Dissecting the role of gut microbial-derived metabolites on epilepsy
剖析肠道微生物代谢物对癫痫的作用
基本信息
- 批准号:10502915
- 负责人:
- 金额:$ 39.07万
- 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:2022-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAcuteAdultAffectAgreementAntiepileptic AgentsBacteriaBlood - brain barrier anatomyBrainC57BL/6 MouseCellsCellular MembraneChronicDataDefectDevelopmentDrug resistanceElectroencephalographyElectrophysiology (science)EpilepsyFrequenciesGeneticHippocampus (Brain)HomeostasisInfectionInflammationInjectionsKainic AcidKnowledgeLinkLiquid ChromatographyMass Spectrum AnalysisMetabolicModelingMolecularMusNervous System PhysiologyNeuraxisNeuronal DysfunctionNeuronsOutcomePatientsPhasePhenotypePhysiologicalPhysiologyPlasmaPlayPredispositionPrevalenceProcessProductionProteinsPublishingResearchResistanceResource-limited settingRisk FactorsRodentRoleSamplingSeizuresSignal PathwaySupplementationSynapsesSynaptic TransmissionTMEVTaxonomyTemporal LobeTemporal Lobe EpilepsyTest ResultTestingTherapeuticTherapeutic InterventionTimeViralVirus DiseasesWorkacquired epilepsyastrogliosisdaidzeindesigndietaryequolgut bacteriagut microbesgut microbiomegut microbiotagut-brain axisinnovationlarge-conductance calcium-activated potassium channelsmicrobialmicrobiomemicrobiome analysismicroorganismmortalityneglectnervous system disorderneuronal excitabilityneuroprotectionnovelnovel strategiespatch clampsynaptic functiontandem mass spectrometrytargeted treatmenttherapeutic targettranscriptome sequencingvoltage
项目摘要
Project Summary
Epilepsy is a common neurological disorder, with a worldwide prevalence of over 65 million. There is general
agreement that epilepsy is caused by hyperexcitable neuronal networks and most therapeutic strategies have
focused on decreasing excitation by targeting neuronal synaptic proteins. Even with the available antiepileptic
drugs, there is still no cure and 30% of patients are resistant to treatment. Historically, epilepsy has been viewed
as driven solely by defects in brain processes; however, this brain-centric perspective neglects the fact that the
function of the nervous system is affected by the metabolic state of the body. Current research recognizes that
microorganisms influence the brain by modifying metabolic factors in the gut, the “gut-brain axis.” Most of the
evidence thus far is correlative showing that changes in the gut microbiota can affect seizure outcomes.
However, there is a gap in knowledge regarding specific mechanisms by which gut microbes contribute to seizure
development that may offer novel approaches to treat epilepsy. Viral infection-induced epilepsy is the most
common cause of epilepsy worldwide and is often difficult to model in rodents due to high mortality rates.
However, the Theiler's murine encephalomyelitis virus (TMEV) is a low-mortality viral-induced model of temporal
lobe epilepsy. Intracranial TMEV injection leads to hippocampal neuronal dysfunction, widespread cortical
astrogliosis, and seizure-genesis peaking at 6 days post infection in ~50% of adult C57BL/6 mice. While central
nervous system inflammation has been posited as a potential modulator of seizure phenotype development in
TMEV infection, the molecular mechanism is unclear. Data obtained from this model surprisingly indicated that
the majority of taxonomies underrepresented in TMEV-infected mice with seizure phenotypes contained genera
associated with the production of the bacterial metabolite S-equol. These bacteria convert dietary daidzein into
S-equol, which has been shown to activate large conductance Ca2+- and voltage-activated K+ (BK) channels.
Activation of BK channels play an important role in controlling neuronal excitability and therefore represents a
novel target for the treatment of epilepsy. This proposal will determine if depletion of the microbial-derived
metabolite, S-equol, increase seizure occurrence in TMEV-injected mice. It further tests the hypothesis that S-
equol-producing microbial species confer neuroprotection against seizure susceptibility and neuronal
hyperexcitability following TMEV injection via activation of BK channels. This hypothesis will be tested using a
combination of EEG and electrophysiology recordings, mass spectrometry and 16S RNA sequencing. To
determine whether these findings are broadly applicable to other types of epilepsy we will examine three models
of epilepsy, TMEV, kainic acid and a genetic epilepsy model. This work takes a critical step causally linking
specific microbial shifts to neuronal excitability, seizures and epilepsy and will identify microbial metabolites that
can be targeted for therapeutic intervention.
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(0)
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Susan Latoya Campbell其他文献
Susan Latoya Campbell的其他文献
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{{ truncateString('Susan Latoya Campbell', 18)}}的其他基金
Dissecting the role of gut microbial-derived metabolites on epilepsy
剖析肠道微生物代谢物对癫痫的作用
- 批准号:
10901461 - 财政年份:2022
- 资助金额:
$ 39.07万 - 项目类别:
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