Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients
评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞衰老情况
基本信息
- 批准号:10153611
- 负责人:
- 金额:$ 48.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-15 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAnimal ModelAnimalsAttentionAutopsyBindingBiologicalBiological AgingBrainCell AgingCell NucleusCellsClinicalColorCopy Number PolymorphismDNADNA DamageDNA copy numberDNA sequencingDefectDependenceDetectionDeveloped CountriesDevelopmentDiseaseDisease ProgressionDisease modelEmbryonic DevelopmentFOXO3A geneFibroblastsFluorescenceGene ExpressionGene Expression ProfileGeneticGenetic VariationHumanImpaired cognitionImpairmentIndividualInduced pluripotent stem cell derived neuronsLifeLightLongevityMeasuresMediator of activation proteinModelingMolecularMonitorMosaicismMutateNeurodegenerative DisordersNeuronsNuclearNuclear ImportNuclear PoreNuclear Pore ComplexNuclear TranslocationPathogenesisPathologicPathologyPatientsPermeabilityPhenotypePlayPopulationPrevalenceProcessProteinsRejuvenationReporterResearchResolutionRisk FactorsRoleSamplingSeedsSolidStimulusSystemTestingTimeTissuesTransgenic MiceWorkage relatedage related neurodegenerationaging brainbasecellular pathologycellular targetingcohortdisorder controlearly onseteffective therapyfamilial Alzheimer diseasehuman modelhuman old age (65+)imaging approachinduced pluripotent stem cellinsightlive cell imagingmiddle agemild cognitive impairmentmutantnormal agingnucleocytoplasmic transportoverexpressionpreservationreceptortandem mass spectrometrytranscriptometranscriptome sequencingwhole genome
项目摘要
SUMMARY
Pathogenesis of Alzheimer’s disease ( AD) is highly age-related and prevalence increases
exponentially after the age of 60. While at the age of 70 around 5% of all people are affected, more than one
third over the age of 85 are afflicted with AD. In addition to the dramatic increase seen in patients suffering
from age-related neurodegenerative disorders in industrialized countries, a substantial increase in AD patients
in the developing world is also observed in tandem with their aging populations. Currently, there are no
treatments available for AD that could slow, halt or reverse the progression of the disease. This growing
problem can only be mitigated if we can gain a more complete understanding of AD pathogenesis,
which obviously demands a solid understanding of human biological aging. This project proposed by Dr.
Gage and colleagues will, for the first time, challenge the importance of cellular aging in a human model for
the disease. The Gage lab has recently shown that direct conversion of human fibroblasts into induced
neurons (iNs) preserves signatures of cell aging, allowing the detection of cellular pathologies relevant to
human aging. By contrast, induced pluripotent stem cell (iPSC) reprogramming erases age-dependent
differences; iPSC-derived neurons thus resemble rejuvenated cells. To better understand the impact of
neuronal cell aging on the pathology of sporadic AD, the first aim of this group is to generate both
phenotypically old and rejuvenated neurons from a large set of clinically well-characterized AD patients and
matched controls. Following an unbiased transcriptome approach, they will analyze for AD-specific gene
expression profiles and work to understand which of the AD-specific gene expression signatures and
related mechanisms are age-dependent and which are age-independent.
Dysregulation of nucleo-cytoplasmic transport and the import receptor RanBP17 are currently emerging
as major topics in aging and neurodegenerative disease research. In their second aim, Dr. Gage's team will
work to identify the binding partners and exact functions of the yet understudied protein RanBP17. In a
third aim, they will harness their recently established reporter system to measure nucleo-
cytoplasmic compartmentalization in young and old AD neurons and probe for nuclear transport-based
mediators of age-dependent AD pathology using live cell imaging approaches.
Age-dependent accumulation of DNA damage contributes to genetic diversity among our cells,
a process known as somatic mosaicism. As recent evidence suggests that AD only needs a small seed
from which the pathology can spread throughout the brain, somatic mosaicism might play an important role
in the development of sporadic AD. In a fourth aim, the Gage team will use simultaneous DNA and RNA
sequencing of single post-mortem neurons and iNs from the same patients and ask to what extent DNA
copy number variations can turn a neuron into a potential `AD seed' cell.
摘要
阿尔茨海默病(AD)的发病机制与年龄高度相关,患病率增加
60岁以后呈指数增长。而在70岁时,大约5%的人受到影响,不止一个
第三,85岁以上的人患有阿尔茨海默病。除了患者数量的急剧增加外,
在工业化国家,AD患者因年龄相关的神经退行性疾病而大幅增加
发展中国家的人口老龄化也伴随着这一趋势。目前,没有
可用于治疗AD的治疗方法可以延缓、阻止或逆转疾病的进展。这一增长
只有对AD的发病机制有了更全面的了解,问题才能得到缓解,
这显然需要对人类的生物衰老有一个坚实的理解。这个项目是由Dr。
盖奇和他的同事将首次在人体模型中挑战细胞衰老的重要性
这种疾病。盖奇实验室最近表明,将人成纤维细胞直接转化为诱导的
神经元(INS)保留了细胞老化的特征,允许检测与
人类的衰老。相比之下,诱导多能干细胞(IPSC)重编程消除了年龄相关性
不同;IPSC来源的神经元因此类似于恢复活力的细胞。为了更好地了解
神经细胞老化对散发性阿尔茨海默病的病理影响,本组研究的首要目标是生成两者
一大组临床特征良好的AD患者和
配对的对照组。在无偏见的转录组方法之后,他们将分析AD特有的基因
表达谱和工作,以了解哪些AD特定的基因表达特征和
相关机制与年龄有关,也与年龄无关。
目前正在出现核质运输和输入受体RanBP17的失调
作为衰老和神经退行性疾病研究的主要课题。在他们的第二个目标中,盖奇博士的团队将
确定尚未被研究的蛋白RanBP17的结合伙伴和确切功能。在一个
第三个目标,他们将利用他们最近建立的报告系统来测量核-
青年和老年阿尔茨海默病神经元的胞质区划及其核转运机制的探讨
使用活细胞成像方法研究年龄依赖性AD病理的介体。
依赖年龄的DNA损伤积累有助于我们细胞之间的遗传多样性,
这一过程被称为体细胞镶嵌。最近的证据表明,阿尔茨海默病只需要一粒小种子
通过这种病理可以传播到整个大脑,体细胞嵌合体可能发挥重要作用
在散发性阿尔茨海默病的发展中。在第四个目标中,Gage团队将同时使用DNA和RNA
对同一患者的单个死后神经元和INS进行测序,并询问DNA的程度
拷贝数的变化可以将神经元转变为潜在的“AD种子”细胞。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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FRED H GAGE其他文献
FRED H GAGE的其他文献
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{{ truncateString('FRED H GAGE', 18)}}的其他基金
Neuronal senescence and inflammation in Alzheimer's disease
阿尔茨海默病的神经元衰老和炎症
- 批准号:
10213563 - 财政年份:2021
- 资助金额:
$ 48.5万 - 项目类别:
Neuronal senescence and inflammation in Alzheimer's disease
阿尔茨海默病的神经元衰老和炎症
- 批准号:
10633023 - 财政年份:2021
- 资助金额:
$ 48.5万 - 项目类别:
Combinatorial Actions of Genetic Variants and Gender Bias of Alzherimer's Disease
阿尔茨海默病的遗传变异和性别偏见的组合作用
- 批准号:
9431031 - 财政年份:2017
- 资助金额:
$ 48.5万 - 项目类别:
Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients
评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞老化
- 批准号:
10522910 - 财政年份:2017
- 资助金额:
$ 48.5万 - 项目类别:
Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients
评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞老化
- 批准号:
10835760 - 财政年份:2017
- 资助金额:
$ 48.5万 - 项目类别:
Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients
评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞老化
- 批准号:
9361030 - 财政年份:2017
- 资助金额:
$ 48.5万 - 项目类别:
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