Investigating the impact of p97 mutation in Amyotrophic Lateral Sclerosis
研究 p97 突变对肌萎缩侧索硬化症的影响
基本信息
- 批准号:10449848
- 负责人:
- 金额:$ 24.75万
- 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:2022-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisATP phosphohydrolaseAdaptor Signaling ProteinAffinityAffinity ChromatographyAgingAmyotrophic Lateral SclerosisAutophagocytosisBindingBrain StemCell AgingCell CycleCell modelCell physiologyCellsCessation of lifeClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsComplexDenervationDevelopmentDiagnosisDiseaseDisease ProgressionEnsureEnzymesFutureGene MutationGenerationsGenesGlycineGoalsHealthcareHomeostasisImpairmentInclusion BodiesIndividualInterventionLeadLeftLinkMissense MutationMitochondriaModelingMolecularMolecular ChaperonesMotor Neuron DiseaseMotor NeuronsMuscleMuscle FibersMuscle functionMuscular AtrophyMutationMyopathyNerve DegenerationNeurodegenerative DisordersNeuronsOrganellesOsteitis DeformansPathway interactionsPatientsPhenotypePhysiologyPrevalenceProteinsProteomeProteomicsQuality ControlReportingResearchRoleSkeletal MuscleSpecificitySpinal CordSymptomsSystemTestingTransformed Cell LineTriageUbiquitinUnited StatesVariantage related neurodegenerationaging populationbasebonecell agecell typecohortdifferentiation protocoldisease phenotypefamilial amyotrophic lateral sclerosisfrontotemporal lobar dementia-amyotrophic lateral sclerosisinduced pluripotent stem cellinsightloss of functionmulticatalytic endopeptidase complexmutantnervous system disordernew therapeutic targetnon-Nativepreventprotein aggregationproteostasissmall moleculestem cell modeltherapy developmentunfoldase
项目摘要
Protein homeostasis decline is a significant contributor to the development of Amyotrophic Lateral Sclerosis
(ALS) and other neurodegenerative disorders. With an ever-expanding aging population and no reliable
therapies, these devastating diseases will place a significant burden on health care in the coming decades.
The p97 AAA-ATPase is a ubiquitin-selective unfoldase that has critical roles in protein quality control.
Dedicated adaptor proteins target p97 to ubiquitylated substrates and thereby impart specificity to this abundant
enzyme. Mutations in p97 cause familial ALS and are reported to impede p97 association with certain adaptors
and impair ER and mitochondria associated quality control suggesting inadequate targeting to these organelles.
However, the impact of p97 mutation on its interactome and ubiquitylated substrates has not been studied
systematically in cell types impacted in disease, namely motor neurons and skeletal muscle.
Here, we will establish an induced pluripotent stem cell (iPSC)-based model of motor neuron disease caused
by distinct p97 mutations. We will use this system to: (1) Investigate how mutant p97 remodels the motor neuron
and skeletal muscle proteome and physiology. Ubiquitylated substrates of p97 will be identified using quantitative
proteomics in each cell type. (2) Examine the impact of p97 mutation on known protein quality control pathways
in motor neurons skeletal muscle cells.
Our studies will provide the first model of ALS caused by p97 mutation and will provide mechanistic insight
into how p97 mutation causes motor neuron and/or skeletal muscle demise. We anticipate our cell-based model
may be used in the future for small molecule screens to identify lead molecules for therapy development. Given
the prevalence of p97 mutation, we anticipate these studies will have broad relevance to other in
neurodegenerative diseases.
蛋白质稳态下降是肌萎缩侧索硬化症发生发展的重要因素
(ALS)和其他神经退行性疾病。随着老龄化人口的不断扩大,没有可靠的
在未来几十年里,这些毁灭性的疾病将给卫生保健带来重大负担。
P97AAA-ATPase是一种泛素选择性解折叠酶,在蛋白质质量控制中具有重要作用。
针对p97泛素化底物的专用接头蛋白,从而赋予这种丰富的
酵素。P97基因突变导致家族性肌萎缩侧索硬化症,并被报道阻碍p97与某些适配器的关联
并损害内质网和线粒体相关的质量控制,表明对这些细胞器的靶向性不足。
然而,p97突变对其相互作用体和泛素化底物的影响尚未被研究。
系统地研究了受疾病影响的细胞类型,即运动神经元和骨骼肌。
在这里,我们将建立一种基于诱导多能干细胞(IPSC)的运动神经元病模型。
通过不同的p97突变。我们将使用这个系统来:(1)研究突变型p97如何重塑运动神经元
和骨骼肌蛋白质组和生理学。P97的泛素化底物将用定量方法鉴定
每种细胞类型的蛋白质组学。(2)检测p97突变对已知蛋白质质量控制途径的影响
在运动神经元和骨骼肌细胞中。
我们的研究将提供第一个由p97突变引起的肌萎缩侧索硬化症模型,并提供机制洞察力。
P97突变是如何导致运动神经元和/或骨骼肌死亡的。我们期待我们的基于细胞的模型
可能在未来用于小分子筛查,以识别用于治疗开发的先导分子。vt.给出
P97突变的流行情况,我们预计这些研究将对其他
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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{{ truncateString('Malavika Raman', 18)}}的其他基金
Investigating the impact of p97 mutation in Amyotrophic Lateral Sclerosis
研究 p97 突变对肌萎缩侧索硬化症的影响
- 批准号:
10558598 - 财政年份:2022
- 资助金额:
$ 24.75万 - 项目类别:
“Regulation of Protein Quality Control by the VCP AAA-ATPase”
– VCP AAA-ATPase 对蛋白质质量控制的调节 –
- 批准号:
10598249 - 财政年份:2018
- 资助金额:
$ 24.75万 - 项目类别:
“Regulation of Protein Quality Control by the VCP AAA-ATPase”
– VCP AAA-ATPase 对蛋白质质量控制的调节 –
- 批准号:
9884781 - 财政年份:2018
- 资助金额:
$ 24.75万 - 项目类别:
“Regulation of Protein Quality Control by the VCP AAA-ATPase”
– VCP AAA-ATPase 对蛋白质质量控制的调节 –
- 批准号:
10379451 - 财政年份:2018
- 资助金额:
$ 24.75万 - 项目类别:
The Role Of p97-Chaperone Complexes In Protein Quality Control
p97-伴侣复合物在蛋白质质量控制中的作用
- 批准号:
9321274 - 财政年份:2015
- 资助金额:
$ 24.75万 - 项目类别:
The Role Of p97-Chaperone Complexes In Protein Quality Control
p97-伴侣复合物在蛋白质质量控制中的作用
- 批准号:
9140089 - 财政年份:2015
- 资助金额:
$ 24.75万 - 项目类别:
The Role Of p97-Chaperone Complexes In Protein Quality Control
p97-伴侣复合物在蛋白质质量控制中的作用
- 批准号:
8486954 - 财政年份:2015
- 资助金额:
$ 24.75万 - 项目类别:
A Global Screen for Genes Regulating Cdt1 Turnover In Response To DNA Damage
针对 DNA 损伤调节 Cdt1 更新的基因的全局筛选
- 批准号:
8166000 - 财政年份:2010
- 资助金额:
$ 24.75万 - 项目类别:
A Global Screen for Genes Regulating Cdt1 Turnover In Response To DNA Damage
针对 DNA 损伤调节 Cdt1 更新的基因的全局筛选
- 批准号:
8292212 - 财政年份:2010
- 资助金额:
$ 24.75万 - 项目类别:
A Global Screen for Genes Regulating Cdt1 Turnover In Response To DNA Damage
针对 DNA 损伤调节 Cdt1 更新的基因的全局筛选
- 批准号:
7912605 - 财政年份:2010
- 资助金额:
$ 24.75万 - 项目类别: