Dynamic two-photon calcium imaging and optogenetic manipulation of epileptic brain circuits in an experimental model of temporal lobe epilepsy
颞叶癫痫实验模型中癫痫脑回路的动态双光子钙成像和光遗传学操作
基本信息
- 批准号:9295077
- 负责人:
- 金额:$ 18.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AchievementAcuteAffectAmericanAnimal ModelAnimalsAppearanceAreaAwardBiomedical ResearchBrainCalciumCell TherapyCell physiologyCellsCerebral cortexCerebrumCharacteristicsChild CareChildhoodChronicChronic DiseaseClinicClinicalCommunitiesDataDevelopmentDevelopment PlansDiseaseDoctor of MedicineDoctor of PhilosophyElectrophysiology (science)EnsureEnvironmentEpilepsyExhibitsExperimental ModelsFailureFloorFunctional disorderFundingFutureGene DeletionGleanGoalsGrantHeadHippocampus (Brain)HumanImageIn VitroIndividualInterneuronsIntractable EpilepsyInvestigationK-Series Research Career ProgramsKnowledgeLabelLaboratoriesLaboratory ResearchLearningMediatingMedicalMentorsMentorshipMethodsModelingMusMutationNervous System PhysiologyNeurobiologyNeurologistNeurologyNeuronsNeurosciencesNeurosciences ResearchOutcomePathogenesisPathologicPathologyPatient CarePatientsPediatric HospitalsPediatric NeurologyPennsylvaniaPerforant PathwayPharmacologic SubstancePhiladelphiaPhysiciansPhysiologyPicrotoxinPopulationPositioning AttributePreparationPreventive InterventionProductivityPyramidal CellsRecruitment ActivityResearchResearch PersonnelResistanceResourcesRiskRoleRunningScienceScientistSeizuresSeriesSliceSomatostatinSpecificityStem cellsSyndromeTechniquesTemporal Lobe EpilepsyTestingTrainingTraining ActivityTraining ProgramsTraining SupportTranslatingTranslational ResearchUnited StatesUniversitiesawakebasecalcium indicatorcareercareer developmentcell typeclinical carecognitive functiondentate gyrusdesignentorhinal cortexexperiencefeedinggranule cellimaging modalityin vivoinsightinterestmedical schoolsmicroendoscopemouse modelmultimodalityneurogeneticsnovelnovel therapeuticsoptogeneticspre-clinicalpreventprofessorprogramsreceptorreconstitutionresponsesuccesssynaptic inhibitiontargeted treatmenttooltwo-photon
项目摘要
PROJECT SUMMARY
This mentored career development award proposal describes an integrated training program designed to
advance my career towards the goal of running an independent R01-funded biomedical research laboratory
focused on the study of epilepsy. Currently, there is no way to prevent epilepsy in at-risk individuals prior to the
appearance of seizures, and there are limited treatment options for patients with medically intractable epilepsy.
With the guidance of my mentor, Dr. Coulter, I have designed a training plan to successfully learn and apply a
coordinated, powerful set of state-of-the-art techniques – including electrophysiology, optogenetics, and two-
photon calcium imaging – in vitro and then in awake, behaving experimental animals in vivo. The proposed
research tests the hypothesis that brain circuit dysfunction in a well-established model of epilepsy is due to
abnormal activity of a defined subtype of inhibitory interneuron, the fast-spiking cells (“FS cells”). This multimodal
analysis of circuit-level mechanisms of epilepsy will yield novel results that will contribute to the development
and application of novel therapeutic strategies to prevent and treat epilepsy.
Candidate: I am currently Assistant Professor in the Division of Neurology at The Children's Hospital of
Philadelphia (CHOP) and Departments of Neurology and Neuroscience at The Perelman School of Medicine at
the University of Pennsylvania (UPenn). I am an M.D./Ph.D. physician-scientist with a strong background in
neuroscience, having received a Ph.D. in Physiology & Neuroscience from NYU in the laboratory of Dr. Bernardo
Rudy. I completed a five-year clinical training program in pediatric neurology at CHOP/UPenn and now take care
of children with epilepsy in General Neurology and Neurogenetics Clinic at CHOP. This proposal builds on my
long-standing interest in the neurobiology of disease and established interests in synaptic inhibition and
GABAergic inhibitory interneurons in the cerebral cortex. This K08 award will provide me with critical training and
support to insure a successful transition to independence and long-term achievement and productivity as a
neuroscientist and academic pediatric neurologist in the field of epilepsy. My goal is to become an R01-funded
independent investigator studying epilepsy in mouse models to inform the development of mechanistically
oriented therapies that could be translated to, and transform, patient care.
Environment: My mentor is Dr. Douglas Coulter, an established investigator in the field of epilepsy and a pioneer
in the application of dynamic imaging methods to the study of epilepsy mechanisms. Dr. Coulter is Director of
the Center for Dynamic Imaging of Nervous System Function at CHOP/UPenn and the Translational Research
Epilepsy Program at CHOP; he has multiple RO1 grants studying epilepsy. Dr. Coulter also has a robust track
record of mentoring trainees who have gone on themselves to be leaders in the field of epilepsy. His laboratory
is located in the Abramson Research Building, where the 4th and 5th floors are dedicated to neuroscience
research and include a collaborative group of highly successful scientists who are interested in and committed
to my career development and success. Dr. Coulter and I have constructed an outstanding mentorship team to
guide the execution of the proposed studies and my overall career development. I will attain mastery in the
clinical field of epilepsy neurogenetics under the guidance of Eric Marsh, M.D., Ph.D., Head of the Section on
Neurogenetics, Division of Neurology, at CHOP, who also runs an R01-funded basic neuroscience laboratory.
Training will occur at CHOP/UPenn, an academically enriching neuroscience community with extensive
resources and opportunities for scientific interaction, including a wide range of available coursework and multiple
ongoing neuroscience-, neurology-, and epilepsy-related seminar series. My career development plan involves
rigorous training in dynamic imaging, optogenetics, and the study of epilepsy in animal models, coursework in
crucial subject areas, as well as formal and informal training in how to properly conduct science and run a
research laboratory. This application is supported enthusiastically by the Division of Neurology at CHOP and
Department of Neurology at UPenn.
Research: My preliminary results show that there is abnormal GABAergic synaptic inhibition in the hippocampus
in a well-established animal model of temporal lobe epilepsy; namely, with failure of the so-called “dentate gate.”
Rather than being a general failure of inhibition, I have determined that a defined subset of GABAergic inhibition
interneuron in dentate gyrus exhibits abnormal activity in epilepsy. This proposal will build on my preliminary
data to test the hypotheses that: (1) the mechanistic basis of the dentate gate is feed-forward inhibition
specifically provided by fast-spiking interneurons, and (2) manipulation of FS cell activity in the epileptic brain
using optogenetics can reconstitute normal circuit activity. I predict that targeted silencing of fast-spiking cells in
control conditions will reproduce epileptic circuit pathology and augmenting the activity of these cells in epileptic
brain will recover normal inhibition. These outcomes will provide novel information regarding the normal function
of fast-spiking interneurons and role of synaptic inhibition in dentate gyrus, as well as establishing important
mechanistic contributions to the pathogenesis of temporal lobe epilepsy.
This mentored career development award will ultimately position me to translate the insights gleaned from basic
neuroscience research to inform and motivate future attempts at the targeted treatment of epilepsy based on
manipulation of GABAergic interneurons.
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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ETHAN M GOLDBERG其他文献
ETHAN M GOLDBERG的其他文献
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{{ truncateString('ETHAN M GOLDBERG', 18)}}的其他基金
Assessing mechanisms of brain malformation in SCN3A encephalopathy using stem cell-based models
使用干细胞模型评估 SCN3A 脑病的脑畸形机制
- 批准号:
10841993 - 财政年份:2023
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$ 18.42万 - 项目类别:
Mechanistically-oriented therapy for a progressive myoclonus epilepsy
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10444009 - 财政年份:2022
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$ 18.42万 - 项目类别:
Mechanistically-oriented therapy for a progressive myoclonus epilepsy
进行性肌阵挛癫痫的机械导向治疗
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10591528 - 财政年份:2022
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$ 18.42万 - 项目类别:
Pathomechanisms of SCN3A-related neurodevelopmental disorder
SCN3A相关神经发育障碍的发病机制
- 批准号:
10308091 - 财政年份:2020
- 资助金额:
$ 18.42万 - 项目类别:
Pathomechanisms of SCN3A-related neurodevelopmental disorder
SCN3A相关神经发育障碍的发病机制
- 批准号:
10544490 - 财政年份:2020
- 资助金额:
$ 18.42万 - 项目类别:
Interneuron axonopathy underlies circuit dysfunction in a mouse model of Dravet syndrome
中间神经元轴突病变是 Dravet 综合征小鼠模型中回路功能障碍的基础
- 批准号:
9910475 - 财政年份:2019
- 资助金额:
$ 18.42万 - 项目类别:
Interneuron axonopathy underlies circuit dysfunction in a mouse model of Dravet syndrome
中间神经元轴突病变是 Dravet 综合征小鼠模型中回路功能障碍的基础
- 批准号:
10372046 - 财政年份:2019
- 资助金额:
$ 18.42万 - 项目类别:
Interneuron axonopathy underlies circuit dysfunction in a mouse model of Dravet syndrome
中间神经元轴突病变是 Dravet 综合征小鼠模型中回路功能障碍的基础
- 批准号:
10599315 - 财政年份:2019
- 资助金额:
$ 18.42万 - 项目类别:
K+ channels in fast-spiking cell synaptic transmission
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- 批准号:
7174626 - 财政年份:2004
- 资助金额:
$ 18.42万 - 项目类别:
K+ channels in fast-spiking cell synaptic transmission
快速尖峰细胞突触传递中的 K 通道
- 批准号:
6992656 - 财政年份:2004
- 资助金额:
$ 18.42万 - 项目类别:
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