Modeling human epilepsy in zebrafish

描述(申请人提供)：癫痫是一种反复发作的慢性疾病。虽然癫痫可以由非遗传因素引起，包括中风、创伤性脑损伤和脑感染，但遗传原因在癫痫病因中仍然是一个重要的组成部分。阐明与癫痫相关的基因和突变的功能将有助于更好地了解普通人群中的癫痫发作障碍，并为减少或抵消癫痫发作的治疗提供信息。虽然已经在数十个孟德尔癫痫家系中发现了致病基因突变，但也有一些例子表明，这些基因与普通人群中的癫痫有关。此外，即使与癫痫有关的基因已经被牵连，我们也缺乏易于处理的动物模型来迅速将这些发现转化为机械性的见解，并最终形成新的抗癫痫疗法。斑马鱼与人类有很高的遗传和生理同源性，并对各种药物和基因操作表现出癫痫样行为。随着人类DNA样本的高通量测序，现在正在识别大量的基因，但它们在疾病状态中的作用尚不清楚。在活的脊椎动物有机体的背景下，开发一种快速方法来阐明新诊断疾病的遗传学、生物化学和病理生理学，是相当有兴趣的。在这里，我们建议使用斑马鱼作为一个模型，以快速表征NIH未诊断疾病计划(UDP)中确定的基因变体的功能，特别是与癫痫相关的15个基因突变。这些目标的成功完成将从功能上表征与癫痫相关的基因，并将确定基因变体对表型的贡献，为开发新的检测方法和疾病修饰疗法提供有价值的见解。我们的长期目标是利用从这次和随后的应用中获得的信息来开发新的治疗方法，以有效地管理癫痫并减少其对个人和社会的影响。

DESCRIPTION (provided by applicant): Epilepsy is a chronic condition of recurrent seizures. Although epilepsy can be caused by non- genetic factors including stroke, traumatic brain injuries, and brain infections, genetic causes remain a significant component in epilepsy etiology. Elucidating the functions of genes and mutations associated with epilepsy would provide a better understanding of seizure disorders in the general population and be informative to therapies that reduce or offset seizure incidences. While the causative gene mutations in dozens of Mendelian epilepsy families have been identified, there are a few examples where these genes have been found to contribute to epilepsy in the general population. Moreover, even when genes involved in epilepsy have been implicated, we lack tractable animal models to rapidly translate these findings into mechanistic insights and ultimately new anti-epileptic therapies. The zebrafish shows high genetic and physiologic homology to humans and displays a seizure-like behavior in response to various pharmacological and genetic manipulations. With high throughput sequencing of human DNA samples, a significant number of genes are now being identified, yet their role in the disease state are unknown. There is considerable interest i developing a rapid method to elucidate the underlying genetics, biochemistry and pathophysiology of newly diagnosed diseases in the context of a living vertebrate organism. Here we propose to use the zebrafish as a model to rapidly characterize the function of gene variants identified in the NIH Undiagnosed Diseases Program (UDP), specifically 15 genes for which mutations have been associated with epilepsy. Successful completion of these aims will functionally characterize the genes associated with epilepsy and will determine the contribution of the gene variant to the phenotype providing valuable insight for the development of new detection methods and disease-modifying therapies. Our long- term goal is to employ the information gained from this and following applications to develop new therapies for the effective management of epilepsy and the reduction of its toll on the individual, and society.