Role of mTORC1 dependent translation in neurological deficits of TSC
mTORC1 依赖性翻译在 TSC 神经功能缺陷中的作用
基本信息
- 批准号:10424796
- 负责人:
- 金额:$ 6.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnatomyAttenuatedAxonBehaviorBehavioralBinding ProteinsBioinformaticsBrainCRISPR/Cas technologyCaregiversClinicalComplexCorpus striatum structureDevelopmentDiseaseElectrophysiology (science)ElectroporationEpilepsyEtiologyEukaryotic Initiation FactorsFRAP1 geneGenesHigh PrevalenceHyperactivityHypertrophyIncidenceIndividualKnowledgeLaboratoriesLeadMedialMicroscopyModelingMolecularMusMutationNeurologicNeurologic DeficitNeuronsPathologicPatientsPhenotypePopulationPrefrontal CortexPropertyRas homolog enriched in brainResearchRoleSDZ RADSeizuresSignal PathwaySignal TransductionSocial BehaviorSocial InteractionSynapsesTSC1 geneTSC2 geneTestingTherapeuticTransgenic ModelTranslationsTuberous SclerosisUltrasonicsWestern Blottingautism spectrum disorderautisticaxon growthbehavioral phenotypingcomorbiditydesigndevelopmental diseaseeffective therapyhippocampal pyramidal neuronin uteroinhibitorinsightmouse modelnovelpreventrelating to nervous systemsmall hairpin RNAsocialsynaptic functiontraittranscriptome sequencingtranslatomevocalization
项目摘要
ABSTRACT
Tuberous sclerosis complex (TSC) is a developmental disorder caused by a mutation in the TSC1 or TSC2
gene. Mutations in TSC genes result in hyperactivation of the mechanistic target of rapamycin complex 1
(mTORC1), a signaling pathway vital for development. Individuals with TSC present with a high incidence of
neurological conditions, among the most prevalent of which are epilepsy and autism spectrum disorder (ASD).
While mTORC1 inhibitors can effectively attenuate seizures, they do not improve TSC’s autistic comorbidity.
Thus, there is a critical need to better understand the etiology of autism traits to identify novel treatments. Our
laboratoryhasdevelopedamousemodelofTSCin which constitutively active Rheb is expressed in developing cortical
neurons of the medial prefrontal cortex (mPFC), a region that is dysregulated in TSC and implicated in ASD.
This model allows for a more precise activation of mTORC1 than transgenic models and is thus ideally suited to
parse out complex etiology. Using this model, our lab found alterations in local mPFC connectivity that resemble
the pathological changes in TSC’s autistic comorbidity. Moreover, when aberrant cap dependent translation was
normalized via the activation of a translational repressor, the observed alterations were prevented. While
connectivity has been examined within the mPFC in a hyperactive mTORC1 state, the accompanying behavioral
phenotype has not been assessed nor have mTORC1’s effects on specific subcortical projections from the
mPFC. To this end, the striatum is a compelling target, as it is heavily interconnected with the mPFC and is
integral to socio-communicative behaviors (core deficits in ASD). However, axonal connectivity in TSC is
understudied and mPFC-striatal projections have not been assessed. Furthermore, while normalizing translation
can mitigate cellular alterations in hyperactive mTORC1 conditions, the specific downstream molecular
alterations that account for these changes are unknown, as are their efficacy to attenuate behavioral deficits.
Therefore, the specific aims are to: 1). Determine whether hyperactive mTORC1 in mPFC-striatal projections
contributes to socio-communicative deficits. 2). Determine whether increasing mTORC1 activity during early
mPFC development leads to alterations in cortico-striatal projections resulting in an excitation-inhibition
imbalance in the striatum. 3). Determine whether altered cap-dependent translation and downstream molecules
contribute to alterations in axonal connectivity and socio-communicative deficits. To address these aims, in utero
electroporation (IUE) will be used to increase mTORC1 in pyramidal neurons of the mPFC. Vocalization and
social interaction tests will assess the phenotype, whereas lightsheet microscopy, axonal tracing, and
electrophysiology will assess mPFC-striatal connectivity. Potential candidate molecules downstream of
translation that control axonal growth will be identified via Trap, and shRNA will be designed to assess the effects
of normalizing the identified genes on socio-communicative deficits and alterations in mPFC-striatal connectivity.
摘要
项目成果
期刊论文数量(0)
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Matthew Binder其他文献
Matthew Binder的其他文献
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{{ truncateString('Matthew Binder', 18)}}的其他基金
Role of mTORC1 dependent translation in neurological deficits of TSC
mTORC1 依赖性翻译在 TSC 神经功能缺陷中的作用
- 批准号:
10689021 - 财政年份:2022
- 资助金额:
$ 6.76万 - 项目类别:
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