder chemotherapy; carbamazepine; disease /disorder model; electrostimulus; epilepsy; laboratory mouse; nonhuman therapy evaluation; pharmacogenetics; phenytoin; quantitative trait loci; valproate

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.

描述（改编自申请人的摘要）：许多癫痫患者 对标准抗惊厥药（ACD）治疗具有抗药性。这个建议 试图阐明影响个体的遗传因素的起源 通过映射影响这些的基因的位置，对ACD的响应 小鼠的反应。该提议有两个阶段。第1阶段涉及 识别最适合剖析遗传影响的小鼠菌株 哪个控制对特定ACD的响应。第2阶段涉及映射这些遗传 对基因组定义区域的影响。在第1阶段，应变特异性 将表征最大电击癫痫发作阈值（MEST）。菌株 具有相似的平均值将被视为癫痫发作敏感，并且 这样的菌株将用于次词抗惊厥药（ACD） 测试。 ACD测试将涉及一组面板的剂量反应研究 临床上相关的ACD：苯妥英钠，卡马西平，瓦吡克和 γ-乙烯基GABA。定量端点将是确定的绝对mest点 在有药物的情况下。菌株将被选择用于定量特质基因座 （QTL）根据其应变特异性响应进行分析，以使成对成对 给定药物对MEST表现出最大差异作用的菌株 （显示最大和最小的抗惊厥作用的菌株）将是 用于QTL研究。 ACD的大脑水平将在父母中确定 应变以解决与与 抗惊厥的反应。在第2阶段，QTL映射研究将是 使用1期表型研究建议的小鼠菌株进行。映射 将利用每个应变对的分离F2（Intross）种群。 在单个F2小鼠中，用于映射的定量表型将是最不适的 用特定的ACD预处理。脑ACD水平将在F2中确定 动物并用作映射的第二个定量表型。为了 区分ACD响应QTL与癫痫发作敏感性QTL，可能分离 在十字架中，将使用A ACD进行平行的QTL研究 独立的F2种群测试了盐水后的MEST，而不是ACD 预处理。 QTL基因型和映射实验将结合15-20 cm 基因组扫描，包括包括参数的全面统计分析 和非参数单和多焦点模型。结果将导致 影响小鼠抗惊厥反应的基因的直接定位 未来涉及鉴定这些基因的方向。这 描述的研究直接源于工作的基础 研究者的实验室映射鼠标基因座，涉及差异灵敏度 化学和电诱导的癫痫发作，并最终导致 重点策略，以调查遗传对反应的影响 患有癫痫的人类的抗惊厥药。人类协会 具有特定基因组变异的抗惊厥反应将导致更多 关于为个别患者选择药物的合理决定以及 一般而言，将在治疗癫痫发作障碍方面取得更大的成功。