Calcium-sensing Receptor Signaling and Epilepsy
Calcium-sensing Receptor Signaling and Epilepsy
批准号:
9280838
负责人:
Stephen M Smith
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-01-01 至 2018-12-31
关键词:
Action PotentialsAddressAffectAgonistAlcohol withdrawal syndromeAnticonvulsantsAntiepileptic AgentsAutomobile DrivingBlood - brain barrier anatomyBrainBrain NeoplasmsCalciumCalcium-Sensing ReceptorsCationsCellsChronicChronic DiseaseCollaborationsCommunicationDNA Sequence AlterationDataDiseaseDrug TargetingElderlyElectroporationEpilepsyEvoked PotentialsExcitatory SynapseFDA approvedFailureG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGlutamatesHeterogeneityHippocampus (Brain)Imaging TechniquesImpact SeizuresInheritedInhibitory SynapseInterneuronsIon ChannelLeadLightLinkMediatingMedicineModelingMolecularMusMutationNerveNeuronsPatch-Clamp TechniquesPathway interactionsPatientsPharmaceutical PreparationsPhysiologicalPilocarpinePlayPositioning AttributePredispositionPrevalenceProbabilityPropertyPublic HealthReagentReceptor ActivationReceptor SignalingRegulationResistanceRiskRoleSeizuresShapesSignal PathwaySignal TransductionStrokeSynapsesSynaptic TransmissionTestingTraumaTraumatic Brain InjuryVeteransWarWorkbiophysical analysisbiophysical propertiescinacalcetdesignexperienceexperimental studyextracellulargamma-Aminobutyric Acidin vivoknock-downlive cell imagingmouse modelmutantneocorticalneuronal cell bodyneuronal excitabilityneurotransmissionneurotransmitter releasenew therapeutic targetnovelpatch clamppublic health relevancereceptorreceptor functionresponsesmall hairpin RNAtransmission processtumorvoltage
中文摘要
描述(由申请人提供):
英文摘要
DESCRIPTION (provided by applicant):
The extracellular calcium-sensing receptor (CaSR) is widely distributed in the brain, is modulated by changes in the external calcium concentration ([Ca2+]o), and impacts neuronal activity in a number of ways. In addition to inhibiting a non-selective cation channel in nerve terminals, inhibiting action potential evoked transmitter release, and stimulating spontaneous neurotransmission, all of which may change the predisposition for seizures to occur, it has also been proposed that CaSR transduces calcium-mediated changes in neuronal excitability. The questions to be addressed are, what are the detailed mechanisms by which CaSR signaling change result in changes of neuronal activity and does CaSR activation impact seizures? In addition as part of this proposal we will determine: 1) if CaSR activation impacts spontaneous and evoked transmission equally, 2) if CaSR signaling is the pathway that mediates [Ca2+]o-dependent changes in neuronal excitability, and 3) which of these changes is likely to mediate an antiepileptic action of CaSR agonists? The hypothesis is that CaSR, a G-protein coupled receptor (GPCR), is an important target for novel antiepileptic drugs. The proposed project is designed to test this hypothesis and determine the mechanism by which the CaSR mutations affect CaSR signaling and neuronal activity using the following four-part approach. First, it will be determined how wild-type and mutant CaSR affect the excitability of neocortical neurons in response to changes in [Ca2+]o. These experiments will employ biophysical measurements from single neurons that are expressing wt CaSR. Second we will use direct recordings from nerve terminals to determine if CaSR signaling at the terminal and soma use the same mechanisms. Third we will determine how CaSR signaling impacts neuron-neuron communication. Here experiments will allow comparison of the effects of CaSR signaling on evoked and spontaneous transmission at inhibitory and excitatory synapses. Fourth we will evaluate if CaSR agonists reduce seizures in two mouse models. Successful completion of this proposal will substantially impact the field by increasing our understanding of calcium regulation in the brain and expanding our understanding of how CaSR signaling might be utilized to treat epilepsy and other forms of seizures.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Sodium channel control of neuronal excitability
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批准号:10153825
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项目类别:
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资助金额:$20.56万
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财政年份:2020
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负责人:Stephen M Smith
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依托单位:
Sodium channel control of neuronal excitability
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批准号:10394713
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项目类别:
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资助金额:$20.56万
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财政年份:2020
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负责人:Stephen M Smith
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依托单位:
Equipment Supplement: Sodium Channel Control of Neuronal Excitability
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批准号:10382711
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项目类别:
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资助金额:$3.73万
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财政年份:2020
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负责人:Stephen M Smith
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依托单位:
Dynamic Chemical Regulation of Voltage-gated Sodium Channels
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批准号:10266071
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项目类别:
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资助金额:$0.0万
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财政年份:2015
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负责人:Stephen M Smith
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依托单位:
Calcium-sensing Receptor Signaling and Epilepsy
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批准号:8993860
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项目类别:
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资助金额:$0.0万
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财政年份:2015
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负责人:Stephen M Smith
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依托单位:
Central calcium and cannabinoid signaling
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批准号:8850871
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项目类别:
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资助金额:$23.94万
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财政年份:2012
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负责人:Stephen M Smith
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依托单位:
Central calcium and cannabinoid signaling
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批准号:8236613
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项目类别:
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资助金额:$29.26万
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财政年份:2012
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负责人:Stephen M Smith
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依托单位:
Central calcium and cannabinoid signaling
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批准号:8462998
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项目类别:
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资助金额:$28.24万
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财政年份:2012
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负责人:Stephen M Smith
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依托单位:
Central calcium and cannabinoid signaling
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批准号:8650902
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项目类别:
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资助金额:$23.94万
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财政年份:2012
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负责人:Stephen M Smith
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依托单位:
ISOLATION OF A NEW HIV-2 GROUP IN THE US
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批准号:8173028
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项目类别:
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资助金额:$6.18万
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财政年份:2010
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负责人:Stephen M Smith
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依托单位:
A novel cannabinoid receptor in cortical nerve terminals
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批准号:7990843
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项目类别:
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资助金额:$23.1万
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财政年份:2010
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负责人:Stephen M Smith
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依托单位:
A novel cannabinoid receptor in cortical nerve terminals
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批准号:8145282
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项目类别:
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资助金额:$18.67万
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财政年份:2010
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负责人:Stephen M Smith
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依托单位:
ISOLATION OF A NEW HIV-2 GROUP IN THE US
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批准号:7958721
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项目类别:
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资助金额:$5.81万
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财政年份:2009
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负责人:Stephen M Smith
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依托单位:
Nerve Terminal Regulation in the Cerebral Cortex
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批准号:7058763
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项目类别:
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资助金额:$24.51万
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财政年份:2003
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负责人:Stephen M Smith
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依托单位:
Nerve Terminal Regulation in the Cerebral Cortex
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批准号:6682091
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项目类别:
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资助金额:$27.48万
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财政年份:2003
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负责人:Stephen M Smith
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依托单位:
Nerve Terminal Regulation in the Cerebral Cortex
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批准号:6890968
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项目类别:
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资助金额:$25.1万
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财政年份:2003
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负责人:Stephen M Smith
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依托单位:
Nerve Terminal Regulation in the Cerebral Cortex
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批准号:6748165
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项目类别:
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资助金额:$25.1万
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财政年份:2003
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负责人:Stephen M Smith
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依托单位:
海外基金