Channelopathy-Associated Epilepsy Research Center

通道病相关癫痫研究中心

基本信息

  • 批准号:
    10477447
  • 负责人:
  • 金额:
    $ 232.53万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-30 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

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.
神经病,特别是涉及电压门控钠(NaV)和钾(KV)通道基因的神经病, 是具有不同临床严重性的多种癫痫综合征的原因。此外,NaV和KV 通道是许多批准的和研究中的抗惊厥药物的重要靶点。在众多 在与癫痫相关的基因中,那些编码NaV和KV通道的基因具有最高的累积变异 负担(人类基因突变数据库中> 2,000个变异),约占所有变异的三分之一。 报告了与癫痫和相关神经发育障碍相关的遗传变异。但 区分致病性和良性变异并建立基因型-表型关系已成为 由于研究中发现的变异数量的爆炸性增长, 临床医学癫痫相关性癫痫代表了迎接挑战的独特机会 因为对于这些蛋白质存在良好建立的体外功能测定范例, 再加上关于它们对神经元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 研究中心将联合收割机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 涉及学术界和工业界科学家的协同合作。项目1将进行大规模的 编码电压门控离子通道的基因变异体的功能评价 单基因癫痫,然后与修订后的变异分类一起整理发现。项目2将 使用常规方法研究通道病相关癫痫人类神经元模型 电生理学方法和特别创新的工业光遗传学方法(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 开发和研究新的通道病相关癫痫小鼠模型,并比较不同的 跨模型系统的通道功能障碍项目将通过与变体优先级的合作来帮助 和固化核心以及诱变和细胞表达核心。我们中心的一个关键目标是确定 非神经元细胞模型在多大程度上可以预测神经元和大脑中离子通道变体的影响。我们 总体目标是促进我们对功能后果的理解的变革性进展 通道病相关癫痫的遗传变异,并实现基因/变异的范式转变- 基于癫痫的分类,与传统的临床分类方案相协调,同时指导 实施精准医疗。

项目成果

期刊论文数量(18)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Epilepsy-associated SCN2A (Na V 1.2) Variants Exhibit Diverse and Complex Functional Properties.
癫痫相关的 SCN2A (Na V 1.2) 变异体表现出多样且复杂的功能特性。
  • DOI:
    10.1101/2023.02.23.529757
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Thompson,ChristopherH;Potet,Franck;Abramova,TatianaV;DeKeyser,Jean-Marc;Ghabra,NoraF;Vanoye,CarlosG;Millichap,John;GeorgeJr,AlfredL
  • 通讯作者:
    GeorgeJr,AlfredL
KCNA1 gain-of-function epileptic encephalopathy treated with 4-aminopyridine.
  • DOI:
    10.1002/acn3.51742
  • 发表时间:
    2023-04
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Mueller, Peter;Takacs, Danielle S.;Hedrich, Ulrike B. S.;Coorg, Rohini;Masters, Laura;Glinton, Kevin E.;Dai, Hongzheng;Cokley, Jon A.;Riviello, James J.;Lerche, Holger;Cooper, Edward C.
  • 通讯作者:
    Cooper, Edward C.
CaMKII Inhibition Attenuates Distinct Gain-of-Function Effects Produced by Mutant Nav1.6 Channels and Reduces Neuronal Excitability.
  • DOI:
    10.3390/cells11132108
  • 发表时间:
    2022-07-04
  • 期刊:
  • 影响因子:
    6
  • 作者:
    Zybura, Agnes S.;Sahoo, Firoj K.;Hudmon, Andy;Cummins, Theodore R.
  • 通讯作者:
    Cummins, Theodore R.
Strain-dependent effects on neurobehavioral and seizure phenotypes in Scn2aK1422E mice.
对 Scn2aK1422E 小鼠神经行为和癫痫表型的菌株依赖性影响。
  • DOI:
    10.1101/2023.06.06.543929
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Echevarria-Cooper,DennisM;Hawkins,NicoleA;Kearney,JenniferA
  • 通讯作者:
    Kearney,JenniferA
Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967.
大麻二酚和 GS967 对人类 Nav1.2 复苏和持续钠电流的差异抑制。
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Alfred L. George其他文献

High-Dose Midazolam for Pediatric Refractory Status Epilepticus: A Single-Center Retrospective Study*
高剂量咪达唑仑治疗小儿难治性癫痫持续状态:单中心回顾性研究*
  • DOI:
    10.1097/pcc.0000000000003043
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Z. S. Daniels;N. Srdanovic;K. Rychlik;Craig M. Smith;Joshua L. Goldstein;Alfred L. George
  • 通讯作者:
    Alfred L. George
Prophecy or empiricism? Clinical value of predicting versus determining genetic variant functions
预言还是经验主义?
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    A. Brunklaus;Alfred L. George;D. Lal;E. Heinzen;A. Goldman
  • 通讯作者:
    A. Goldman
Scanning mutagenesis of the voltage-gated sodium channel NasubV/sub1.2 using base editing
使用碱基编辑对电压门控钠通道 NaV1.2 进行扫描诱变
  • DOI:
    10.1016/j.celrep.2023.112563
  • 发表时间:
    2023-06-27
  • 期刊:
  • 影响因子:
    6.900
  • 作者:
    Juan Lorenzo B. Pablo;Savannah L. Cornett;Lei A. Wang;Sooyeon Jo;Tobias Brünger;Nikita Budnik;Mudra Hegde;Jean-Marc DeKeyser;Christopher H. Thompson;John G. Doench;Dennis Lal;Alfred L. George;Jen Q. Pan
  • 通讯作者:
    Jen Q. Pan
Paramyotonia congenita without paralysis on exposure to cold: a novel mutation in the SCN4A gene (Val1293Ile).
先天性副肌强直,接触寒冷后不瘫痪:SCN4A 基因 (Val1293Ile) 的新突变。
  • DOI:
  • 发表时间:
    1995
  • 期刊:
  • 影响因子:
    1.7
  • 作者:
    Manuela C. Koch;Karin Baumbach;Alfred L. George;Kenneth Ricker
  • 通讯作者:
    Kenneth Ricker
Mutant Channels Contribute Ͻ50% to Na Ϩ Current in Paramyotonia Congenita Muscle
先天性副肌强直中突变通道对 Na 电流贡献 Ͻ50%
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
    N. Mitrović;Alfred L. George;Reinhardt Rü Del;F. Lehmann‐Horn;H. Lerche
  • 通讯作者:
    H. Lerche

Alfred L. George的其他文献

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{{ truncateString('Alfred L. George', 18)}}的其他基金

Northwestern University O'Brien Kidney National Resource Center
西北大学奥布莱恩肾脏国家资源中心
  • 批准号:
    10754080
  • 财政年份:
    2023
  • 资助金额:
    $ 232.53万
  • 项目类别:
Cellular Pathophysiology of Neuronal Na/K-ATPase Dysfunction
神经元 Na/K-ATP 酶功能障碍的细胞病理生理学
  • 批准号:
    10539624
  • 财政年份:
    2022
  • 资助金额:
    $ 232.53万
  • 项目类别:
Cellular Pathophysiology of Neuronal Na/K-ATPase Dysfunction
神经元 Na/K-ATP 酶功能障碍的细胞病理生理学
  • 批准号:
    10646335
  • 财政年份:
    2022
  • 资助金额:
    $ 232.53万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10657773
  • 财政年份:
    2021
  • 资助金额:
    $ 232.53万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10285156
  • 财政年份:
    2021
  • 资助金额:
    $ 232.53万
  • 项目类别:
Kinetic Imaging Plate Reader for Drug Discovery and Biology
用于药物发现和生物学的动态成像读板仪
  • 批准号:
    10177367
  • 财政年份:
    2021
  • 资助金额:
    $ 232.53万
  • 项目类别:
Decrypting Variants of Uncertain Significance in Long-QT Syndrome
解密长QT综合征中不确定意义的变异
  • 批准号:
    10004933
  • 财政年份:
    2020
  • 资助金额:
    $ 232.53万
  • 项目类别:
2019 Cardiac Arrhythmia Mechanisms GRC/GRS
2019心律失常机制GRC/GRS
  • 批准号:
    9755670
  • 财政年份:
    2019
  • 资助金额:
    $ 232.53万
  • 项目类别:
Pilot and Feasibility Component
试点和可行性部分
  • 批准号:
    10203941
  • 财政年份:
    2018
  • 资助金额:
    $ 232.53万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10477448
  • 财政年份:
    2018
  • 资助金额:
    $ 232.53万
  • 项目类别:

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