Adipokines, Aging, and Alzheimers Disease
脂肪因子、衰老和阿尔茨海默病
基本信息
- 批准号:10378046
- 负责人:
- 金额:$ 47.45万
- 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:2020-06-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:3xTg-AD mouseAdipocytesAdipose tissueAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmino Acyl-tRNA SynthetasesAmishAnimal ModelAnimalsBehaviorBiological AgingBiological MarkersBrainCCL2 geneCell AgingChronicChronic DiseaseClinical TrialsCoenzyme ACognitiveCognitive deficitsComplexCyclin-Dependent KinasesDataDevelopmentDisease ProgressionElderlyExhibitsFatty acid glycerol estersGeneticGenetic CodeGenetic DiseasesGeroscienceHigh Fat DietImpaired cognitionInflammationInflammatoryInsulinInterventionIntervention StudiesKnock-inKnock-in MouseKnock-outKnowledgeLCN2 geneLaboratoriesLeadLearningLongevityMediatingMediator of activation proteinMemoryMetabolic PathwayMolecularMolecular TargetMusMutant Strains MiceMutationObesityOnset of illnessPathogenesisPathway interactionsPharmacologyPhenotypePhosphorylationPhosphotransferasesPlasminogen ActivatorProcessProteinsRoleSERPINE1 geneSerumSeveritiesSignal TransductionSiteTestingTherapeuticThinnessTissue DonorsTransfer RNATransplantationVisceralWild Type Mouseadipokinesage relatedbasecognitive functiondiet-induced obesityinhibitormembermouse modelneuropathologynovelnull mutationpre-clinicalprogramsprolylglutamic acidsenescenceside effect
项目摘要
Project Summary/Abstract
Advanced age is the leading risk factor for Alzheimer's disease (AD). Our program is based on a central tenet of
geroscience that select pathways and mechanisms are shared between advanced age and chronic disease,
and knowledge of one can inform the other. The mTORC1-S6K1 kinase axis is an obesity-activated pathway
that restricts longevity, and targeting this pathway extends lifespan in animal models. This pathway has been
implicated in AD pathogenesis, and pre-clinical intervention studies are promising. However, pharmacological
inhibition causes harmful side-effects, deterring therapeutic application. We have discovered a Cdk5-driven
bifurcation of the mTORC1-S6K1 pathway that contributes to aging and adiposity. We identified a novel, triply-
phosphorylated form of S6K1 (we term S6K1*) phosphorylated at two sites in the C-terminus, as well as at
Thr389, the classical mTORC1 activation site. Multi-site phosphorylated S6K1 directs phosphorylation of novel
targets, including the dual function tRNA synthetase, Glu-Pro tRNA synthetase (EPRS), coenzyme A synthase
(CoASY), and lipocalin-2 (Lcn2). Importantly, mice bearing a phospho-deficient mutation of EPRS at the critical
Ser999 residue are lean and exhibit ~120-day lifespan extension. Ser999 EPRS phosphorylation is required for
elevated adipocyte expression of key longevity-related adipokines, including monocyte chemoattractant protein-
1 (MCP1) and plasminogen-activator-1 (PAI-1). MCP1 is a pro-inflammatory protein predominant in the
senescence-associated secretory phenotype (SASP); PAI-1 is a marker and mediator of cell senescence and
aging, and a null mutation in SERPINE1, the gene encoding PAI-1, protects against biological aging.
Importantly, these novel, age-related targets of S6K1* also are implicated in AD progression. For example,
serum MCP1 level is associated with cognitive decline in mouse AD models and AD patients, and PAI-1
knockout, or pharmacologic inhibition, reduces AD in mice. We hypothesize that the extended mTORC1-S6K1
pathway and its effectors contribute to AD onset and progression, and that genetic inhibition of the pathway will
retard AD onset and reduce its severity with minimal adverse side effects. Also, mice fed a high-fat diet will
show that obesity influences aging and AD progression by a common pathway. We will test these hypotheses in
two Specific Aims. In the first Aim, we will elucidate the role of the S6K1* pathway in AD progression. AD-
susceptible mice will be bred with two genetic mouse models of S6K1* pathway inhibition developed in our
laboratory, namely, EPRS phospho-deficient knock-in mice bearing a Ser999-to-Ala mutation, and our newly
developed S6K1 Ser429-to-Ala mouse model, that lacks the extended S6K1* substrate selection, but exhibits
unaltered canonical S6K1 kinase activity. We will determine effects of S6K1* pathway inhibition on AD
pathology and adverse cognitive side-effects. In the second Aim we will determine the influence of obesity on
S6K1* pathway-mediated AD progression. Our program will establish new mechanisms and molecular targets
for intervention in the aging process and AD.
项目摘要/摘要
高龄是阿尔茨海默病(AD)的主要危险因素。我们的计划基于一个中心原则,即
选择途径和机制的老年学在高龄和慢性病之间是共享的,
而对其中一个的了解可以告知另一个。MTORC1-S6K1激动轴是肥胖激活的途径
这限制了寿命,而靶向这一途径延长了动物模型的寿命。这条路一直是
阿尔茨海默病的发病机制和临床前干预研究前景看好。然而,药理学
抑制会导致有害的副作用,阻碍治疗应用。我们发现了一种由CDK5驱动的
导致衰老和肥胖的mTORC1-S6K1通路的分叉。我们发现了一部小说,三重-
S6K1的磷酸化形式(我们称为S6K1*)在C末端的两个位点以及在
Thr389,经典的mTORC1激活位点。多位点磷酸化的S6K1直接磷酸化新基因
靶点包括双功能tRNA合成酶、Glu-Pro tRNA合成酶(Eprs)、辅酶A合成酶
(Coasy)和Lipocalin-2(Lcn2)。重要的是,携带Eprs缺磷突变的小鼠在危急时刻
Ser999残留物很瘦,寿命延长了约120天。Ser999 EPRS磷酸化是必需的
脂肪细胞表达与长寿相关的关键脂肪因子,包括单核细胞趋化蛋白-
1(MCP1)和纤溶酶原激活物-1(PAI-1)。MCP1是一种促炎蛋白,主要存在于
衰老相关分泌表型(SASP);PAI-1是细胞衰老的标志和介体
衰老,以及编码PAI-1的基因SERPINE1的零突变,可以防止生物衰老。
重要的是,S6K1*的这些新的、与年龄相关的靶点也与AD的进展有关。例如,
血清MCP1水平与小鼠AD模型和AD患者认知功能减退及PAI-1相关
基因敲除或药物抑制可以减少小鼠的阿尔茨海默病。我们假设扩展的mTORC1-S6K1
该通路及其效应器参与了AD的发生和发展,而该通路的遗传抑制将
延缓阿尔茨海默病的发病,减轻其严重程度,副作用最小。此外,喂食高脂肪食物的小鼠将
表明肥胖通过一条共同的途径影响衰老和AD进展。我们将在以下方面测试这些假设
有两个明确的目标。在第一个目标中,我们将阐明S6K1*通路在AD进展中的作用。广告-
用本实验室建立的两种S6K1*通路抑制基因小鼠模型培育易感小鼠
实验室,即携带Ser999到Ala突变的EPRS磷酸缺陷型敲入小鼠,以及我们新的
开发了S6K1 Ser429-to-ALA小鼠模型,缺少扩展的S6K1*底物选择,但表现出
标准的S6K1激酶活性没有改变。我们将确定S6K1*通路抑制对AD的影响
病理学和不良认知副作用。在第二个目标中,我们将确定肥胖对
S6K1*通路介导的AD进展。我们的计划将建立新的机制和分子靶点
用于干预衰老过程和AD。
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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PAUL L FOX其他文献
PAUL L FOX的其他文献
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{{ truncateString('PAUL L FOX', 18)}}的其他基金
The Untranslated 3'End of SARS-CoV-2 RNA as a Determinant of Obesity-Accelerated Infectivity
SARS-CoV-2 RNA 的非翻译 3 末端是肥胖加速感染的决定因素
- 批准号:
10318871 - 财政年份:2021
- 资助金额:
$ 47.45万 - 项目类别:
The Untranslated 3'End of SARS-CoV-2 RNA as a Determinant of Obesity-Accelerated Infectivity
SARS-CoV-2 RNA 的非翻译 3 末端是肥胖加速感染的决定因素
- 批准号:
10689137 - 财政年份:2021
- 资助金额:
$ 47.45万 - 项目类别:
Assay Development for Discovery of a Small Molecule Inhibitor of a Novel Metabolic Pathway that Drives Obesity
发现导致肥胖的新型代谢途径的小分子抑制剂的检测方法开发
- 批准号:
10320035 - 财政年份:2020
- 资助金额:
$ 47.45万 - 项目类别:
Assay Development for Discovery of a Small Molecule Inhibitor of a Novel Metabolic Pathway that Drives Obesity
发现导致肥胖的新型代谢途径的小分子抑制剂的检测方法开发
- 批准号:
10115720 - 财政年份:2020
- 资助金额:
$ 47.45万 - 项目类别:
Multisite phosphorylated S6K1 directs a regulatory module determining adipocyte lipid metabolism
多位点磷酸化 S6K1 指导决定脂肪细胞脂质代谢的调节模块
- 批准号:
10349543 - 财政年份:2020
- 资助金额:
$ 47.45万 - 项目类别:
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