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PHARMACOGENOMIC STUDY OF ANTICONVULSANT THERAPY

抗惊厥治疗的药物基因组学研究

基本信息

批准号：
6627683
负责人：
THOMAS N FERRARO
金额：
$ 31.7万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-01-29 至 2004-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6627683
关键词：
anticonvulsants brain disorder chemotherapy carbamazepine disease /disorder model electrostimulus epilepsy laboratory mouse nonhuman therapy evaluation pharmacogenetics phenytoin quantitative trait loci valproate

项目摘要

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物 (ACD) 治疗有抵抗力。这个提议旨在阐明影响个体的遗传因素的起源通过绘制影响 ACD 的基因位置来响应 ACD 小鼠的反应。该提案分为两个阶段。第一阶段涉及鉴定最适合剖析遗传影响的小鼠品系控制对特定 ACD 的响应。第二阶段涉及绘制这些遗传图谱对基因组特定区域的影响。在第一阶段，菌株特异性将表征最大电击癫痫阈值（MEST）。菌株具有相似平均 MEST 将被视为同等癫痫敏感且这样的菌株对将用于后续的抗惊厥药物（ACD）测试。 ACD 测试将涉及一组剂量反应研究临床相关的 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。将针对数量性状位点选择菌株（QTL）基于其品系特异性反应的分析，使得成对的对给定药物的 MEST 表现出最大差异效应的菌株（显示最大和最小抗惊厥作用的菌株）将是用于QTL研究。 ACD 的大脑水平将在父母中确定菌株，以解决与相关的一种可能的主要共同表型抗惊厥药 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。测绘将为每个菌株对使用分离的 F2（交叉）群体。用于作图的定量表型将是 F2 小鼠个体中的 MEST 用特定的 ACD 进行预处理。大脑 ACD 水平将在 F2 中确定动物并用作绘图的第二定量表型。为了区分 ACD 反应 QTL 和癫痫敏感性 QTL，后者可能会分离在交叉中，将使用每个 ACD 进行平行 QTL 研究独立的 F2 群体在生理盐水而不是 ACD 后进行 MEST 测试预处理。 QTL基因型和作图实验将结合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以及涉及这些基因鉴定的未来方向。这所描述的研究直接建立在工作的基础上研究人员实验室绘制参与差异敏感性的小鼠位点图谱化学和电诱发的癫痫发作，并最终导致研究遗传对反应的影响的重点策略癫痫患者的抗惊厥药物。人类的协会特定基因组变异的抗惊厥反应将导致更多针对个体患者的药物选择做出合理的决定总体上将导致治疗癫痫症取得更大的成功。