Modeling human epilepsy in zebrafish

描述（由申请人提供）：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，但遗传原因仍然是癫痫病因学的重要组成部分。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的癫痫发作障碍，并为减少或抵消癫痫发作发生率的治疗提供信息。虽然已经确定了几十个孟德尔癫痫家族的致病基因突变，但在一般人群中发现这些基因导致癫痫的例子很少。此外，即使涉及到癫痫的基因，我们也缺乏可控制的动物模型来迅速将这些发现转化为机制见解并最终形成新的抗癫痫疗法。斑马鱼与人类具有高度的遗传和生理同源性，并在各种药理和基因操作下表现出类似癫痫发作的行为。随着人类DNA样本的高通量测序，大量基因现已被确定，但它们在疾病状态中的作用尚不清楚。有相当大的兴趣是发展一种快速的方法来阐明潜在的遗传学，生物化学和病理生理的新诊断的疾病在一个活的脊椎动物的背景下。在这里，我们建议使用斑马鱼作为模型来快速表征NIH未诊断疾病计划（UDP）中确定的基因变异的功能，特别是15个突变与癫痫相关的基因。这些目标的成功完成将在功能上表征与癫痫相关的基因，并将确定基因变异对表型的贡献，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项研究和后续应用中获得的信息，开发有效管理癫痫的新疗法，并减少其对个人和社会造成的损失。

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.