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
基本信息
- 批准号:10522910
- 负责人:
- 金额:$ 116.96万
- 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 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAdultAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease therapeuticAntineoplastic AgentsApolipoprotein EAstrocytesAutopsyBindingBiological AssayBiological ProcessBrainBuffersCell AgingCell NucleusCellsChemicalsClinicalClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCouplingCytoplasmDataDetectionDiseaseDisease MarkerDisease ProgressionEffectivenessElderlyEngineeringEnvironmentEpigenetic ProcessEtiologyFibroblastsGeneticGenomicsGoalsHumanIncidenceIndividualKnowledgeLeadMalignant NeoplasmsMetabolicMitoticModelingMolecularNerve DegenerationNervous system structureNeurogliaNeuronal DysfunctionNeuronsNuclearOncogenicOnset of illnessParaffinPathogenesisPathogenicityPathologicPathologyPathway interactionsPatientsPersonsPharmaceutical PreparationsPharmacologyProtein IsoformsProteinsProteomicsProtocols documentationPyruvate KinaseRNA SplicingRoleStructureTestingTherapeuticTissuesTransgenesTransgenic OrganismsVariantWarburg Effectabeta depositionage relatedage related neurodegenerationagedanticancer researchbasebase editingcancer cellcellular pathologydisease phenotypedisorder controldrug developmentdrug discoverygenome editinginjuredinsightlipidomicsmetabolic abnormality assessmentmetabolomicsmultiple omicsneuroinflammationneuronal metabolismnovelnovel strategiesparacrinepreservationprogramssenescencesingle-cell RNA sequencingspatial relationshiptargeted treatmenttau Proteinstranscriptome sequencing
项目摘要
SUMMARY
Alzheimer’s disease (AD) affects over 50 million people worldwide. The vast majority of patients, AD
develops sporadically in the absence of any known etiology other than advanced age. Despite the fact that AD
has been studied for over a century, its pathogenesis is still not completely understood, and drugs that could
stop or reverse the disease progression are not yet available. Similar to the age-dependent incidence of many
cancers, AD onset is believed to be caused by multiple hits of environmental, genomic, and aging-related
factors. To better understand the cellular and molecular interactions between human aging and AD
pathogenesis, induced neurons (iNs) directly converted from AD patient fibroblasts offer unique possibilities to
model and study the disease in a human age-equivalent neuronal model.
The teams around Dr. Gage and Dr. Mertens have recently shown that direct conversion of human AD
patient-derived fibroblasts into induced neurons (iNs) preserves signatures of cell aging and sporadic AD and
allows for the detection of cellular pathologies and disease drivers. Neuronal hypo-maturity represents a
fundamental AD-related cellular state in iNs, and the cancer-associated Pyruvate Kinase M2 (PKM2) splice
variant emerged as a key player that compromises mature neuronal metabolism and neuronal identity. PKM2
promotes neuronal vulnerability and de-differentiation via metabolic changes in the cytoplasm, and via
epigenetic processes in the nucleus, but the relative contribution of the two mechanisms remains elusive and
might differ substantially between cancer cells and post-mitotic neurons. To understand PKM2 in AD, and to
develop PKM-directed therapeutics, more knowledge regarding (1) the relationship between neuronal PKM2
and hallmarks of AD in the human brain, (2) the fundamental cell biological functions of PKM2 in aged human
neurons, and (3) the crosstalk between PKM-compromised neurons and their glial environment is needed.
This project will challenge the importance of shared pathogenic pathways between cancer and AD, and
assess age-dependently compromised neurons in the context of AD. First, the team will study the relationship
between cancer-related PKM2-positive neurons and AD pathology in the post-mortem human brain. Second,
the mechanistic impact of PKM2 imbalance on the metabolic state and neuronal fate stability of patient-specific
iNs will be assessed by transgene- and genome editing-based approaches. Third, pharmacological
compounds from the cancer field as a basis for developing PKM2-targeted therapeutics for AD will be
leveraged. Fourth, using a novel human iN-based three-dimensional multicellular model, the team will study
neuron-astrocyte coupling in the context of metabolically challenged iNs and their metabolic crosstalk with
human astrocytes. The ultimate goals of these four aims are to gain insight into the roles of the well-
established cancer protein PKM2 in age-related neurodegeneration and to exploit this knowledge to develop
therapeutic strategies against AD.
总结
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Aging in a Dish: iPSC-Derived and Directly Induced Neurons for Studying Brain Aging and Age-Related Neurodegenerative Diseases.
- DOI:10.1146/annurev-genet-120417-031534
- 发表时间:2018-11-23
- 期刊:
- 影响因子:11.1
- 作者:Mertens J;Reid D;Lau S;Kim Y;Gage FH
- 通讯作者:Gage FH
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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:
$ 116.96万 - 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:
$ 116.96万 - 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:
$ 116.96万 - 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:
$ 116.96万 - 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衰老情况
- 批准号:
10153611 - 财政年份:2017
- 资助金额:
$ 116.96万 - 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:
$ 116.96万 - 项目类别:
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