Exploratory determination of the role of L-type calcium channels in mediating abnormal plasticity and behavior after early life seizures
Exploratory determination of the role of L-type calcium channels in mediating abnormal plasticity and behavior after early life seizures
批准号:
9454781
负责人:
TIMOTHY A BENKE
金额:
$18.99万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-15 至 2019-08-31
关键词:
ARHGEF5 geneAddressAgeAnatomyBehaviorBehavioralBindingBiochemistryBiological MarkersCattleCellsChildhoodChronicClinicalClinical ResearchDataDevelopmentEarly treatmentEpilepsyFMRPFRAP1 geneFunctional disorderFutureGeneticGenetic ModelsHippocampus (Brain)Hyperactive behaviorImmunohistochemistryIn VitroInjuryIntellectual functioning disabilityIsradipineL-Type Calcium ChannelsLifeLinkLong-Term DepressionLong-Term PotentiationMeasurementMeasuresMediatingModelingNeurocognitionNeurocognitiveNeurocognitive DeficitPathway interactionsPatientsPeptidesPeritoneumPharmacologyPlayProtein phosphataseProteinsPublishingRattusRodent ModelRoleSeizuresSignal TransductionSliceSynaptic plasticitySyndromeTestingWorkautism spectrum disorderbasebehavioral studyepileptic encephalopathiesexperimental studyimmunocytochemistryimprovedkainatenovelnovel therapeuticsprotein protein interactionsecondary outcometherapeutic target
中文摘要
摘要:“探究l型钙通道在介导异常可塑性中的作用
英文摘要
ABSTRACT: “Exploratory determination of the role of L-type calcium channels in mediating abnormal plasticity
and behavior after early life seizures”
Pediatric epileptic encephalopathy (P-EE) syndromes, characterized by frequent early-life seizures (ELS),
are associated with catastrophic neurocognitive impairment including autism spectrum disorder and intellectual
disability (ASD/ID). P-EE can be associated with injury or genetic causes. Currently, clinical opinions by leaders
vary widely in the field, with some believing that ELS adds insult to injury and favoring the aggressive treatment
of ELS. For most of our patients, “the cow is already out of the barn”: ELS has already happened and there are
no therapies to address the long-term consequences of ELS itself. Therefore, there is an urgent need to
investigate these issues with rodent models: 1) What are the mechanisms? 2) Can this be treated?
We hypothesize that hyperactive L-type calcium channels (LTCCs) play a substantial role to mediate
abnormal plasticity and behavior in P-EE. Studies in CA1 hippocampal slices in vitro will pharmacologically
compare mechanistic changes in synaptic plasticity (SA1) mediated by LTCCs that have developed chronically
(P60+) after ELS. Behavioral studies (SA2) will determine the neurocognitive benefit of an LTCC antagonist after
ELS. Our rationale is that these studies will segue to mechanistically inspired, novel therapeutics for
neurocognitive deficits associated with ELS where none exist that could provide significant societal benefit.
Specific Aim 1 (SA1): Mechanistically link KA-ELS-mediated LTCC dysfunction to disruption of key LTCC
protein-protein interactions that impact mGluR-LTD.
Specific Aim 2 (SA2): Determine whether chronic LTCC antagonism ameliorates neurocognitive impairment
after KA-ELS.
These exploratory studies will lay the groundwork to segue into comprehensive studies investigating the
mechanistic roles of LTCC in mediating neurocognitive deficits in P-EE with ELS. By understanding
mechanistically how LTCC modulate plasticity after ELS (SA1) and determining whether broad-spectrum LTCC
inhibition improves neurocognition (SA2), we can then advance LTCC-related neurotherapeutic strategies for
application to genetic models of P-EE with ELS, to be characterized in future studies. These studies are
essential, as genetic or other protein replacement strategies in P-EE may be insufficient to correct the long-term
consequences of ELS.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
University of Colorado Rocky Mountain NeuroNEXT (UNCOMON) Clinical Research Consortium.
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批准号:10744629
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项目类别:
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资助金额:$42.9万
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财政年份:2023
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负责人:TIMOTHY A BENKE
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依托单位:
Multi-Site Validation of Biomarkers and Core Clinical Outcome Measures for Clinical Trials Readiness in CDKL5 Deficiency Disorder
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批准号:10569019
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项目类别:
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资助金额:$90.23万
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财政年份:2021
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负责人:TIMOTHY A BENKE
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依托单位:
Multi-Site Validation of Biomarkers and Core Clinical Outcome Measures for Clinical Trials Readiness in CDKL5 Deficiency Disorder
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批准号:10338135
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项目类别:
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资助金额:$92.42万
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财政年份:2021
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负责人:TIMOTHY A BENKE
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依托单位:
Colorado Neurological Sciences Academic Development Award (NSADA)
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批准号:8788338
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项目类别:
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资助金额:$15.17万
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财政年份:2015
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负责人:TIMOTHY A BENKE
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依托单位:
Molecular mechanisms linking early life seizures, autism and intellectual disabil
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批准号:8217756
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项目类别:
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资助金额:$33.24万
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财政年份:2011
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负责人:TIMOTHY A BENKE
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依托单位:
Molecular mechanisms linking early life seizures, autism and intellectual disabil
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批准号:8533043
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项目类别:
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资助金额:$31.36万
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财政年份:2011
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负责人:TIMOTHY A BENKE
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依托单位:
Molecular mechanisms linking early life seizures, autism and intellectual disabil
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批准号:8323875
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项目类别:
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资助金额:$33.35万
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财政年份:2011
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负责人:TIMOTHY A BENKE
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依托单位:
Molecular mechanisms linking early life seizures, autism and intellectual disabil
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批准号:8909216
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项目类别:
-
资助金额:$33.19万
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财政年份:2011
-
负责人:TIMOTHY A BENKE
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依托单位:
Rocky Mountain Network for Neuroscience Clinical Studies (RMNNCS)
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批准号:8866484
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项目类别:
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资助金额:$30.6万
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财政年份:2011
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负责人:TIMOTHY A BENKE
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依托单位:
Molecular mechanisms linking early life seizures, autism and intellectual disabil
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批准号:8722047
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项目类别:
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资助金额:$32.63万
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财政年份:2011
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负责人:TIMOTHY A BENKE
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依托单位:
Rocky Mountain Network for Neuroscience Clinical Studies (RMNNCS)
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批准号:8722637
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项目类别:
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资助金额:$29.6万
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财政年份:2011
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负责人:TIMOTHY A BENKE
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依托单位:
Impact of early life seizures on glutamate receptors and synaptic function
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批准号:7394992
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项目类别:
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资助金额:$18.74万
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财政年份:2007
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负责人:TIMOTHY A BENKE
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依托单位:
Impact of early life seizures on glutamate receptors and synaptic function
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批准号:7262203
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项目类别:
-
资助金额:$18.74万
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财政年份:2007
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负责人:TIMOTHY A BENKE
-
依托单位:
Impact of early life seizures on glutamate receptors and synaptic function
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批准号:7591131
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项目类别:
-
资助金额:$18.74万
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财政年份:2007
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负责人:TIMOTHY A BENKE
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依托单位:
Core C: Neural & Behavioral Phenotyping
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批准号:8990164
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项目类别:
-
资助金额:$18.77万
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财政年份:2004
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负责人:TIMOTHY A BENKE
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依托单位:
Core C: Neural & Behavioral Phenotyping
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批准号:9198065
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项目类别:
-
资助金额:$19.13万
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财政年份:2004
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负责人:TIMOTHY A BENKE
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依托单位:
Impact of Early-Life Seizures on Synaptic Plasticity
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批准号:6318920
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项目类别:
-
资助金额:$12.66万
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财政年份:2001
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负责人:TIMOTHY A BENKE
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依托单位:
Impact of Early-Life Seizures on Synaptic Plasticity
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批准号:6942966
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项目类别:
-
资助金额:$13.07万
-
财政年份:2001
-
负责人:TIMOTHY A BENKE
-
依托单位:
Impact of Early-Life Seizures on Synaptic Plasticity
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批准号:6795086
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项目类别:
-
资助金额:$13.07万
-
财政年份:2001
-
负责人:TIMOTHY A BENKE
-
依托单位:
Impact of Early-Life Seizures on Synaptic Plasticity
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批准号:6656219
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项目类别:
-
资助金额:$13.07万
-
财政年份:2001
-
负责人:TIMOTHY A BENKE
-
依托单位:
海外基金