The Role of Fos and the BAF Complex in Neuronal Activity-Dependent Chromatin Remodeling and Gene Expression
Fos 和 BAF 复合物在神经元活动依赖性染色质重塑和基因表达中的作用
基本信息
- 批准号:10572785
- 负责人:
- 金额:$ 19.4万
- 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:2023-04-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:Advisory CommitteesAffectAnimal ModelAreaBindingBinding SitesBrainCRISPR/Cas technologyCellsChildhoodChromatinChromatin Remodeling FactorCollectionComplexDataDevelopmentDevelopmental ProcessDiseaseDisease modelDistalDistal Enhancer ElementsEnhancersEpilepsyEthicsExhibitsFibroblastsFunctional disorderGene ExpressionGenesGeneticGenetic DatabasesGenetic TranscriptionGenetic VariationGenomicsHeterozygoteHumanHuman ActivitiesHuman GeneticsHuman GenomeIn VitroIndividualIntellectual functioning disabilityKnowledgeLaboratoriesLifeLightMediatingMentorsMentorshipModelingMolecularMorbidity - disease rateMusNeurodevelopmental DisorderNeuronal PlasticityNeuronsNeurosciencesNeurosciences ResearchNucleic Acid Regulatory SequencesPathogenesisPathway interactionsPatientsPediatric NeurologyPhenotypePhysiciansPhysiologicalPlayPositioning AttributeProcessProgram DevelopmentRegulationRegulator GenesRegulatory ElementRegulonResearchRoleScientistSiteSourceStimulusTechniquesTechnologyTestingTherapeuticTimeTrainingVariantVisual CortexWorkautism spectrum disorderbehavioral phenotypingbrain abnormalitiescareercareer developmentcell typechildhood epilepsychromatin remodelingdbSNPdesigndevelopmental diseaseexperimental studygenetic varianthuman diseasehuman embryonic stem cellhuman embryonic stem cell linehuman modelin vitro Modelin vivoin vivo Modelinsightmouse modelneural circuitneurodevelopmentneurogeneticsnew therapeutic targetnext generation sequencingnovel therapeuticsprogramsrecruitresponsesingle-cell RNA sequencingsynaptic pruningtranscription factortranslational neuroscience
项目摘要
Pediatric neurodevelopmental disorders (NDD), including pediatric epilepsy, autism spectrum disorder, and
intellectual disability, represent a major source of morbidity, yet our therapeutic options remain limited.
Development of novel therapies for NDD will require a deeper mechanistic understanding of normal and
abnormal brain development. This proposal focuses on genetic programs that are activated in response to
neuronal activity and that are fundamental to normal neurodevelopment and on-going neuronal plasticity
throughout life. Fos is a major activity-dependent transcription factor that binds to distal enhancer elements and
regulates downstream activity-dependent genetic programs in a cell-type-specific manner to promote key
processes, including synaptic pruning and the recruitment of inhibition in the developing brain. Despite its role in
key developmental processes, we do not understand how Fos is differentially targeted to cell-type-specific
binding sites, nor how genetic variation at these sites impacts neurodevelopment and neuronal function.
Interestingly, Fos has been shown to physically interact with the BAF chromatin remodeling complex, and it is
possible that this interaction is critical to Fos function. Many BAF subunits, most frequently ARID1B, are
implicated in human NDD, but whether the BAF complex regulates neuronal activity-dependent genetic
programs, and how this underlies aspects of BAF complex-related NDD, is previously unexplored. The research
in this proposal will address these gaps in knowledge by: (a) profiling Fos and BAF complex neuronal binding
sites across the human genome; (b) assessing human genetic variants at these sites in individuals with NDD vs
controls; and (c) determining the effects of BAF complex perturbation on neuronal activity-dependent genetic
programs in vitro and in vivo. Overall, this work will lead to greater insight into how activity-dependent genetic
programs contribute to NDD pathogenesis. Additionally, by identifying specific activity-regulated genes and
pathways that are mis-regulated downstream of Fos and the BAF complex, these experiments could highlight
novel therapeutic targets for NDD.
This research is the basis for a five-year career development program designed to build on Dr. Trowbridge’s
background in molecular neuroscience, pediatric neurology/epilepsy, and neurogenetics, by providing her with
additional training in analysis of human sequencing data, use of in vitro and in vivo models of NDD, and next-
generation sequencing technologies. Her primary mentor, Dr. Mike Greenberg, and her scientific advisory
committee, Drs. Annapurna Poduri and Chris Walsh, will provide guidance in these areas, as well as mentorship
in the rigorous and ethical conduct of translational neuroscience research. Thus the proposed training plan will
position Dr. Trowbridge to launch her independent career as a clinician-scientist focused on understanding the
role of activity-dependent genetic programs in NDD.
小儿神经发育障碍(NDD),包括小儿癫痫、自闭症谱系障碍和
项目成果
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