Using Zebrafish to Advance our Understanding and Treatment of Epilepsy

描述（由申请人提供）：传统的癫痫药物发现项目以抗惊厥作用为目标，几乎完全依赖于成年啮齿动物的诱发癫痫模型。然而，现在已经描述了许多模仿人类癫痫许多特征的遗传模型。这些模型提供了重要的信息，但不容易适应药物发现计划。作为一种简单的脊椎动物物种，适合快速基因操作和高通量药物筛选，我们提出了一种替代方法，使用具有自发复发性癫痫表型（即癫痫）的突变斑马鱼（Danio rerio）作为平台，以确定医学上难治性癫痫的新治疗方法。

DESCRIPTION (provided by applicant): Traditional drug discovery programs for epilepsy target anticonvulsant effects and rely, almost exclusively, on induced seizure models in adult rodents. However, numerous genetic models that mimic many features of human epilepsies have now been described. These models provide important information but are not easily adapted to drug discovery programs. As a simple vertebrate species amenable to rapid genetic manipulation and high-throughput drug screening, we propose an alternative approach using mutant zebrafish (Danio rerio) with spontaneous recurrent seizure phenotypes (i.e., epilepsy) as a platform to identify new treatments for medically refractory epilepsy. We recently began to explore the possibility that spontaneous single-gene mutations in zebrafish - especially those mimicking catastrophic forms of epilepsy often seen in children - result in epileptic phenotypes. Zebrafish mutants featuring a loss-of-function sodium channel (Nav1.1/SCN1A) mutation (e.g., a gene family identified in children with Severe Myoclonic Epilepsy of Infancy and Dravet syndrome) were recently identified by our laboratory as epileptic zebrafish with phenotypes similar to the human condition. Using large-scale transcriptome analysis, automated behavioral tracking, in vivo electrophysiology and pharmacological approaches we describe a novel approach to further our understanding and potential treatment of debilitating epilepsy disorders associated with Nav1.1 mutation. In this EUREKA proposal we will use these mutant zebrafish in our efforts to (i) identify molecular targets for therapeutic treatment of DS/SMEI and (ii) identify drug candidates for therapeutic treatment of DS/SMEI. Our results promise to establish an alternative, zebrafish-based, approach for high-throughput small-molecule drug discovery targeted to monogenic epilepsy disorders seen primarily in children.