Manipulation of neuron identity towards in-vivo circuit reprogramming in the cerebral cortex
操纵神经元身份以实现大脑皮层体内电路重编程
基本信息
- 批准号:10755203
- 负责人:
- 金额:$ 4.87万
- 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:2023-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAgingAreaAxonBiologyBrainBrain StemCellsCerebral cortexCharacteristicsComplementCre driverDevelopmentDevelopmental GeneEffectivenessEmbryoEquilibriumExhibitsFutureGenesGeneticGenetic TranscriptionGoalsHistologyImageInduced MutationInjuryInstitutionInvestmentsKnock-outKnowledgeLaboratoriesLearningLesionLifeLightMaintenanceMapsMediatingMentorsMethodsMicroscopyModelingMolecularMolecular BiologyMolecular TargetMorphologyMotorMotor CortexMovementMusMutationNeurodegenerative DisordersNeuronsOutcomeParalysedPathway interactionsPatternPhasePopulationPositioning AttributePrefrontal CortexProcessPropertyRNARegenerative MedicineReporterResearchResearch PersonnelResolutionScientistSensorySignal TransductionSpecific qualifier valueSpinal cord damageSpinal cord injurySystemTechnical ExpertiseTechniquesTestingThalamic structureTherapeutic UsesTracerTrainingTraining SupportTransgenic MiceUp-RegulationVisualizationVulnerable PopulationsWorkbrain repaircareercell typecellular targetingcentral nervous system injuryclinically relevantefficacy evaluationexperienceexperimental studyfrontotemporal lobar dementia amyotrophic lateral sclerosisin vitro Assayin vivoinjuredinjury and repairinsightinterestlight microscopymature animalmolecular markermouse modelmulti-photonneuralneuron developmentneuroregulationnovelnovel strategiespost-doctoral trainingpostnatalpreventprogramsrepairedskillssuccesstenure tracktooltranscriptometranscriptome sequencingtranscriptomics
项目摘要
Project Summary
Sub-Cerebral Projection Neurons (SCPNs) are a clinically relevant neuron class that controls voluntary
movement and whose loss in Amyotrophic Lateral Sclerosis and Fronto-temporal dementia or injury (e.g.,
damaged by spinal cord injury) leads to paralysis. Currently, there are no methods to replenish injured or lesioned
SCPNs. A milestone in regenerative medicine is to utilize cellular reprogramming for brain and circuit repair. This
approach uses developmental genes and identity maintenance pathways to switch one cell type to another to
replenish vulnerable neuron types. However, there is a significant gap in knowledge in understanding the
mechanisms that control identity maintenance in neurons as the brain matures. Our current knowledge is limited
to reprogramming projection neurons in-vivo during embryonic stages, limiting potential therapies and the
advancement of in-vitro assays. This proposal directly addresses these needs by targeting a identity
maintenance mechanism in Layer 6-Cortico Thalamic Neurons (CTns) to shift the balance of cell identity toward
Layer 5 (L5) SCPNs. CTns share a developmental origin, differentiation pathways, and morphological
characteristics with SCPNs, similarities that are known to facilitate the conversion between cell types. Our group
and others have found that CTns can be switched into SCPNs upon loss of the transcriptional regulator Bce1. I
hypothesize that knock-out of Bce1 is an effective means of generating SCPNs until post-natal day 14 using re-
wiring the CTn axon to the brainstem and the upregulation of L5 markers as readouts of reprogramming success.
To target CTns in the motor cortex for reprogramming across developmental stages, I first sought to characterize
a novel and broadly necessary Cre- transgenic mouse line (Syt6-Cre) (Aim 1 Part 1). This approach allows
access to previously inaccessible CTn populations in the motor areas. Next (Aim 1 Part 2), I will determine the
potential and effectiveness of Bce1 mutation in CTns at different maturation stages in generating SCPNs in the
motor cortex. In Aim 1 Experiment 1, I investigate the extent that Bce1 mutation induces in-vivo reprogramming
of CTns into SCPNs at different cortical maturation stages. I use circuit mapping with retrograde tracers, testing
for a new brainstem-projecting axon, and histology for SCPN and CTns molecular markers to determine the
efficacy of the approach. Then, in Aim 1 Experiment 2, I use RNA-seq to identify downstream effectors of Bce1
required for reprogrammed CTns to acquire SCPN characteristics. For my (K00 phase), I will transition into the
field of CNS repair and regenerative medicine. Aim 2 focuses on visualizing cellular repair within single neurons
at the sub-cellular level. This will involve 1) learning a mouse model for CNS injury and repair. Then 2) apply
Spatial Transcriptomics to the system. Then 3) test functional hypotheses with high-resolution multi-photon or
light sheet microscopy to visualize the process in-vivo. Overall, these techniques will combine my refined skills
in light microscopy and developing skills in molecular biology with my interest in CNS repair and are universally
applicable thought my career on my path towards independence and a tenure track position.
项目总结
项目成果
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