Bidirectional control of Chd2 haploinsufficiency
Chd2 单倍体不足的双向控制
基本信息
- 批准号:10586860
- 负责人:
- 金额:$ 53.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAnatomyAreaAutomobile DrivingBasic ScienceBehaviorBehavioralBenchmarkingBrainBrain regionCancer cell lineCandidate Disease GeneChromatinChromatin Remodeling FactorChromosome MappingClinicClustered Regularly Interspaced Short Palindromic RepeatsCommunicationComplexDNA Sequence AlterationDataDevelopmentDiabetes MellitusDiseaseElectrophysiology (science)EmbryoEngineeringEpilepsyEventExhibitsGene ExpressionGene MutationGenesGenetic RiskGenetic studyGenomicsGlutamatesHeterozygoteHippocampusHumanImmunohistochemistryIn VitroIndividualInduced pluripotent stem cell derived neuronsIntellectual functioning disabilityLaboratoriesLiteratureLongevityMalignant NeoplasmsMediatingMemoryMemory impairmentMetforminMolecularMusMutationNational Institute of Neurological Disorders and StrokeNeurodevelopmental DisorderNeurologicNeuronsPathologicPathologyPatientsPharmaceutical PreparationsPhotosensitivity DisordersPopulationProliferatingPyramidal CellsReportingResearchSeriesSignal TransductionStem cell transplantStructureSynapsesTestingTherapeuticTranslatingTransplantationWestern BlottingWorkautism spectrum disorderbehavioral studydosagehippocampal pyramidal neuronin vivoinduced pluripotent stem cellloss of function mutationmigrationmouse geneticsneurodevelopmentneuronal excitabilityneurotransmissionnew therapeutic targetnovelnovel therapeuticspharmacologicpreventstem cellssynaptic functiontherapeutic evaluation
项目摘要
ABSTRACT
Major advances have been made in mapping the genetic basis of epilepsy and other neurodevelopmental
disorders (NDDs). In many cases, a candidate gene mutation has been identified, but there is no robust
understanding of the neuronal causes for the particular disorder. Mutations in genes encoding chromatin
regulators are commonly identified in human NDDs, with intellectual disability, autism and/or epilepsy often co-
occurring in the same individual. Our recent work showed that mice with germline heterozygous mutations in
Chd2 exhibit pathological changes across genomic, anatomical, electrophysiological and behavioral domains.
Here, we propose studies to bidirectionally control Chd2 dosage in the developing or adult brain. Our approach
involves a combination of sophisticated cellular, molecular, pharmacologic and electrophysiological
approaches in conditional Chd2+/- mice and human-derived neurons. If successful, our results will provide
important new information about the effects of chromatin regulators in driving NDD-associated pathologies in
vivo and would provide critical proof-of-concept for the therapeutic potential of pharmacologically increasing
Chd2 expression that could be rapidly translated into a new targeted therapy for Chd2 haploinsufficiency.
摘要
在绘制癫痫和其他神经发育的遗传基础图方面取得了重大进展
精神障碍(NDDS)。在许多情况下,已经确定了候选基因突变,但没有可靠的
了解导致这种特殊疾病的神经原因。染色质编码基因的突变
调节剂通常在人类NDD中被发现,并伴有智力残疾、自闭症和/或癫痫。
发生在同一个人身上的。我们最近的工作表明,具有生殖系杂合突变的小鼠
CHD2表现出跨越基因组、解剖、电生理和行为领域的病理变化。
在这里,我们建议研究在发育中或成人大脑中双向控制CHD2的剂量。我们的方法
涉及复杂的细胞、分子、药理学和电生理学的组合
条件性CHD2+/-小鼠和人源性神经元的研究方法。如果成功,我们的结果将提供
关于染色质调节剂在推动新城疫相关病理中的作用的重要新信息
并将为药物增加的治疗潜力提供关键的概念验证
CHD2的表达,可迅速转化为CHD2单倍体功能不全的新靶向治疗。
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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Robert F Hunt其他文献
Robert F Hunt的其他文献
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{{ truncateString('Robert F Hunt', 18)}}的其他基金
Rewiring the Injured Brain with GABA Progenitors
用 GABA 祖细胞重新连接受损的大脑
- 批准号:
10211616 - 财政年份:2016
- 资助金额:
$ 53.72万 - 项目类别:
Rewiring the injured brain with GABA progenitors.
用 GABA 祖细胞重新连接受伤的大脑。
- 批准号:
9215702 - 财政年份:2016
- 资助金额:
$ 53.72万 - 项目类别:
Rewiring the Injured Brain with GABA Progenitors
用 GABA 祖细胞重新连接受损的大脑
- 批准号:
10367991 - 财政年份:2016
- 资助金额:
$ 53.72万 - 项目类别:
Rewiring the Injured Brain with GABA Progenitors
用 GABA 祖细胞重新连接受损的大脑
- 批准号:
10619546 - 财政年份:2016
- 资助金额:
$ 53.72万 - 项目类别:
Functional engraftment of stem cell-derived cortical interneurons
干细胞来源的皮质中间神经元的功能植入
- 批准号:
9266837 - 财政年份:2015
- 资助金额:
$ 53.72万 - 项目类别:
Functional engraftment of stem cell-derived cortical interneurons
干细胞来源的皮质中间神经元的功能植入
- 批准号:
8618809 - 财政年份:2013
- 资助金额:
$ 53.72万 - 项目类别:
Functional engraftment of stem cell-derived cortical interneurons
干细胞来源的皮质中间神经元的功能植入
- 批准号:
8738733 - 财政年份:2013
- 资助金额:
$ 53.72万 - 项目类别:
Functional integration of inhibitory interneuron progenitors in the adult brain
成人大脑中抑制性中间神经元祖细胞的功能整合
- 批准号:
8452226 - 财政年份:2012
- 资助金额:
$ 53.72万 - 项目类别:
Functional integration of inhibitory interneuron progenitors in the adult brain
成人大脑中抑制性中间神经元祖细胞的功能整合
- 批准号:
8311375 - 财政年份:2012
- 资助金额:
$ 53.72万 - 项目类别:
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