Modeling DYT1 Dystonia in Patient-derived Neurons
患者源性神经元中 DYT1 肌张力障碍的建模
基本信息
- 批准号:10863331
- 负责人:
- 金额:$ 36.5万
- 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:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAddressAnimal ModelAnimalsArtificial IntelligenceBiochemistryBiological AssayBiological ModelsCell NucleusCellsChildhoodCo-ImmunoprecipitationsCoupledCytoplasmDeep Brain StimulationDiagnosisDiseaseDisease modelDown-RegulationDyskinetic syndromeDystoniaElectron MicroscopeElectrophysiology (science)EtiologyFunctional disorderGAG GeneGenesGenomeGoalsHeterozygoteHumanImpairmentIn VitroInheritedIntramuscularLMNB1 geneLabelMass Spectrum AnalysisMembraneMessenger RNAModelingMolecularMolecular BiologyMorphologyMotor NeuronsMovement DisordersMuscle ContractionMutationNervous SystemNeuritesNeuromuscular JunctionNeuronsNuclearNuclear EnvelopeNuclear LaminaPathogenesisPathologicPathologyPatientsPosturePrimary DystoniasProteinsProteomicsRecyclingResearchRoleSignal PathwayStudy modelsSymptomsSynaptic VesiclesSystemTOR1A geneTOR1A proteinTestingbotulinum neurotoxin injectionexperimental studyexportin 1 proteininsightloss of function mutationneurodevelopmentneuron developmentnovelnovel strategiesnucleocytoplasmic transportpatch clampprotein protein interactiontranscriptomicstransmission process
项目摘要
TITLE
Modeling DYT1 Dystonia in Patient-derived Neurons
PROJECT SUMMARY
The overall goal of this project is to develop novel cellular systems for dystonia research and determine the
molecular pathogenesis of DYT1 dystonia using patient-derived neurons. Dystonia is the third most common
movement disorder and the pathological mechanisms responsible for dystonia remain largely unknown 1-5.
Current therapies are largely symptom-based and only partially satisfactory 6,7. DYT1 dystonia, which represents
the most frequent and severe form of hereditary primary dystonia, provides an excellent model for studies that
aim to understand the pathogenesis of this disease 8,9. Typical DYT1 dystonia is caused by a heterozygous GAG
deletion in the TOR1A gene (ΔE). Even though animal models provide insights into disease mechanisms,
significant species-dependent differences exist because animals with identical heterozygous mutation (ΔE) fail
to show the pathology seen in human patients 10. In addition, the limited access to patient neurons greatly
impedes the progress of research in dystonia. In a breakthrough, we have developed a novel cellular system for
modeling DYT1 dystonia with patient-specific neurons 11,12. These human neurons retain the
heterozygous TOR1A mutation and recapitulate disease-dependent cellular deficits. The most unexpected
finding is that nuclear lamina protein LMNB1 was dysregulated at expression and subcellular distribution.
Interestingly, downregulation of LMNB1 can largely ameliorate all the cellular deficits in DYT1 neurons 11. These
results demonstrate the high value of disease modeling using human patient-derived neurons and indicate that
dysregulation of nuclear LMNB1 may constitute a major molecular mechanism underlying DYT1 pathology. How
does dysregulated LMNB1 contribute to the pathogenesis of dystonia? What other proteins and genes could be
disrupted by ΔE? Answers to these questions are critical in understanding the pathophysiology of DYT1 dystonia.
We hypothesize that the dysregulation of nuclear LMNB1 is the major contributor to the cellular deficits, and the
mislocalized LMNB1 in the cytoplasm could trap factors in critical signaling pathways and lead to widescale
cellular dysfunction. We will use patient-derived neurons to test this hypothesis and address pertaining questions
via three specific aims. Aim 1 is to determine how dysregulated LMNB1 contributes to the cellular dysfunction in
DYT1 neurons, including examination of nuclear morphology using TEM and immunogold labeling, and
identification of mislocalized LMNB1-interacting proteins. In Aim 2, we will identify ΔE-disrupted factors using
proteomic studies and examine the abnormal protein-protein interactions using the combination of Artificial
Intelligence (AI)-based structural prediction and approaches in molecular biology and biochemistry. In Aim 3, we
will identify dysregulated genes using transcriptomic study and examine the functional alterations via
electrophysiology analysis and in vitro neuromuscular junction formation assay. The successful completion of
these Aims will allow us to gain a more in-depth understanding of the pathogenesis of dystonia.
标题
项目成果
期刊论文数量(1)
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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Baojin Ding其他文献
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{{ truncateString('Baojin Ding', 18)}}的其他基金
Determining the pathogenesis of DYT1 dystonia in reprogrammed human neurons
确定重编程人类神经元 DYT1 肌张力障碍的发病机制
- 批准号:
10556991 - 财政年份:2020
- 资助金额:
$ 36.5万 - 项目类别:
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