Elucidating cellular mechanisms underlying neurodegeneration
阐明神经变性的细胞机制
基本信息
- 批准号:10435954
- 负责人:
- 金额:$ 57.57万
- 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:2022-06-17 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinAdolescentAlzheimer&aposs DiseaseAmino AcidsAntisense OligonucleotidesAutophagocytosisAutophagosomeAxonAxonal TransportBehavioralCell Culture TechniquesCell NucleusCell physiologyCellsClinicComplexDataDegradation PathwayDiseaseEnvironmentEventExcisionFamilyFunctional disorderFutureGenesGoalsImpairmentIntermediate FilamentsIntracellular TransportKnock-outKnockout MiceLightLysosomesMediatingMitochondriaModelingMovementMusMutateMutationNamesNerve DegenerationNeuritesNeurodegenerative DisordersNeurologic SymptomsNeuronsOrganellesParkinson DiseasePathogenesisPathologicPathologyPathway interactionsPeripheral Nervous SystemPhenotypePhosphorylationPlayProcessProteinsProteomicsQuality ControlRegulationReportingResearchRoleSeveritiesShapesSignal PathwaySignal TransductionSirolimusSiteSpinal GangliaStable Isotope LabelingTestingUbiquitinUbiquitinationanalogbasecell typeearly onsetexperimental studygiant axonal neuropathygigaxoninloss of function mutationmembermulticatalytic endopeptidase complexnervous system disorderneurofilamentneuropathologynovelprotein degradationsmall hairpin RNAsmall moleculetherapeutic targettherapy developmenttreatment strategyubiquitin ligaseubiquitin-protein ligase
项目摘要
Giant axonal neuropathy (GAN) is an early-onset, autosomal recessive neurodegenerative disease that
impacts the central and peripheral nervous systems. Pathologically, GAN is characterized by the
disorganization and aggregation of intermediate filaments (IF). Formed from self-assembling subunits, the IF
network spans the cell from the nucleus to the periphery. In GAN, many cell types show abnormalities in the
organization of IF, but neurons clearly bear the brunt of the pathology. Axons swell with the accumulation of
neuronal IF, and degenerate to cause the neurological symptoms of GAN. The gene mutated in GAN encodes
gigaxonin, a protein that belongs to the BTB/Kelch family of E3 ligase-like adaptor proteins. These proteins
typically play a role in ubiquitin-proteasome mediated protein degradation. Based on our own data that GAN
degrades neuronal IFs, we hypothesize that neurofilament aggregation creates steric roadblocks in neurites
that interfere with intracellular transport of organelles such as mitochondria and lysosomes, resulting in
downstream pathology. Furthermore, our preliminary data suggest gigaxonin plays a direct role in autophagy
via degradation of other substrates. We hypothesize that the disruption of this critical process exacerbates
GAN neuropathology by dysregulation of protein and organellar quality control. This proposal comprehensively
tests these models; thus the overall goal of our research is to understand the cellular pathogenesis of GAN
with a view to inspiring novel treatment strategies.
巨轴索神经病(GAN)是一种早发的常染色体隐性神经退行性疾病
项目成果
期刊论文数量(0)
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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Puneet Opal其他文献
Puneet Opal的其他文献
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{{ truncateString('Puneet Opal', 18)}}的其他基金
VEGF-Mimetic Supramolecular Nanoparticles for Treating Spinocerebellar Ataxia Type 1
VEGF 模拟超分子纳米颗粒用于治疗 1 型脊髓小脑共济失调
- 批准号:
10578485 - 财政年份:2023
- 资助金额:
$ 57.57万 - 项目类别:
Equipment Supplement: Understanding the Cellular Basis of Movement Disorders
设备补充:了解运动障碍的细胞基础
- 批准号:
10755946 - 财政年份:2023
- 资助金额:
$ 57.57万 - 项目类别:
Elucidating cellular mechanisms underlying neurodegeneration
阐明神经变性的细胞机制
- 批准号:
10647869 - 财政年份:2022
- 资助金额:
$ 57.57万 - 项目类别:
Developing novel treatment strategies for Spinocerebellar ataxia type 1
开发 1 型脊髓小脑共济失调的新治疗策略
- 批准号:
9226821 - 财政年份:2016
- 资助金额:
$ 57.57万 - 项目类别:
Understanding the cellular basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
8876831 - 财政年份:2013
- 资助金额:
$ 57.57万 - 项目类别:
Understanding the cellular basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
8631893 - 财政年份:2013
- 资助金额:
$ 57.57万 - 项目类别:
Understanding the Cellular Basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
10630308 - 财政年份:2013
- 资助金额:
$ 57.57万 - 项目类别:
Understanding the Cellular Basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
10403448 - 财政年份:2013
- 资助金额:
$ 57.57万 - 项目类别:
Understanding the cellular basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
8719191 - 财政年份:2013
- 资助金额:
$ 57.57万 - 项目类别:
Understanding the Cellular Basis of Movement Disorders
了解运动障碍的细胞基础
- 批准号:
10160963 - 财政年份:2013
- 资助金额:
$ 57.57万 - 项目类别:
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