Understanding the Etiology of CASK Associated Epileptic Encephalopathy
了解 CASK 相关癫痫性脑病的病因
基本信息
- 批准号:10211576
- 负责人:
- 金额:$ 41.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:APBA1 geneATP phosphohydrolaseAcetatesAcuteAdultAffectAffinity ChromatographyAgeAge of OnsetAmericanAnimal ModelApoptosisBehavioralBiogenesisBiological AssayBiological MarkersBrainBrain DiseasesCalciumCellsCessation of lifeChildhoodClinicalCognitiveDNA Sequence AlterationDNA cassetteDiseaseDopamineEarly Infantile Epileptic EncephalopathyElectroencephalogramElectrophysiology (science)Endoplasmic ReticulumEnergy MetabolismEpilepsyEquilibriumEtiologyExhibitsFaceFunctional disorderGene ExpressionGeneral PopulationGenesGlucoseGlutamate ReceptorGlutamatesGlutaminaseGlutamineGoalsGrowthHydroxybutyratesImpaired cognitionImpairmentIn Situ Nick-End LabelingInfantile spasmsInhibitory SynapseInterventionIsotopesKetone BodiesKnockout MiceLabelLeadLifeLinkLiteratureMammalsMass Spectrum AnalysisMeasuresMembraneMessenger RNAMetabolicMetabolic PathwayMetabolismMethodsMitochondriaMitochondrial ProteinsModelingMultienzyme ComplexesMusMutationMyoclonusNADHNMR SpectroscopyNeomycinNeonatalNeurogliaNeuronsNeurotransmittersNicotinamide MononucleotideOuter Mitochondrial MembraneOxidative PhosphorylationPathogenicityPathway interactionsPatientsPharmacologyPhenotypePhysiologyPlayPrognosisProtein Interaction MappingProteinsPyruvateReactive Oxygen SpeciesRecurrenceReflex actionResidual stateRoleSIRT1 geneScanning Electron MicroscopySliceSpasmStructural defectStructureSynapsesTestingTherapeuticTimeTissuesTracerX-linked intellectual disabilitybasebehavioral impairmentearly onseteffective therapyepileptic encephalopathiesexperimental studygamma-Aminobutyric Acidhuman diseaseimprovedin vivoinfancyinhibitory neuroninnovationmalemitochondrial dysfunctionmitochondrial membranemortalitymouse modelneonatal miceneuron lossneuronal excitabilityneurophysiologynovelnovel therapeutic interventionoxidationoxidative damagepatch clamppostnatalreceptorsuccesssynaptic functiontherapeutic evaluation
项目摘要
PROJECT ABSTRACT
Epileptic encephalopathies (EEs) are severe brain disorders of early infantile and childhood age onset
characterized by epileptic seizures, abnormal electroencephalogram (EEG), severe cognitive and behavioral
impairments that might lead to early death. It is estimated that ~2.9 million Americans live with epilepsy and
the mortality rate in people with epilepsy is ~2-3 times higher than the general population. Several genetic
mutations associate with EEs including mutations in the X-linked intellectual disability gene CASK that are
found in patients with Ohtahara syndrome (OS) and West Syndrome (WS). Constitutive CASK deletion in
mammals is incompatible with life and the prognosis of CASK hemizygous male patients remains extremely
grim. The precise function of CASK and the potential mechanisms by which CASK mutation produces EE
remains obscure. Because the constitutive CASK-/- knockout mice exhibited neonatal lethality, we recently
generated a novel mouse model of EE by deleting CASK specifically from the neurons (CASKNKO). We found
that CASKNKO mice display severe growth retardation, recurrent tonic spasms, EEG anomalies, and
myoclonus beginning postnatal day 17 that leads to death by postnatal day 25. Multiple studies have shown
that CASK protein is localized at the mitochondrial membranes. Recently, CASK gene expression was found
to be regulated in an NAD+/Sirtuin1 dependent manner in mouse neurons. Moreover, we found that
mammalian CASK interacts and co-localizes with mitochondrial proteins, and significantly modulates
mitochondrial function and number. Based on the evidences from literature and our findings we hypothesize
that CASK plays a role in brain mitochondrial function and metabolism, and is critical for optimum neuronal
excitability in vivo. To test this hypothesis, we will examine the brain mitochondrial, metabolic, and
electrophysiological functional changes as well as synaptic excitatory/inhibitory balance in the CASKNKO mice.
We will further identify the specific domain/s of CASK that interacts with mitochondrial proteins, and determine
if SIRT1-dependent mitochondrial biogenesis pathway is dysregulated in the brain of CASKNKO mice.
Experiments will be performed before and after the onset of myoclonus to distinguish between a potential
cause and consequence relation with the disease. We will also test if pharmacological activation of
NAD+/SIRT1 pathway can stimulate mitochondrial biogenesis in the brain and CASK expression in glial cells
to rescue EE phenotype in the CASKNKO mice. Success in the proposed project will uncover how loss of
neuronal CASK alters mitochondrial and synaptic functions to produce EE. The long-term goal of our project
is to use the novel CASKNKO EE mouse model to identify potential disease biomarkers and test therapeutic
strategies for clinical intervention.
项目摘要
项目成果
期刊论文数量(0)
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Sarika Srivastava其他文献
Sarika Srivastava的其他文献
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{{ truncateString('Sarika Srivastava', 18)}}的其他基金
Understanding the Etiology of CASK Associated Epileptic Encephalopathy
了解 CASK 相关癫痫性脑病的病因
- 批准号:
10533820 - 财政年份:2021
- 资助金额:
$ 41.54万 - 项目类别:
Understanding the Etiology of CASK Associated Epileptic Encephalopathy
了解 CASK 相关癫痫性脑病的病因
- 批准号:
10378009 - 财政年份:2021
- 资助金额:
$ 41.54万 - 项目类别: