Mechanisms of Neurodegeneration in KIF5A ALS/FTD
KIF5A ALS/FTD 神经退行性变的机制
基本信息
- 批准号:10740732
- 负责人:
- 金额:$ 20.82万
- 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 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:ALS patientsAdaptor Signaling ProteinAffectAgeAmyotrophic Lateral SclerosisApplications GrantsAxonAxonal TransportBehaviorBehavioralBindingBiochemicalBiologyBrainC-terminalCRISPR/Cas technologyCellsCessation of lifeComplexCytoplasmic GranulesCytoskeletonDataDefectDevelopmentDevelopment PlansDiseaseDistalDoctor of MedicineDoctor of PhilosophyExclusionExonsFluorescence MicroscopyFoundationsFrontotemporal DementiaFunctional disorderFundingFutureGeneticGenetic EngineeringGenetically Engineered MouseGliosisGoalsHealthHomeostasisHumanHyperactivityImageImaging TechniquesIn VitroInduced pluripotent stem cell derived neuronsKinesinKnowledgeLabelLanguageLongevityLysosomesMaintenanceManuscriptsMentorsMentorshipMicrotubulesMitochondriaMorphologyMotorMotor Neuron DiseaseMotor NeuronsMusMutationNerve DegenerationNeuritesNeurodegenerative DisordersNeuromuscular JunctionNeuronsOrganellesPathogenesisPathogenicityPathologyPatientsPatternPhysiciansPost-Translational Protein ProcessingPreparationProductionProteinsProteomicsPublicationsRNARNA InterferenceRNA SplicingRecordsRegulationResearchResourcesRoleScientistSiteSlideSolidSpinal CordSplice-Site MutationStructureSynapsesTechniquesTestingTherapeuticTimeTissuesTrainingTransmission Electron MicroscopyUniversitiesWestern BlottingWorkage relatedagedcareer developmentcausal variantcell motilitycognitive functioncohortconfocal imagingfrontotemporal lobar dementia amyotrophic lateral sclerosisgain of functiongain of function mutationgenetic regulatory proteinhuman diseasein vivoinduced pluripotent stem cellinsightlive cell imagingmouse modelmutantneurofilamentneuron lossnovelprogramsprotein TDP-43protein aggregationrational designskillssmall moleculetooltraffickingultra high resolution
项目摘要
Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the dysfunction and death of motor
neurons. Some ALS patients develop widespread neuronal damage leading to Frontotemporal Dementia (FTD),
which is characterized by progressive behavioral change and language decline. Significant overlap exists
between ALS and FTD regarding the genetic causes, suggesting that they may share common pathogenic
mechanisms. Recently, mutations in motor protein, KIF5A, were identified in patients with ALS, ALS/FTD, and
FTD alone. These concentrate in the splicing regulatory sites flanking exon 27 leading to its exclusion and
abnormal KIF5A C-terminal domain structure. Our preliminary findings suggest that KIF5A ALS/FTD mutations
result in the production of a constitutively active protein that causes disease through toxic gain of function. This
proposal will test the hypothesis that KIF5A ALS/FTD is caused by gain of function of KIF5A activity in axonal
transport and cytoskeletal regulation. To ensure that our work will be highly disease relevant we will utilize human
iPSC derived motor neurons and mouse models harboring KIF5A ALS/FTD mutation. In Aim 1: we will define
the effects of KIF5A ALS mutations on the assembly and motility of motor/cargo complexes. Specifically, we will
utilize live-cell imaging of cargo motility, assessment of cargo distribution by IHC and transmission electron
microscopy (TEM), candidate-based biochemical assessment of interactions with cargo adaptors, and unbiased
assessment of interactions with potentially novel cargo adaptors and regulatory proteins using proximity labelling.
In Aim 2: we will characterize the effects of KIF5A ALS/FTD mutation on cytoskeletal structure using IHC and
TEM, live-imaging of MT dynamics and sliding, and analysis of MT post-translational modifications. In Aim 3: we
will develop a mouse model of KIF5A ALS/FTD and perform analysis of longevity, behavior, and pathology. The
mouse model will be an invaluable resource to validate findings from our in vitro studies and to advance
knowledge regarding key features of neurodegeneration in KIF5A ALS/FTD. My ultimate goal is to become a
successful physician-scientist with an independent research program investigating the mechanisms of
neurodegeneration in motor neuron disease with a specific focus on axonal transport and cytoskeletal dynamics.
Northwestern University has unique strengths in the study of ALS, FTD, and cytoskeletal biology and an
outstanding commitment to the development of physician-scientists. The mentorship team includes renowned
scientists with strong records in mentorship including Han-Xiang Deng M.D., Ph.D. (Primary Mentor) and Robert
Kalb M.D (co-mentor). The career development plan focuses on broadening the awardee’s portfolio of research
publications and presentations, which will be necessary for successful competition for RO1 funding. Career
development activities will bolster grantsmanship and manuscript preparation skills and provide extensive
didactic training in advanced imaging techniques, proteomics, cytoskeletal biology and ALS/FTD degenerative
mechanisms.
肌萎缩性侧索硬化症(ALS)是一种以运动功能障碍和死亡为特征的致命性疾病
项目成果
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Jonathan Robert Brent其他文献
Jonathan Robert Brent的其他文献
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