Investigation of synergism between mTOR and eEF2 kinase pathways
Investigation of synergism between mTOR and eEF2 kinase pathways
批准号:
8729435
负责人:
ALEXEY G. RYAZANOV
金额:
$18.78万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-09-30 至 2014-06-30
关键词:
AblationAffectAgingAging-Related ProcessApoptosisApoptoticAutophagocytosisCellsCellular StressChronicDNA DamageDoctor of PhilosophyEmbryoFibroblastsFutureGeneticGlutamic AcidGrowthHematopoieticHematopoietic SystemHematopoietic stem cellsInvestigationKnock-outKnockout MiceLeadLifeLife Support CareLongevityMediatingMetabolismMitochondriaMolecularMusOrganismOxidative StressPathway interactionsPeptide Elongation Factor 2Pharmaceutical PreparationsPhenocopyPhosphorylationPhosphotransferasesPlayPrincipal InvestigatorProcessProductionProtein BiosynthesisProteinsRadioresistanceRegulationResearchResistanceRespirationRibosomal Protein S6 KinaseRoleSignal TransductionSirolimusStressStress Response SignalingTestingTherapeuticTimeTissuesTranslationsWorkabstractingage effectagedanti agingbiological adaptation to stresscalmodulin-dependent protein kinase IIIcell growthdetection of nutrienthuman FRAP1 proteinin vitro activityknockout animalmTOR Inhibitormimeticsmouse modelmutantnovelpractical applicationpreventprogramsprotein misfoldingreconstitutionresponsestemstem cellssynergismtheories
中文摘要
项目负责人/主要研究者(最后,第一,中间):PI:Alexey G. Ryazanov博士
摘要
TOR通路在衰老中起着重要作用。已经证明,
雷帕霉素导致多种生物体的寿命延长。TOR通路的组成部分之一是
eEF 2激酶(eEF 2K)通过磷酸化
延伸因子2(eEF 2)。TOR的激活导致eEF 2K的抑制,作为以下机制的一部分:
增加蛋白质合成的速率。最近,我们产生了敲除eEF 2K的小鼠,发现其
失活保护干细胞免于凋亡并延缓衰老。因此,存在一个悖论:一方面,
抑制TOR可以减缓衰老,另一方面,抑制TOR可以通过以下途径加速衰老:
eEF 2K的激活。因此,雷帕霉素对TOR的抑制导致两个相反的信号:
TOR通路减缓衰老,同时激活eEF 2K,这可能会抵消抗-
雷帕霉素的衰老效应。因此,我们假设同时抑制TOR和eEF 2K可以增加细胞的增殖。
TOR抑制对衰老的影响。我们将通过确定eEF 2K的失活是否可以
与雷帕霉素协同产生抗衰老作用。
PHS 398/2590(Rev. 06/09)第1页
英文摘要
Program Director/Principal Investigator (Last, First, Middle): PI: Alexey G. Ryazanov, Ph.D.
Abstract
The TOR pathway plays an important role in aging. It has been demonstrated that treatment with
rapamycin leads to prolongation of life span in diverse organisms. One of the components of TOR pathway is
eEF2 kinase (eEF2K) which regulates the global rate of protein synthesis through phosphorylation of
elongation factor 2 (eEF2). Activation of TOR results in the inhibition of eEF2K as a part of the mechanism that
increases the rate of protein synthesis. Recently, we generated mice with knockout of eEF2K and found that its
inactivation protects stem cells from apoptosis and retards aging. Thus, there exists a paradox: on one hand
inhibition of TOR slows down aging, on the other hand inhibition of TOR may accelerate aging through
activation of eEF2K. Therefore, the inhibition of TOR by rapamycin results in two opposite signals: inhibition of
the TOR pathway slows down aging and at the same time activates eEF2K, which may counteract the anti-
aging effect of rapamycin. Thus, we hypothesize that simultaneous inhibition of TOR and eEF2K increases the
effect of TOR inhibition on aging. We will test this hypothesis by determining whether inactivation of eEF2K can
synergize with rapamycin in producing an anti-aging effect.
PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page
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会议论文
Use of EF2K Inhibitors to Reduce Toxicity to Normal Tissues in Chemotherapy
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批准号:8782369
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项目类别:
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资助金额:$22.2万
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财政年份:2014
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依托单位:
Investigation of synergism between mTOR and eEF2 kinase pathways
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资助金额:$0.0万
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Investigation of synergism between mTOR and eEF2 kinase pathways
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批准号:8445866
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财政年份:2009
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Translational Control of Radiation-Induced Apoptosis
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批准号:8018134
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资助金额:$5.4万
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财政年份:2009
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负责人:ALEXEY G. RYAZANOV
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依托单位:
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财政年份:2009
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Translational Control of Radiation-Induced Apoptosis
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批准号:7764154
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项目类别:
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资助金额:$6.11万
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Project 2: Structure Function of TRPM6/7 Alpha Kinase Domains
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批准号:7285826
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财政年份:2007
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Regulation of Metal Ion Homeostasis by Channel Kinases
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批准号:7248888
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项目类别:
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资助金额:$185.3万
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财政年份:2007
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Regulation of Metal Ion Homeostasis by Channel Kinases
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批准号:7843623
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项目类别:
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资助金额:$174.99万
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财政年份:2007
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Regulation of Metal Ion Homeostasis by Channel Kinases
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批准号:8138424
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资助金额:$172.15万
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财政年份:2007
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Regulation of Metal Ion Homeostasis by Channel Kinases
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批准号:7690825
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项目类别:
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资助金额:$172.73万
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财政年份:2007
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Core A: Administrative Support
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批准号:7285833
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项目类别:
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资助金额:$4.42万
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财政年份:2007
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Development of New Drugs that Protect Gastrointestinal Tract from Radiation
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批准号:7472938
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项目类别:
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资助金额:$75.0万
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财政年份:2007
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负责人:ALEXEY G. RYAZANOV
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依托单位:
Regulation of Metal Ion Homeostasis by Channel Kinases
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批准号:7409180
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项目类别:
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资助金额:$169.11万
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财政年份:2007
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负责人:ALEXEY G. RYAZANOV
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依托单位:
THE ROLE OF PROTEIN TURNOVER IN AGING
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批准号:6533940
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项目类别:
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资助金额:$39.25万
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财政年份:2001
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负责人:ALEXEY G. RYAZANOV
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依托单位:
THE ROLE OF PROTEIN TURNOVER IN AGING
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财政年份:2001
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负责人:ALEXEY G. RYAZANOV
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依托单位:
THE ROLE OF PROTEIN TURNOVER IN AGING
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批准号:6941598
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项目类别:
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资助金额:$39.25万
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财政年份:2001
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负责人:ALEXEY G. RYAZANOV
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依托单位:
THE ROLE OF PROTEIN TURNOVER IN AGING
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批准号:6649758
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项目类别:
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资助金额:$39.25万
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财政年份:2001
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负责人:ALEXEY G. RYAZANOV
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依托单位:
THE ROLE OF PROTEIN TURNOVER IN AGING
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资助金额:$39.25万
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依托单位:
海外基金