Systemic Cell Senescence as a Mediator of Brain Aging Through Circulation
系统细胞衰老是通过循环调节大脑衰老的介质
基本信息
- 批准号:10191895
- 负责人:
- 金额:$ 47.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:Adipose tissueAdverse effectsAgeAgingAttenuatedBiology of AgingBloodBlood CirculationBlood VesselsBrainCell AgingCellsCognitive agingCytometryDementiaDeteriorationEncephalitisFunctional disorderGoldHeartHomeostasisHumanImageImpaired cognitionIn VitroInflammationInflammatoryKidneyKnowledgeLabelLiverLungMediator of activation proteinMetabolicMethionineMethionine-tRNA LigaseMethodsModelingMolecular AnalysisMonitorMusMuscleOperative Surgical ProceduresParabiosisPathogenicityPharmacologyPhenotypePlasmaPlasma ExchangePlasma ProteinsPreventionProblem SolvingProductionProteinsProteomeProteomicsPublishingResearchRisk FactorsSourceSpleenTamoxifenTestingTherapeuticTissuesTransgenic MiceTransgenic ModelTransgenic OrganismsTravelWild Type Mouseage effectage relatedagedaging brainbasebrain dysfunctionbrain healthcognitive performancecognitive testingdesigneffective therapyexperimental studyimprovedinnovationmouse modelmutantneurogenesisnovel strategiesnovel therapeutic interventionpre-clinicalpreventsenescence
项目摘要
PROJECT SUMMARY
Aging is the strongest risk factor for cognitive decline and dementia. Targeting fundamental aging mechanisms
offers promising new strategies to counter brain dysfunction. Recent breakthroughs have demonstrated that
proteins in aged blood circulation mechanistically contribute to accelerated brain aging, and senescent cells
(SCs) accumulate in aging and may drive tissue deterioration, in part, through the proinflammatory senescence
associated secretory phenotype (SASP). This research is designed to test whether progeronic SASP
proteins produced by systemic SCs mechanistically contribute to accelerated brain aging through
blood circulation. This premise is based on published findings establishing that aged blood circulation and/or
direct administration of progeronic plasma proteins that are putative SASP factors are sufficient to transfer an
accelerated aging phenotype to young mouse brain and our research demonstrating that systemic SC
clearance attenuates the SASP in circulation, which is associated with improvements in brain inflammatory
parameters and cognitive decline. To test our central hypothesis, we will combine circulatory exchange
methods with mouse models in which SCs can be eliminated or production of the SC proteome can be
precisely monitored, which will enable us to study whether reducing the circulating SASP is sufficient
to ameliorate the adverse influence of aged blood on brain homeostasis. We will develop an innovative
transgenic mouse model that will enable bioorthogonal labeling of the nascent p16+ SC proteome. This will
empower our discovery of the age- and tissue-specific p16+SC-proteome, its contribution to the
circulating progeronic proteome, and its responsivity to SC clearance. Administration of bioorthogonally
labeled aged plasma +/- SC clearance to young mice will facilitate discovery of candidate SASP proteins
responsible for accelerated aging brain phenotypes for further mechanistic interrogation. Modifying aged blood
composition and targeting SCs are therapeutics actively being pursued for ameliorating age-related decline.
This project is designed to mechanistically synergize and advance these two promising concepts. Our research
may preclinically implicate systemic SC clearance as an option to deplete the progeronic influence of aged
blood, ultimately revealing a novel approach for treatment or prevention of age-dependent cognitive decline
and dementia.
项目概要
衰老是认知能力下降和痴呆的最强危险因素。针对基本的衰老机制
提供了有前景的新策略来对抗大脑功能障碍。最近的突破表明
衰老血液循环中的蛋白质在机制上会加速大脑衰老和衰老细胞
(SC)在衰老过程中积累,可能部分通过促炎性衰老导致组织恶化
相关分泌表型(SASP)。本研究旨在测试早老 SASP 是否
系统性 SC 产生的蛋白质通过机制加速大脑衰老
血液循环。这一前提是基于已发表的研究结果,证实老化的血液循环和/或
直接施用早老血浆蛋白(推定的 SASP 因子)足以转移
加速年轻小鼠大脑的衰老表型,我们的研究表明系统性 SC
清除可减弱循环中的 SASP,这与脑炎症的改善有关
参数和认知能力下降。为了检验我们的中心假设,我们将结合循环交换
使用小鼠模型的方法,其中可以消除 SC 或可以产生 SC 蛋白质组
精确监测,这将使我们能够研究减少循环 SASP 是否足够
改善老化血液对大脑稳态的不利影响。我们将开发创新的
转基因小鼠模型将能够对新生 p16+ SC 蛋白质组进行生物正交标记。这将
使我们能够发现年龄和组织特异性的 p16+SC 蛋白质组,它对
循环早老蛋白组及其对 SC 清除的响应。生物正交管理
对年轻小鼠进行标记的老年血浆 +/- SC 清除将有助于发现候选 SASP 蛋白
负责加速老化的大脑表型,以进行进一步的机械审讯。改变老化血液
组合物和靶向 SC 是人们正在积极寻求的用于改善与年龄相关的衰退的治疗方法。
该项目旨在机械地协同和推进这两个有前途的概念。我们的研究
临床前可能表明全身性 SC 清除是消除老年人早衰影响的一种选择
血液,最终揭示了一种治疗或预防年龄依赖性认知衰退的新方法
和痴呆症。
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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Marissa Joy Schafer其他文献
Marissa Joy Schafer的其他文献
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{{ truncateString('Marissa Joy Schafer', 18)}}的其他基金
Spatially-resolved protein and transcriptome mapping of senescent cells
衰老细胞的空间分辨蛋白质和转录组图谱
- 批准号:
10684900 - 财政年份:2022
- 资助金额:
$ 47.66万 - 项目类别:
Spatially-resolved protein and transcriptome mapping of senescent cells
衰老细胞的空间分辨蛋白质和转录组图谱
- 批准号:
10551944 - 财政年份:2022
- 资助金额:
$ 47.66万 - 项目类别:
Spatially-resolved protein and transcriptome mapping of senescent cells
衰老细胞的空间分辨蛋白质和转录组图谱
- 批准号:
10684900 - 财政年份:2022
- 资助金额:
$ 47.66万 - 项目类别:
Systemic Cell Senescence as a Mediator of Brain Aging Through Circulation
系统细胞衰老是通过循环调节大脑衰老的介质
- 批准号:
10394326 - 财政年份:2021
- 资助金额:
$ 47.66万 - 项目类别:
Senescent Vascular Cells as Mediators of Cognitive Decline
衰老血管细胞作为认知衰退的介质
- 批准号:
10282110 - 财政年份:2021
- 资助金额:
$ 47.66万 - 项目类别:
Senescent Vascular Cells as Mediators of Cognitive Decline
衰老血管细胞作为认知衰退的介质
- 批准号:
10319630 - 财政年份:2021
- 资助金额:
$ 47.66万 - 项目类别:
Senescent Vascular Cells as Mediators of Cognitive Decline
衰老血管细胞作为认知衰退的介质
- 批准号:
10534767 - 财政年份:2021
- 资助金额:
$ 47.66万 - 项目类别:
Systemic Cell Senescence as a Mediator of Brain Aging Through Circulation
系统细胞衰老是通过循环调节大脑衰老的介质
- 批准号:
10574590 - 财政年份:2021
- 资助金额:
$ 47.66万 - 项目类别:
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