Rewiring the Injured Brain with GABA Progenitors
Rewiring the Injured Brain with GABA Progenitors
批准号:
10367991
负责人:
Robert F Hunt
金额:
$43.35万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
未结题
起止时间:
2016-02-15 至 2026-03-31
关键词:
AcuteAddressAdolescentAdultAmericanAnxietyAreaBehaviorBehavioralBehavioral AssayBenchmarkingBrainBrain InjuriesCell TherapyCell TransplantationCellsChronicClinicClosed head injuriesCognitiveCraniocerebral TraumaDevelopmentDiseaseElectroencephalographyElectrophysiology (science)EmbryoEpilepsyFluorescent Antibody TechniqueFundingGangliaGenerationsGoalsHippocampus (Brain)HumanImageImpairmentIn VitroInjectionsInjuryInterneuronsLaboratoriesLightLong-Term EffectsMedialMemoryMemory impairmentModelingMonitorMotorMusNational Institute of Neurological Disorders and StrokeNeuronsOutputPatientsPatternPost-Traumatic EpilepsyPre-Clinical ModelProceduresPropertyReplacement TherapyResearchRodentRodent ModelSeizuresSliceSourceSupportive careSynapsesTBI treatmentTechnologyTherapeuticTherapeutic EffectTissuesTranslatingTransplantationTraumatic Brain InjuryTreatment EfficacyViralWorkcell typeclinically relevantcontrolled cortical impactcostdesigndisabilitygamma-Aminobutyric Acidhuman pluripotent stem cellimprovedinduced pluripotent stem cellinhibitory neuronmigrationmouse modelnerve stem cellnervous system disorderneural circuitnovel therapeuticsoptogeneticspatch clamppreventprogenitorside effectstem cellssynaptic inhibitiontherapeutic evaluation
中文摘要
摘要
神经祖细胞移植在治疗许多神经系统方面具有非凡的潜力
失调。最近的几项研究表明,源自小鼠胚胎内侧的祖细胞
神经节隆起 (MGE) 保留了迁移和分化为 GABA 能中间神经元的独特能力
移植到幼年或成年啮齿动物大脑后。我们最近证明这些细胞
在小鼠模型中可有效纠正记忆障碍并预防自发性癫痫发作
脑外伤。然而,尚不清楚是否可以达到类似的治疗效果
临床相关的细胞来源,例如人类多能干细胞。在这里,我们提出研究来评估
人源中间神经元在创伤性脑损伤临床前模型中的作用。我们的方法包括
将人类中间神经元祖细胞移植到广泛使用的闭合性头部损伤的啮齿动物模型中
损伤后的不同阶段,然后进行体外膜片钳记录、免疫荧光技术
和神经回路映射来评估移植神经元的突触整合。行为电池
检测和视频脑电图监测也将被应用。提出了两个具体目标:(i) 确定如何
人源性 GABA 祖细胞整合到脑损伤的海马体中,并且 (ii) 测试治疗效果
人类 GABA 神经元在小鼠脑外伤模型中的功效。如果成功,我们的结果将有所帮助
通过为人类建立相对直接的概念证明,使这些令人兴奋的技术更接近临床
中间神经元移植治疗创伤性脑损伤。
英文摘要
Abstract
Transplantation of neural progenitor cells has extraordinary potential for the treatment of many nervous system
disorders. Several recent studies have shown that progenitor cells derived from the embryonic mouse medial
ganglionic eminence (MGE) retain a unique ability to migrate and differentiate into GABAergic interneurons
following transplantation into the juvenile or adult rodent brain. We recently demonstrated that these cells are
effective in correcting memory impairments and preventing spontaneous seizures in a mouse model of
traumatic brain injury. However, it is not known whether similar therapeutic effects can be achieved with
clinically-relevant cell sources, such as human pluripotent stem cells. Here, we propose studies to evaluate the
effect of human-derived interneurons in a pre-clinical model of traumatic brain injury. Our approach involves
transplantation of human interneuron progenitors into a widely-used rodent model of closed-head injury at
different stages following injury followed by in vitro patch-clamp recordings, immunofluorescence techniques
and neural circuit mapping to evaluate the synaptic integration of grafted neurons. A battery of behavioral
assays and video-EEG monitoring will also be applied. Two specific aims are proposed: (i) determine how
human-derived GABA progenitors integrate into brain injured hippocampus, and (ii) test the therapeutic
efficacy of human GABA neurons in a mouse model of traumatic brain injury. If successful, our results will help
move these exciting technologies closer to the clinic by establishing relatively direct proof of concept for human
interneuron transplantation to treat traumatic brain injury.
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会议论文
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批准号:10586860
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项目类别:
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资助金额:$53.72万
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财政年份:2023
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负责人:Robert F Hunt
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依托单位:
Rewiring the Injured Brain with GABA Progenitors
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批准号:10211616
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资助金额:$45.16万
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财政年份:2016
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负责人:Robert F Hunt
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依托单位:
Rewiring the injured brain with GABA progenitors.
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批准号:9215702
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项目类别:
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资助金额:$33.8万
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财政年份:2016
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负责人:Robert F Hunt
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依托单位:
Rewiring the Injured Brain with GABA Progenitors
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批准号:10619546
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项目类别:
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资助金额:$43.35万
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财政年份:2016
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负责人:Robert F Hunt
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依托单位:
Functional engraftment of stem cell-derived cortical interneurons
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批准号:9266837
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项目类别:
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资助金额:$24.9万
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财政年份:2015
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负责人:Robert F Hunt
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依托单位:
Functional engraftment of stem cell-derived cortical interneurons
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批准号:8618809
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项目类别:
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资助金额:$8.8万
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财政年份:2013
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负责人:Robert F Hunt
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依托单位:
Functional engraftment of stem cell-derived cortical interneurons
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批准号:8738733
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项目类别:
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资助金额:$8.8万
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财政年份:2013
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负责人:Robert F Hunt
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依托单位:
Functional integration of inhibitory interneuron progenitors in the adult brain
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批准号:8452226
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项目类别:
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资助金额:$0.74万
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财政年份:2012
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负责人:Robert F Hunt
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依托单位:
Functional integration of inhibitory interneuron progenitors in the adult brain
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批准号:8311375
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项目类别:
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资助金额:$4.92万
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财政年份:2012
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负责人:Robert F Hunt
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依托单位:
海外基金