Dysregulation of p97/VCP disease mutants in IBM and FTLD-U
IBM 和 FTLD-U 中 p97/VCP 疾病突变体的失调
基本信息
- 批准号:9889186
- 负责人:
- 金额:$ 51.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:ALS patientsATP phosphohydrolaseAffectAffinityAllelesAmino AcidsAmyotrophic Lateral SclerosisAnimal ModelApoptosisAreaAutophagocytosisBindingBiochemicalBioinformaticsBiological AssayBiological ProcessBrainCell DeathCellsClinicalDataDefectDegenerative DisorderDevelopmentDiseaseDisease MarkerEmery-Dreifuss Muscular DystrophyEnzymesExcisionExhibitsFibroblastsFrontotemporal DementiaGeneticGenotypeGoalsGolgi ApparatusHela CellsHeterogeneous-Nuclear RibonucleoproteinsHumanImpairmentInclusion BodiesInclusion Body Myopathy with Early-Onset Paget DiseaseInheritedIntegral Membrane ProteinKnock-in MouseKnock-outLeadLeadershipLoxP-flanked alleleMeasuresMediatingMethodologyMissense MutationMitoticModelingMolecularMolecular ConformationMotor Neuron DiseaseMotor NeuronsMuscle CellsMutateMutationMyopathyNeurodegenerative DisordersNeuronsOsteitis DeformansPathogenicityPathologyPathway interactionsPatientsPenetrancePhenotypePrecision therapeuticsProtein FamilyProteinsProteomicsPublic HealthPublishingQuality ControlRecyclingRegulationReporterSourceSymptomsSystemTestingTherapeutic InterventionUbiquitinWorkage relatedbasecaveolin 1cofactordesigndisease phenotypeexperienceexperimental studyimprovedinduced pluripotent stem cellinhibitor/antagonistknock-downmacromoleculemouse modelmulticatalytic endopeptidase complexmutantnervous system disordernew therapeutic targetnovel therapeuticsoverexpressionp97 ATPasepreventprotein TDP-43protein misfoldingskillssmall molecule inhibitorstem cellstargeted treatmentvalosin-containing protein
项目摘要
Many neurodegenerative diseases are thought to be caused by a buildup of toxic proteins in the brain from or
resulting in promotion of apoptosis. p97 AAA ATPase (also known as VCP, CDC48, TER ATPase) functions in
multiple biological processes, targeting proteins to 2 major degradation systems, the proteasome and
autophagy machinery. The key role of p97 in proteasome and autophagy degradations underscores its
importance and supports involvement of p97 dysregulation in protein misfolding, aggregation, and processing
errors, eventually resulting in cell death. Single amino acid mutations in p97/VCP cause autosomal dominant
human disorders including hereditary frontotemporal dementia hereditary (FTD) and a specific condition called
inclusion body myopathy with Paget disease of the bone plus ALS, a motor neuron disease also known as Lou
Gehrig's disease. Mutation sources could be genetic, environmental, spontaneous, or age related. The goal of
this project is to identify key pathogenic mechanisms that will be used to develop precision therapy to correct
the defect due to p97 disease mutations, without damaging normal p97 functions. Our central hypothesis: p97
disease mutants have abnormal conformation, which in turn leads to altered protein interactome that in specific
cells including neuronal cells cause pathogenic effect To test this hypothesis and to identify key pathogenic
mechanisms that can act as targets for therapeutic intervention, we propose to compare the interactome of WT
and disease mutants of p97 in neuronal and muscle cells derived from patient fibroblasts and then use genetic
and biochemical approaches to determine the effect of the altered interactors in regulating p97 ATPase activity
and in modulating the disease phenotype. Overall, a new paradigm of how to develop mutant-targeted
therapeutics for neurodegenerative diseases—especially for causative mutants in the ATPase protein family—
will be established.
许多神经退行性疾病被认为是由大脑中有毒蛋白质的积累引起的
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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Tsui-Fen Chou其他文献
Tsui-Fen Chou的其他文献
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{{ truncateString('Tsui-Fen Chou', 18)}}的其他基金
Phosphoproteomic Analyses of Understudied Protein Kinases that affect Zebrafish Sleep
影响斑马鱼睡眠的正在研究的蛋白激酶的磷酸化蛋白质组学分析
- 批准号:
10437190 - 财政年份:2022
- 资助金额:
$ 51.85万 - 项目类别:
Using HTS to Identify Inhibitors of R155H-p97/VCP Mutant to treat IBMPFD/ALS
使用 HTS 鉴定 R155H-p97/VCP 突变体抑制剂来治疗 IBMPFD/ALS
- 批准号:
10065879 - 财政年份:2019
- 资助金额:
$ 51.85万 - 项目类别:
Dysregulation of p97/VCP disease mutants in IBM and FTLD-U
IBM 和 FTLD-U 中 p97/VCP 疾病突变体的失调
- 批准号:
10166541 - 财政年份:2018
- 资助金额:
$ 51.85万 - 项目类别:
Dysregulation of p97/VCP disease mutants in IBM and FTLD-U
IBM 和 FTLD-U 中 p97/VCP 疾病突变体的失调
- 批准号:
10403447 - 财政年份:2018
- 资助金额:
$ 51.85万 - 项目类别:
Dysregulation of p97/VCP disease mutants in IBM and FTLD-U
IBM 和 FTLD-U 中 p97/VCP 疾病突变体的失调
- 批准号:
10065216 - 财政年份:2018
- 资助金额:
$ 51.85万 - 项目类别:














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