High Resolution Profiling of Senescent Neurons and Their Microenvironments in Postmortem Human Brain Tissue Spanning Eight Decades of Life
跨八个十年生命的死后人脑组织中衰老神经元及其微环境的高分辨率分析
基本信息
- 批准号:10414099
- 负责人:
- 金额:$ 38.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-10 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAgeAgingAlzheimer&aposs DiseaseAmericasApoptosisAutomobile DrivingAutopsyBiological AgingBiology of AgingBrainBrain DiseasesCause of DeathCell AgingCell CycleCell Cycle ArrestCell DeathCell Differentiation processCell NucleusCellsCellular biologyChronicChronologyClinicalColorDataDementiaDepositionDiseaseDisease ProgressionElderlyEnvironmentFunctional disorderGene ExpressionGerm CellsHealthHistologicHumanInflammationInterventionLasersLifeLinkLongevityMediatingMediator of activation proteinMethodsMitoticMolecularNerve DegenerationNeurofibrillary TanglesNeuronsNeurosciencesNeurosciences ResearchOrangesParticipantPathogenesisPathogenicityPathologyPathway interactionsPatternPharmacologyPhenotypePopulationProcessResearchResearch ProposalsResolutionRisk FactorsRoleSmall Nuclear RNASourceTauopathiesTestingTissuesToxic effectTransgenic MiceTranslatingUniversitiesWashingtonbiobankbiological adaptation to stressbrain healthbrain tissuecell injurydigitaleffective therapyentorhinal cortexexperimental studylaser capture microdissectionnew therapeutic targetnovelnovel therapeuticsprotein expressionsenescencetau Proteinstau aggregationtissue degenerationtranscriptome sequencingtranscriptomicstreatment strategy
项目摘要
Project Summary/Abstract
Advanced chronological age is the greatest risk factor for developing Alzheimer’s disease. Accumulating
evidence suggests that disease processes may begin decades prior to dementia. Therefore, cellular and
molecular processes that contribute to biological aging may also modulate Alzheimer’s disease pathogenesis.
We recently identified a fundamental cellular aging stress response, cellular senescence, as a pathogenic
process driving neurodegeneration in tauopathies, brain diseases histologically defined by tau protein
accumulation. Features of cellular senescence include stable cell cycle arrest and toxic secretory phenotype.
In this way, senescent cells escape cell death and become persistently deleterious to their surrounding
environment. We have found a causal relationship connecting tau accumulation (i.e. neurofibrillary tangles),
a neuronal senescence-like phenotype, and chronic neurodegeneration in tauopathies, including Alzheimer’s
disease. As terminally differentiated cells, neurons may seem incapable of initiating a senescence stress
response. However, our data indicate that neurons with mature neurofibrillary tangles are arrested in a
cellular senescence-like state. The objective of this project is to identify the upstream molecular mediators
and downstream cellular consequences of neuronal senescence in the human brain. High resolution profiling
methods will be applied to analyze neurons across the adult human lifespan, and throughout the progressive
stages of Alzheimer’s disease. This project will significantly advance the basic understanding of this novel
neuronal cell fate, cellular senescence, and its influence on brain health. Moreover, the cellular and molecular
pathways identified in our project may reveal novel therapeutic targets for intervention, and the age/stage of
disease where they would be most beneficial.
项目总结/文摘
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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Miranda Ethel Orr其他文献
Miranda Ethel Orr的其他文献
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{{ truncateString('Miranda Ethel Orr', 18)}}的其他基金
High Resolution Profiling of Senescent Cells in ALS Brain and Spinal Cord
ALS 大脑和脊髓中衰老细胞的高分辨率分析
- 批准号:
10487832 - 财政年份:2022
- 资助金额:
$ 38.76万 - 项目类别:
High Resolution Profiling of Senescent Neurons and Their Microenvironments in Postmortem Human Brain Tissue Spanning Eight Decades of Life
跨八个十年生命的死后人脑组织中衰老神经元及其微环境的高分辨率分析
- 批准号:
10044272 - 财政年份:2020
- 资助金额:
$ 38.76万 - 项目类别:
High Resolution Profiling of Senescent Neurons and Their Microenvironments in Postmortem Human Brain Tissue Spanning Eight Decades of Life
跨八个十年生命的死后人脑组织中衰老神经元及其微环境的高分辨率分析
- 批准号:
10651762 - 财政年份:2020
- 资助金额:
$ 38.76万 - 项目类别:
High Resolution Profiling of Senescent Neurons and Their Microenvironments in Postmortem Human Brain Tissue Spanning Eight Decades of Life
跨八个十年生命的死后人脑组织中衰老神经元及其微环境的高分辨率分析
- 批准号:
10259700 - 财政年份:2020
- 资助金额:
$ 38.76万 - 项目类别:
Alzheimer’s disease-associated tau toxicity induces cellular senescence in the brain.
阿尔茨海默病相关的 tau 蛋白毒性会导致大脑细胞衰老。
- 批准号:
10266059 - 财政年份:2017
- 资助金额:
$ 38.76万 - 项目类别:
Alzheimer’s disease-associated tau toxicity induces cellular senescence in the brain.
阿尔茨海默病相关的 tau 蛋白毒性会导致大脑细胞衰老。
- 批准号:
10132465 - 财政年份:2017
- 资助金额:
$ 38.76万 - 项目类别:
Alzheimer’s disease-associated tau toxicity induces cellular senescence in the brain.
阿尔茨海默病相关的 tau 蛋白毒性会导致大脑细胞衰老。
- 批准号:
9352624 - 财政年份:2017
- 资助金额:
$ 38.76万 - 项目类别:
Alzheimer’s disease-associated tau toxicity induces cellular senescence in the brain.
阿尔茨海默病相关的 tau 蛋白毒性会导致大脑细胞衰老。
- 批准号:
9980174 - 财政年份:2017
- 资助金额:
$ 38.76万 - 项目类别:
Novel Stem Cell and Mouse Models to Study Frontotemporal Dementia
研究额颞叶痴呆的新型干细胞和小鼠模型
- 批准号:
7614715 - 财政年份:2008
- 资助金额:
$ 38.76万 - 项目类别:
Novel Stem Cell and Mouse Models to Study Frontotemporal Dementia
研究额颞叶痴呆的新型干细胞和小鼠模型
- 批准号:
7697113 - 财政年份:2008
- 资助金额:
$ 38.76万 - 项目类别:
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