Understanding ANK3-associated epileptic encephalopathies
了解 ANK3 相关癫痫性脑病
基本信息
- 批准号:9808091
- 负责人:
- 金额:$ 42.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:ANK2 geneANK3 geneAction PotentialsAffectAxonBehavioralCell membraneCellsChinaClosure by clampComplexDataDefectDevelopmentDiseaseElectrophysiology (science)Enterobacteria phage P1 Cre recombinaseEpilepsyEtiologyFluorescent Antibody TechniqueFunctional disorderGated Ion ChannelGenerationsGenesGeneticGenetic ScreeningGoalsHippocampus (Brain)HumanInhibitory SynapseInterneuronsIon ChannelIon Channel GatingKnock-outLigandsLinkLiteratureMeasuresMediatingMusNeurologicNeuronsOutputPatientsPhenotypePlayPotassiumPropertyProtein IsoformsPublishingPyramidal CellsRNA SplicingRanvier&aposs NodesRegulationResearchRoleSeizuresSiteSodiumSourceStructureSudden DeathSynapsesSyndromeTestingTherapeuticTonic - clonic seizuresTransfectionUniversitiesVariantWorkcohortearly childhoodepileptic encephalopathiesexome sequencinghigh riskhippocampal pyramidal neuroninfancyinhibitory neuroninnovationinsightloss of functionmutantnervous system disorderneuronal excitabilityneurotransmissionnovelpostsynapticreceptorsudden unexpected death in epilepsytreatment strategyvariant of unknown significancevoltage
项目摘要
Developmental and epileptic encephalopathies (DEEs) are severe epilepsy syndromes that manifest in infancy
or early childhood and are characterized by intractable seizures, neurological and behavioral deficits, and a high
risk of Sudden Unexpected Death in Epilepsy (SUDEP). While most DEEs are linked to variants in genes
encoding ion channels, especially that of voltage-gated sodium (NaV) and potassium (KV) channels, DEE-linked
variants in non-ion-channel genes may provide important insights into the etiology of disease. Recently, whole
exome sequencing of DEE patients by our Peking University colleagues in China identified variants of uncertain
significance (VUS) in ANK3, suggesting that deficits in ion channel localization may contribute to disease
mechanisms. A large body of literature has shown that ankyrin-G, encoded by the ANK3 gene, plays a
fundamental role in the localization of voltage-gated ion channels to critical neuronal plasma membrane
subdomains, including the axon initial segment (AIS) and nodes of Ranvier, which are the sites of action potential
(AP) initiation and propagation, respectively. Recently, we have discovered novel functions for ankyrin-G in the
regulation of inhibitory synapses and control of neuronal excitability. However, the mechanisms underlying the
link between ANK3 and epilepsy are incompletely understood. The long-term goal of our work is to understand
how ankyrin-G dysfunction contributes to the etiology of neurological disorders, like DEE. The objective of this
application is to use a knockout and rescue strategy to understand the cellular and electrophysiological effects
of variants identified in the Peking University DEE cohort. Our central hypothesis is that DEE-associated ANK3
variants affect ankyrin-G function in controlling localization and function of voltage- and ligand-gated ion channels
resulting in pyramidal cell dysfunction, contributing to the pathophysiology of DEE. We will test our hypothesis
by pursuing two Specific Aims: 1) To understand the effects of human DEE-associated ANK3 variants on ankyrin-
G-mediated ion channel localization. 2) To determine the electrophysiological consequences of ANK3 DEE-
associated variants. The mechanisms underlying the link between ANK3 and epilepsy are incompletely
understood, yet the recently discovered VUS from the DEE patient cohort in China suggest a novel DEE
mechanism. The results of this work will have an important positive impact on the understanding of how ankyrin-
G regulates neuronal excitability and how ankyrin-G loss-of-function contributes to complex neurological
disorders, such as DEE. Most of the published work investigating DEE mechanisms has focused on patient
variants within ion channel genes. However, treatment strategies targeted against perturbations in ion channel
function have proven ineffective for many DEEs. Our approach may yield novel targets, which could serve as a
guide to develop innovative therapeutic strategies to treat DEE and possibly other idiopathic forms of epilepsy.
In addition, the results of these studies may uncover previously unappreciated functions of AnkG in
neurotransmission.
发展性和癫痫性脑病(dee)是在婴儿期出现的严重癫痫综合征
项目成果
期刊论文数量(0)
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Paul Michael Jenkins其他文献
Paul Michael Jenkins的其他文献
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{{ truncateString('Paul Michael Jenkins', 18)}}的其他基金
Mechanisms of Ciliary Trafficking of the Olfactory CNG Channel
嗅觉 CNG 通道的纤毛运输机制
- 批准号:
7545606 - 财政年份:2008
- 资助金额:
$ 42.9万 - 项目类别:
Mechanisms of Ciliary Trafficking of the Olfactory CNG Channel
嗅觉 CNG 通道的纤毛运输机制
- 批准号:
7636913 - 财政年份:2008
- 资助金额:
$ 42.9万 - 项目类别: