Using Zebrafish to Advance our Understanding and Treatment of Epilepsy

利用斑马鱼促进我们对癫痫的理解和治疗

基本信息

批准号：
8442276
负责人：
Scott C Baraban
金额：
$ 29.82万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442276
关键词：
Address Adult Adverse effects Alleles Anticonvulsants Antiepileptic Agents Award Behavior Behavioral Benchmarking Biological Biological Assay Cells Child Childhood Data Disease Electrophysiology (science)Engineering Epilepsy Febrile Convulsions Fibroblasts Fishes Funding Gene Expression Gene Expression Profile Gene Expression Profiling Gene Family Gene Mutation Generalized Epilepsy Genes Genetic Genetic Models Goals Human In Situ Hybridization Institutes Investigation Laboratories Libraries Liquid substance Mental Retardation Modeling Molecular Molecular Biology Molecular Target Mus Mutation Myoclonic Epilepsies National Institute of Neurological Disorders and Stroke Patients Pharmaceutical Preparations Pharmacological Treatment Phenotype Preclinical Drug Evaluation Recurrence Refractory Research Resistance Robot Rodent Rodent Model SCN1A protein Seizures Sodium Channel Spasm Syndrome Testing Therapeutic Time Zebrafish base conventional therapy cost design drug candidate drug discovery genetic manipulation in vitro Model in vivo induced pluripotent stem cell infancy innovation loss of function mutant nervous system disorder novel novel strategies pre-clinical prevent programs research study scale up screening small molecule small molecule libraries tool voltage

项目摘要

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.

描述（由申请人提供）：传统的癫痫药物发现计划以抗惊厥作用为目标，几乎完全依赖于成年啮齿类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信息，但不容易适应药物发现项目。作为一种易于快速遗传操作和高通量药物筛选的简单脊椎动物，我们提出了一种替代方法，使用具有自发性复发性癫痫表型（即癫痫）的突变斑马鱼（Danio rerio）作为平台来确定医学难治性癫痫的新疗法。我们最近开始探索斑马鱼自发单基因突变（尤其是那些模仿儿童中常见的灾难性癫痫形式的突变）导致癫痫表型的可能性。我们的实验室最近将具有功能丧失性钠通道 (Nav1.1/SCN1A) 突变（例如，在患有婴儿期严重肌阵挛性癫痫和 Dravet 综合征的儿童中发现的一个基因家族）的斑马鱼突变体鉴定为具有相似表型的癫痫斑马鱼到人类的状况。使用大规模转录组分析、自动行为跟踪、体内电生理学和药理学方法，我们描述了一种新方法，以进一步了解和潜在治疗与 Nav1.1 突变相关的衰弱性癫痫疾病。在此 EUREKA 提案中，我们将使用这些突变斑马鱼来 (i) 确定 DS/SMEI 治疗的分子靶标，以及 (ii) 确定 DS/SMEI 治疗的候选药物。我们的研究结果有望建立一种基于斑马鱼的替代方法，用于针对主要见于儿童的单基因癫痫病的高通量小分子药物发现。