Multi-scale disease modeling of SCN2A-related epilepsy due to gain-of-function variants
由于功能获得性变异导致 SCN2A 相关癫痫的多尺度疾病模型
基本信息
- 批准号:10652642
- 负责人:
- 金额:$ 22.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAnimal ModelAnimalsAreaAwardBenchmarkingBiological MarkersBiophysical ProcessBrainCell LineChildhoodDataDevelopmentDiseaseDisease modelDisparateElectrodesElectroencephalographyElectrophysiology (science)EpilepsyEquilibriumExhibitsFosteringFoundationsFunctional disorderFundingFutureGenesGeneticGenetic DiseasesGenetic ModelsGlutamatesHippocampusHumanImpairmentImplantInduced pluripotent stem cell derived neuronsInterneuronsIntractable EpilepsyIon ChannelK-Series Research Career ProgramsLinkMentorsMissense MutationModelingMusNational Institute of Neurological Disorders and StrokeNeurodevelopmental DisorderNeuronal DysfunctionNeuronsOpticsOutputPathogenicityPatientsPharmaceutical PreparationsPhenotypePhysiciansPopulationPopulation AnalysisQuality of lifeRecurrenceReporterResearchSCN1A proteinSCN2A proteinScientistSeizuresSeveritiesSignal TransductionSliceSodium ChannelSodium Channel BlockersSudden DeathSynapsesTeacher Professional DevelopmentTrainingUnited StatesVariantanimal tissueautism spectrum disordercareercareer developmentcausal variantchildhood epilepsyclinical phenotypecollaborative environmentdesigndravet syndromeearly onsetepileptic encephalopathiesexcitatory neurongain of functiongenetic analysisgenetic variantgenome editinghuman stem cellshuman tissuein silicoin vivoinduced pluripotent stem cellinfancyinhibitory neuroninsightinterestloss of functionmortalitymouse modelmulti-scale modelingnetwork dysfunctionneural circuitneurodevelopmentneuronal circuitryneuronal excitabilityneurophysiologynovel strategiesprogramsresearch studyspatiotemporalvoltage
项目摘要
Project Summary Epilepsy affects up to 1% of the population worldwide, and 3 million in the United States
alone. A growing proportion of pediatric epilepsies are tied to causative variants in ion channel genes, including
the voltage-gated sodium channel gene SCN2A. The 2020 Epilepsy Research Benchmarks of NINDS prioritize
identifying how genetic variants cause epilepsy and related neurodevelopmental disorders. SCN2A variants that
manifest with loss-of-function are associated with severe neurodevelopmental disorders and late-onset epilepsy.
On the other hand, gain-of-function SCN2A variants predominantly have a phenotype of early-onset epilepsy.
The encoded sodium channel (NaV1.2) is highly expressed in excitatory glutamatergic neurons early in
development, presenting a unique opportunity to examine how excitatory neuron dysfunction leads to early-onset
epilepsy. Animal and human tissue-derived neuron models have brought mechanistic insight to how Dravet
syndrome results in interneuron dysfunction and epilepsy. Among SCN2A-related diseases, animal models
illuminate how loss-of-function leads to autism spectrum disorder with late-onset epilepsy. Due to lack of readily
available disease models, there is sparse mechanistic understanding of how excitatory neuron dysfunction early
in development leads to early-onset epilepsy. This proposal will exploit two early-onset epilepsy variants of
SCN2A that have a convergent clinical phenotype yet divergent biophysical mechanisms. Patient-derived neuron
models and mouse models provide the opportunity to define the point of mechanistic convergence at multiple
scales: from single neurons to neural circuits influencing epilepsy phenotype. Aim 1 will determine how two gain-
of-function SCN2A variants, encoding missense mutations M1879T and E430A, confer increased excitability by
distinct mechanisms. Functional analysis of iPSC-derived neurons in isolation and in elementary circuits will
define how the different variants impact excitability and thus converge toward an epileptic phenotype. Aim 2 will
define hippocampal higher-level circuit perturbations in epileptic mice designed with genome editing to
recapitulate the SCN2A-E430A human epileptic encephalopathy. Ex vivo analysis of changes in excitability,
synaptic signaling, and network output in the hippocampus will lead to new understanding of how gain-of-function
SCN2A variants affect neuronal networks. EEG and depth electrodes will provide spatiotemporal correlate to the
in vivo epilepsy phenotype. This proposal will propel the awardee to independence as a physician-scientist by
incorporating new expertise in multi-scale modeling of genetic epilepsy, focused relevant didactics, and a diverse
career development team specializing in neurodevelopmental and genetic disorders, all in a highly collaborative
environment fostering junior faculty development. This award will provide a platform to 1) define variant-specific
contributions to epilepsy phenotype in self-limited and intractable epilepsies and 2) investigate how targeted
epileptic circuit dysfunction influences circuit output and epilepsy phenotype in future R01-funded independent
research.
癫痫影响全球1%的人口,在美国有300万人
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
SCOTT K. ADNEY其他文献
SCOTT K. ADNEY的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('SCOTT K. ADNEY', 18)}}的其他基金
Multi-scale disease modeling of SCN2A-related epilepsy due to gain-of-function variants
由于功能获得性变异导致 SCN2A 相关癫痫的多尺度疾病模型
- 批准号:
10525781 - 财政年份:2022
- 资助金额:
$ 22.02万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 22.02万 - 项目类别:
Grant-in-Aid for Early-Career Scientists