Inflammatory regulation of neurotrophin signaling in epileptogenesis
癫痫发生中神经营养蛋白信号传导的炎症调节
基本信息
- 批准号:10303038
- 负责人:
- 金额:$ 33.25万
- 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:2018-08-03 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAddressAmericanAmygdaloid structureAnimal ExperimentsAntiepileptic AgentsAntiepileptogenicBDNF geneBehavioralBiochemicalBiological ModelsBrainBrain-Derived Neurotrophic FactorCREB1 geneChronicClinical ResearchCognitive deficitsComplementCoupledCyclic AMPCyclic AMP-Dependent Protein KinasesDarknessDataDevelopmentDinoprostoneDiseaseDoseEP4 receptorElectroencephalographyElementsEpilepsyEpileptogenesisEventFDA approvedGTP-Binding Protein alpha Subunits, GsGene StructureGeneticGenetic TranscriptionGlial Fibrillary Acidic ProteinGliosisGoalsHippocampusIn VitroInflammationInflammatoryInjectionsInterleukin-1 betaInterleukin-6IsoenzymesLightMediatingMediatorMental DepressionMessenger RNAMicrodialysisModelingModificationMolecularMolecular TargetMusMutant Strains MiceNerve DegenerationNeuroblastomaNeuronsNeurotrophic Tyrosine Kinase Receptor Type 2OutcomePLC gamma1Pathway interactionsPatientsPharmaceutical PreparationsPhosphorylationPhosphotransferasesPlayPopulationPreventionPrevention strategyProcessProductionRecurrenceRegulationResistanceRoleSamplingSeizuresSeveritiesSignal PathwaySignal TransductionStainsStatus EpilepticusTNF geneTestingTimeTropomyosinVariantWFDC2 geneWorkacquired epilepsyaddictionantagonistanxiety-like behaviorbrain abnormalitiescomorbiditycytokinedesigndisorder preventionexperienceexperimental studyfluoro jadein vivoin vivo Modelinhibitorinterestkainatemouse PGE synthase 1nervous system disorderneuroinflammationneuron lossneuropathologyneurotrophic factornovelnovel therapeuticsobject recognitionpainful neuropathypharmacologicpreclinical studypreventpreventable epilepsypromoterreceptorresponsesmall molecule inhibitortooltranscription factor
项目摘要
PROJECT SUMMARY
Epilepsy is a common neurological disorder that afflicts about 1% of the population. Although seizures can be
partially controlled by current medications, there is no US FDA-approved drug that can provide disease
prevention or modification despite remarkable advances in epilepsy treatment over the past decades. A major
obstacle to finding such an antiepileptogenic drug is that the molecular mechanisms by which a normal brain is
transformed to generate epileptic seizures remain unsolved. Accumulating evidence from recent clinical and
preclinical studies suggests that the abnormal activation of the brain-derived neurotrophic factor (BDNF)
receptor TrkB (tropomyosin-related kinase receptor B) and its downstream effector phospholipase Cγ1 (PLCγ1)
is sufficient to produce epilepsy following status epilepticus (SE). As TrkB and PLCγ1 are emerging as
attractive molecular targets to prevent acquired epilepsy, a key unsolved puzzle is the signaling events that are
triggered by SE and cause the irregular BDNF/TrkA activity in the hippocampus, thereby leading to
epileptogenesis. In preliminary studies we have demonstrated that the seizure-induced hippocampal
BDNF/TrkB abnormality is largely suppressed by blocking prostaglandin E2 (PGE2) synthesis or signaling. Our
main hypothesis is that PGE2 via a Gαs-dependent signaling pathway upregulates hippocampal BDNF/TrkB
activity and contributes to epileptogenesis following prolonged seizures. Our general approach is to use
biochemical, pharmacological, genetic tools, and multiple in vitro and in vivo model systems to test a
hypothesis that PGE2 is involved in the hippocampal BDNF induction and TrkB activation after SE, to
determine whether seizure-mediated BDNF/TrkB activity involves cAMP/PKA signaling and which Gαs-coupled
PGE2 receptor is engaged, and to determine whether PGE2 signaling via its Gαs-coupled receptors plays a
dominant role in the development of epilepsy and/or the associated behavioral comorbidities after SE.
Successful completion of this project might lead to the discovery of novel molecular targets for the prevention
strategies of acquired epilepsy.
项目总结
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(1)
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Jianxiong Jiang其他文献
Jianxiong Jiang的其他文献
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{{ truncateString('Jianxiong Jiang', 18)}}的其他基金
Targeting TRPC3 Channels for Epileptic Seizures
针对癫痫发作的 TRPC3 通道
- 批准号:
10531252 - 财政年份:2021
- 资助金额:
$ 33.25万 - 项目类别:
Targeting TRPC3 Channels for Epileptic Seizures
针对癫痫发作的 TRPC3 通道
- 批准号:
10353604 - 财政年份:2021
- 资助金额:
$ 33.25万 - 项目类别:
Inflammatory regulation of neurotrophin signaling in epileptogenesis
癫痫发生中神经营养蛋白信号传导的炎症调节
- 批准号:
10058296 - 财政年份:2018
- 资助金额:
$ 33.25万 - 项目类别:
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