Elucidating the impact of FIC-1/FICD-mediated AMPylation on polyglutamine aggregation dynamics and toxicity
阐明 FIC-1/FICD 介导的 AMPylation 对聚谷氨酰胺聚集动力学和毒性的影响
基本信息
- 批准号:10464265
- 负责人:
- 金额:$ 3.95万
- 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:2022-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Adenosine MonophosphateAffectAgingAllelesAnimalsAttenuatedBiochemicalBiological AssayBuffersCRISPR interferenceCaenorhabditis elegansCellsCellular StructuresChemicalsDataDevelopmentDiseaseDisease modelExcisionFailureFamilyGeneral PopulationGenesGeneticGoalsHeat-Shock Proteins 70HumanHuntington DiseaseHuntington geneIn VitroInclusion BodiesIndividualInheritedKnock-outKnowledgeLengthLinkMJD1 proteinMachado-Joseph DiseaseMaintenanceMediatingMediator of activation proteinMolecularMolecular ChaperonesMutagenesisNeurodegenerative DisordersNeuronsOrthologous GenePathogenicityPathologicPathway interactionsPatientsPhysiologicalPost-Translational Protein ProcessingPost-Translational RegulationPrevalenceProcessProteinsQuality ControlRNA InterferenceRegulationReportingResearchRoleSignal PathwaySolubilityStressSumTechniquesTestingTherapeuticTherapeutic InterventionTissuesToxic effectTrinucleotide Repeat ExpansionType 1 Spinocerebellar AtaxiaWorkarmbasebiological adaptation to stressdisease-causing mutationfollow-upfunctional declinehuman embryonic stem cellin vitro Modelknock-downmisfolded proteinmutantneuron lossnoveloverexpressionpolyglutamineprotein aggregationprotein functionprotein misfoldingproteostasisresponsestem cellstargeted treatment
项目摘要
PROJECT SUMMARY
Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3) are inherited aging-associated diseases
that have a devastating impact on patients and family caretakers relative to their prevalence in the general
population. These conditions belong to a family of polyglutamine (polyQ) expansion diseases caused by
mutations resulting in the pathological expansion of trinucleotide (CAGn) repeats in distinct genes. Increases in
CAG repeat length give rise to proteins containing aberrantly expanded polyQ tracts, which interfere with normal
protein function and promote misfolding. Toxicity in these diseases is thought to arise in part from the formation
of pathological inclusion bodies comprised of aberrantly conformed mutant proteins, a hallmark observed in
numerous aging-associated neurodegenerative diseases. Despite extensive efforts to decipher the mechanisms
underlying toxicity in polyQ diseases, however, little progress has been made towards identifying targets for
therapeutic intervention.
Recently, the post-translational modification (PTM), AMPylation, has emerged as a novel regulator of HSP70
family chaperones, crucial components of the cell’s protein quality control machinery that buffer against protein
misfolding stress. Protein AMPylation is carried out by the fic-type AMPylase, FICD in humans, and its ortholog
FIC-1, in C. elegans, respectively. Work in our lab has established that FIC-1-mediated AMPylation directly alters
polyQ aggregation dynamics and toxicity. Further, my preliminary data as presented in this proposal identifies
fic-1 deficiency as sufficient to rescue survival of C. elegans expressing aggregation-prone polyQs during
development in a polyQ length-dependent manner. Taken together, these findings suggest that the loss of FIC-
1/FICD-mediated AMPylation bolsters proteostasis network capacity to alleviate toxicity induced by polyQ protein
aggregation.
This project will utilize cross-disciplinary approaches to generate a holistic characterization of FICD/FIC-1-
mediated AMPylation in polyQ diseases. To this end, I will harness the powerful genetics of C. elegans to uncover
novel pathway(s) that promote survival in the face of pathogenic polyQ aggregation (Aim 1). In tandem, I will
employ functional assays in neurons derived from HD and SCA3 patient stem cells to profile how FICD activity
affects polyQ aggregation and toxicity in these disease models (Aim 2). The results of these studies will advance
our knowledge of how AMPylation regulates proteostasis in polyQ diseases. The ultimate goal of my research is
to capitalize on these findings to develop translatable therapeutic approaches for aging-associated diseases.
项目总结
亨廷顿病(HD)和脊髓小脑性共济失调3型(SCA3)是遗传性衰老相关疾病
与患者和家庭照顾者的普遍患病率相比,这些疾病对患者和家庭照顾者具有毁灭性的影响
人口。这些疾病属于聚谷氨酰胺(PolyQ)扩张性疾病家族,由
突变导致不同基因中三核苷酸(CAGn)重复序列的病理性扩张。增加了
CAG重复长度导致含有异常扩张的多聚Q链的蛋白质,这干扰了正常
蛋白质的功能和促进错误折叠。这些疾病的毒性被认为部分是由于形成的
病理性包涵体由异常整合的突变蛋白组成,这是在
许多与衰老相关的神经退行性疾病。尽管人们做出了大量努力来破译这些机制
然而,多药耐药疾病的潜在毒性在确定靶点方面进展甚微。
治疗性干预。
最近,翻译后修饰(PTM),即AMP化,已经成为HSP70的一种新的调节因子
家族伴侣是细胞蛋白质质量控制机制的关键组成部分,可以缓冲蛋白质
错折应力。在人类中,蛋白质AMPylase FICD及其同源基因是通过Fic型AMPylase来执行的
FIC-1,分别在线虫中。我们实验室的工作已经证实,FIC-1介导的AMP化直接改变
多Q聚集动力学和毒性。此外,我在这项提案中提出的初步数据表明
FIC-1缺陷足以挽救表达易于聚集的多QS的线虫在
以依赖于多个Q长度的方式发展。综上所述,这些发现表明,FIC的损失-
1/FICD介导的AMP化增强蛋白稳定网络能力以减轻多聚Q蛋白诱导的毒性
聚合。
该项目将利用跨学科的方法来生成FICD/FIC-1的整体特征-
多聚Q疾病中介导的AMP化。为此,我将利用线虫强大的遗传学来揭示
面对致病多Q聚集促进生存的新途径(S)(目标1)。一齐,我会
利用HD和SCA3患者干细胞来源的神经元的功能分析来描述FICD的活性
在这些疾病模型中影响多Q聚集和毒性(目标2)。这些研究的结果将会取得进展
我们对AMP化如何调节多聚Q疾病中的蛋白平衡的了解。我研究的最终目标是
利用这些发现,开发可翻译的治疗衰老相关疾病的方法。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Kate Matthys Van Pelt其他文献
Kate Matthys Van Pelt的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Kate Matthys Van Pelt', 18)}}的其他基金
Elucidating the impact of FIC-1/FICD-mediated AMPylation on polyglutamine aggregation dynamics and toxicity
阐明 FIC-1/FICD 介导的 AMPylation 对聚谷氨酰胺聚集动力学和毒性的影响
- 批准号:
10656221 - 财政年份:2022
- 资助金额:
$ 3.95万 - 项目类别:
相似海外基金
Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
- 批准号:
495182 - 财政年份:2023
- 资助金额:
$ 3.95万 - 项目类别:
Parkinson's disease and aging affect neural activation during continuous gait alterations to the split-belt treadmill: An [18F] FDG PET Study.
帕金森病和衰老会影响分体带跑步机连续步态改变期间的神经激活:[18F] FDG PET 研究。
- 批准号:
400097 - 财政年份:2019
- 资助金额:
$ 3.95万 - 项目类别:
The elucidation of the mechanism by which intestinal epithelial cells affect impaired glucose tolerance during aging
阐明衰老过程中肠上皮细胞影响糖耐量受损的机制
- 批准号:
19K09017 - 财政年份:2019
- 资助金额:
$ 3.95万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Does aging of osteocytes adversely affect bone metabolism?
骨细胞老化会对骨代谢产生不利影响吗?
- 批准号:
18K09531 - 财政年份:2018
- 资助金额:
$ 3.95万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Links between affect, executive function, and prefrontal structure in aging: A longitudinal analysis
衰老过程中情感、执行功能和前额叶结构之间的联系:纵向分析
- 批准号:
9766994 - 财政年份:2018
- 资助金额:
$ 3.95万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9320090 - 财政年份:2017
- 资助金额:
$ 3.95万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
10166936 - 财政年份:2017
- 资助金额:
$ 3.95万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9761593 - 财政年份:2017
- 资助金额:
$ 3.95万 - 项目类别:
Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms
衰老过程中抑郁症的实验模型:失眠、炎症和影响机制
- 批准号:
9925164 - 财政年份:2016
- 资助金额:
$ 3.95万 - 项目类别:
Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms
衰老过程中抑郁症的实验模型:失眠、炎症和影响机制
- 批准号:
9345997 - 财政年份:2016
- 资助金额:
$ 3.95万 - 项目类别: