Channelopathy-Associated Epilepsy Research Center

通道病，特别是涉及电压门控钠(NAV)和钾(KV)通道基因的那些， 导致各种临床严重程度不同的癫痫综合征。此外，NAV和KV 通道是许多已批准的和研究中的抗惊厥药物的重要靶点。在众多的 与癫痫相关的基因，编码NAV和KV通道的基因具有最高的累积变异量 Burden(&gt；人类基因突变数据库中的2000个变体)，约占总数的三分之一 已报道的与癫痫和相关神经发育障碍相关的基因变异。但 区分致病和良性变异并建立基因-表型关系已经成为 越来越具有挑战性，因为研究和研究中发现的变种数量呈爆炸性增长 临床医学。与经络病相关的癫痫是迎接挑战的独特机会 因为对于这些蛋白质存在良好的体外功能分析范例， 再加上关于它们对神经功能和药物反应的贡献的广泛知识。 我们建议建立一个多机构和跨学科的通道病相关癫痫 研究中心将把高通量技术与高含量的人类神经元和 动物模型系统。该中心将由三个综合研究项目和两个科学核心组成 涉及学术和行业科学家的协同混合。项目1将进行大规模的 编码电压门控离子通道基因变异的功能评估 单基因癫痫，然后结合修订的不同分类来整理发现。项目2将 用常规方法研究人类经络病相关癫痫的神经元模型 电生理方法和一种特别创新的工业光遗传方法(Optopatch) 以单细胞精度同时刺激和记录数百个神经元的数据。项目3将 建立和研究新的经络病相关癫痫小鼠模型并比较变异离子 跨模型系统的渠道功能障碍。项目将通过不同优先顺序的协作得到帮助 和一个突变和细胞表达核心。我们中心的一个主要目标是确定 非神经细胞模型能在多大程度上预测神经元和大脑中离子通道变异的影响。我们的 首要目标是促进我们对功能后果的理解取得变革性的进展 在通道病相关癫痫中的遗传变异，并使范式转变为基因/变异- 基于癫痫的分类学，与传统的临床分类方案相协调，同时指导 实施精准医疗。

Channelopathies, particularly those involving voltage-gated sodium (NaV) and potassium (KV) channel genes, are responsible for a variety of epilepsy syndromes having diverse clinical severity. Further, NaV and KV channels are important targets for many approved and investigational anticonvulsant drugs. Among the many genes associated with epilepsy, those encoding NaV and KV channels have the highest cumulative variant burden (>2,000 variants in the Human Gene Mutation Database), accounting for approximately one third of all reported genetic variants associated with epilepsy and related neurodevelopmental disorders. But differentiating pathogenic from benign variants and establishing genotype-phenotype relationships has become increasingly challenging because of explosive growth in the number of variants discovered in research and clinical medicine. Channelopathy-associated epilepsies represent unique opportunities to meet the challenge of variant annotation because well-established in vitro functional assay paradigms exist for these proteins, coupled with extensive knowledge regarding their contributions to neuronal function and drug response. We propose to create a multi-institutional and interdisciplinary CHANNELOPATHY-ASSOCIATED EPILEPSY RESEARCH CENTER that will combine high-throughput technologies with high-content human neuron and animal model systems. The Center will consist of three integrated research projects and two scientific cores involving a synergistic mixture of academic and industry scientists. Project 1 will conduct a large-scale functional evaluation of variants in genes encoding voltage-gated ion channels frequently associated with monogenic epilepsy, then curate findings in tandem with revised variant classifications. Project 2 will investigate human neuron models of channelopathy-associated epilepsy using conventional electrophysiological methods and an especially innovative, industrial optogenetic approach (Optopatch) to stimulate and record data from hundreds of neurons simultaneously with single-cell precision. Project 3 will develop and investigate new mouse models of channelopathy-associated epilepsy and compare variant ion channel dysfunction across model systems. Projects will be aided by collaboration with a Variant Prioritization and Curation Core and a Mutagenesis and Cell Expression Core. A key objective of our Center is to determine to what extent non-neuronal cell models can predict effects of ion channel variants in neurons and brain. Our overarching goal is to promote transformative advances in our understanding of the functional consequences of genetic variants in channelopathy-associated epilepsy, and to enable a paradigm shift to a gene/variant- based taxonomy of epilepsy that harmonizes with traditional clinical classification schemes while guiding the implementation of precision medicine.