Uncovering the Roles of Chaperonin CCT in Neural Health and Disease.
揭示伴侣蛋白 CCT 在神经健康和疾病中的作用。
基本信息
- 批准号:10607652
- 负责人:
- 金额:$ 4.13万
- 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:2023-02-07 至 2025-02-06
- 项目状态:未结题
- 来源:
- 关键词:4D ImagingActinsAfferent NeuronsAtrophicAttenuatedBiochemicalBiologicalCellsClustered Regularly Interspaced Short Palindromic RepeatsCo-ImmunoprecipitationsComplexCoupledCullin ProteinsCytoskeletonCytosolDataDendritesDevelopmentDiseaseDrosophila genusDrosophila melanogasterEducational process of instructingEnsureEnvironmentExhibitsF Box DomainGeneticGoalsGrowthHealthHomeostasisHumanHuntington DiseaseHuntington geneImageImaging TechniquesIn VitroIndividualInstitutionInvestigationKnowledgeLarvaLeadLinkMachado-Joseph DiseaseMaintenanceMediatingMentorsMicroscopyMicrotubulesModelingMolecularMolecular ChaperonesMolecular ConformationMonitorMorphologyMovementMutationNerve DegenerationNervous SystemNervous System PhysiologyNeurodegenerative DisordersNeuronsNeuropathyPathogenicityPathway interactionsPharmaceutical PreparationsPharmacology StudyPhenotypePilot ProjectsProcessProtein BiochemistryProteinsPublishingRNA InterferenceRegulationReporter GenesResearchResearch InfrastructureResolutionRibosomal Protein S6 KinaseRoleShapesSignal PathwaySignal TransductionSpinocerebellar AtaxiasStable PopulationsSystemTechniquesTestingTimeTrainingTransgenic OrganismsTubulinVisualizationWestern BlottingWorkcareer developmentchaperoninexperimental studyin vivoknock-downlive cell imagingmisfolded proteinmutantneuralneurogeneticsnoveloverexpressionpolypeptidepostmitoticpreservationprotein aggregationprotein functionproteostasisreconstructionresponsesuperresolution microscopyubiquitin-protein ligaseultra high resolution
项目摘要
Project Summary/Abstract
Protein homeostasis, or proteostasis, is critical to neuronal cellular and molecular processes and
derangements in proteostasis machinery have been linked to neurodegenerative protein aggregates. This project
will investigate roles of the Chaperonin-Containing TCP-1 (CCT) complex in regulating cytoskeletal modulation
in both homeostatic and proteinopathic disease conditions and how those roles mechanistically impact dendrite
development and maintenance. The two specific aims will (1) examine how CCT facilitates the formation of
complex dendritic arbors through secondary regulation of microtubules both directly and indirect and (2) parse
how CCT attenuates the accumulation of neuropathogenic protein aggregates in vivo and genetically interacts
with mutant Ataxin and Huntingtin to preserve arbor morphology. CCT is a cytosolic multi-subunit chaperone that
folds de novo proteins, misfolded proteins in the cytosol, and mutant aggregate-prone proteins commonly
associated with neurodegenerative diseases such as Huntington’s Disease and Spinocerebellar Ataxia (SCA).
We were first to demonstrate that individual CCT subunit mutants in Drosophila Class IV multidendritic sensory
neurons caused severe reductions in dendritic branching. I have carried out further experiments showing that
CCT mutants results in underlying changes to the dendritic cytoskeleton, especially disrupting microtubules.
While it is well-established that CCT folds tubulin, whether and how CCT is influencing the assembly of
microtubules through direct or indirect means is unknown. Furthermore, preliminary data reveals a putative
relationship between Cullin1, a component of the SkpA-F-box-Cullin E3 ubiquitin ligase, and CCT in the
regulation of microtubules. A common target of Cullin1 and CCT is TORC1, and thus, I propose to investigate
the associated molecular pathway in the regulation of the dendritic cytoskeleton in cellular homeostasis. For
these analyses, I will leverage our expertise in neurogenetics, phenotypic analyses, time-lapse 4D imaging,
neuromorphometrics and drug pharmacology studies. I have also completed pilot studies that reveal reductions
in dendritic branching due to expression of mutant Huntingtin and Ataxin proteins. CCT is known to interact with
these mutant proteins in vitro and mitigate aggregation, but the relationship has not been examined in vivo in
neurons. Using advanced imaging techniques including time-lapse imaging, expansion and super-resolution
microscopy as well as traditional biochemical techniques like Western blot and co-immunoprecipitation, I will
investigate the ameliorative effects of CCT on mutant protein aggregates in vivo and examine how the
relationships that support dendritic formation in homeostasis are maintained or deranged in the context of
disease. Beyond the goals of the research plan, my training goals include new technical training in advanced
imaging/microscopy and protein biochemistry coupled to mentoring/teaching activities and career development
activities/networking. I have assembled an expert team of scientific and technical advisors which coupled to
institutional environment and research infrastructure will support and advance my overall training goals.
项目总结/文摘
项目成果
期刊论文数量(0)
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