Promotion of satellite cell proliferation by cAMP signaling
Promotion of satellite cell proliferation by cAMP signaling
批准号:
9884731
负责人:
Rebecca L Berdeaux
金额:
$38.54万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-03-04 至 2024-02-29
关键词:
Activator AppliancesAcuteAdultAgingAreaBiochemicalBiochemical GeneticsCREB1 geneCREBBP geneCell NucleusCell ProliferationChIP-seqComplexCoupledCyclic AMPCyclic AMP-Responsive DNA-Binding ProteinElderlyEmbryoEmbryonic DevelopmentG-Protein-Coupled ReceptorsGene ActivationGenesGeneticGenetic TranscriptionGoalsHealthIn VitroIndividualInjuryKnock-inKnockout MiceLigandsMaintenanceMass Spectrum AnalysisMolecularMusMuscleMuscle FibersMuscle functionMuscle satellite cellMuscular DystrophiesMyoblastsMyopathyNatural regenerationPathway interactionsPatientsPharmacologyPopulationPost-Translational Protein ProcessingProliferatingRegulationRoleSignal PathwaySignal TransductionSignaling ProteinSkeletal MuscleSkeletal Muscle Satellite CellsTestingTranscription Coactivatorage relatedchemical geneticsdesigner receptors exclusively activated by designer drugsgain of functiongenomic profilesimprovedin vitro testingin vivoin vivo regenerationinnovationinsightmuscle formmuscle regenerationmutantnew therapeutic targetoverexpressionpreservationprogenitorprogramspromoterrecruitrelease factorresponseresponse to injurysarcopeniasatellite cellskeletal disorderskeletal muscle wastingstem cell populationstem cell proliferationstem cellstooltranscription factortranscriptome sequencingtranscriptomics
中文摘要
总结
骨骼肌再生需要已知的干细胞常驻群体的激活和增殖。
作为卫星细胞。卫星细胞不仅是受伤后肌肉再生所必需的,
有助于持续维持肌肉质量。不幸的是,这些祖细胞的数量和活性
随着年龄的增长和肌肉萎缩而下降。 因此,药理学策略,以促进扩大
肌源性卫星细胞可用于促进肌肉再生和保护肌肉功能
在患有肌肉疾病的个体或高龄个体中。 通过cAMP途径的信号传导
在胚胎发育过程中刺激肌原祖细胞增殖,
这些细胞在体外增殖。这一途径在成年小鼠的再生过程中也被激活。但
尚不清楚肌源性祖细胞对损伤的反应中的cAMP信号传导是否足以增强
体内增殖。 我们先前的研究表明,cAMP-β反应性转录因子CREB被激活,
小鼠急性肌肉损伤后的增殖区域以及表达CREB激活突变体的小鼠
增强了损伤后成肌细胞的增殖。该项目采用生物化学和化学遗传学工具
以确定是否在卫星中特异性地化学诱导遗传升高和cAMP信号传导的遗传调节,
细胞通过调节CREB/CRTC转录改变体内增殖和肌肉再生
配合物 我们将探讨cAMP-β调节的CREB共激活因子(CRTCs)在细胞内的调节和功能。
卫星细胞增殖,并使用无偏转录组学方法来鉴定CREB/CRTC靶基因,
有助于cAMP-β驱动的增殖反应。 我们将进行机制研究,
CRTC的分子调控和CRTC募集到cAMP-β调节基因的机制,
增殖的卫星细胞 该项目的结果将深入了解驱动
卫星细胞增殖和扩张。长期目标是确定新的药理学靶点,
肌肉疾病和与年龄相关的肌肉减少症患者的肌肉再生和功能。
英文摘要
SUMMARY
Skeletal muscle regeneration requires activation and proliferation of a resident population of stem cells known
as satellite cells. Satellite cells are not only required for muscle regeneration after injury but are also thought to
contribute to ongoing maintenance of muscle mass. Unfortunately, the number and activity of these progenitors
declines with aging and muscular dystrophy. Therefore, pharmacologic strategies to promote expansion of
myogenic satellite cells could potentially be used to improve muscle regeneration and preserve muscle function
in individuals with muscle disease or individuals of advanced age. Signaling through the cAMP pathway
stimulates myogenic progenitor cell proliferation during embryonic development and is sufficient to stimulate
proliferation of these cells in vitro. This pathway is also activated during regeneration in adult mice. However, it
is unknown whether cAMP signaling in myogenic progenitor cells in response to injury is sufficient to enhance
proliferation in vivo. We previously showed that the cAMP-responsive transcription factor CREB is activated in
areas of proliferation after acute muscle injury in mice and that mice expressing an activated mutant of CREB
have enhanced myoblast proliferation after injury. This project employs biochemical and chemical-genetic tools
to determine whether chemical-genetic elevation and genetic regulation of cAMP signaling specifically in satellite
cells alters proliferation and muscle regeneration in vivo through regulation of CREB/CRTC transcriptional
complexes. We will interrogate the regulation and function of cAMP-regulated CREB co-activators (CRTCs) in
satellite cell proliferation and use unbiased transcriptomic approaches to identify CREB/CRTC target genes that
contribute to the cAMP-driven proliferative response. We will undertake mechanistic studies to characterize
molecular regulation of CRTCs and the mechanism of CRTC recruitment to cAMP-regulated genes in
proliferating satellite cells. Results of this project will yield insights into fundamental mechanisms that drive
satellite cell proliferation and expansion. The long-term goal is to identify new pharmacologic targets to improve
muscle regeneration and function in patients with muscle disease and age-related sarcopenia.
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Promotion of satellite cell proliferation by cAMP signaling
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批准号:10363649
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项目类别:
-
资助金额:$37.08万
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财政年份:2019
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负责人:Rebecca L Berdeaux
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依托单位:
Promotion of satellite cell proliferation by cAMP signaling
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批准号:10583531
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项目类别:
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资助金额:$37.18万
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财政年份:2019
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负责人:Rebecca L Berdeaux
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依托单位:
Dynamic regulation of hepatic SIK1 during fasting and feeding
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批准号:8798882
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项目类别:
-
资助金额:$1.27万
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财政年份:2014
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负责人:Rebecca L Berdeaux
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依托单位:
The role of SIK1 in myogenic differentiation and skeletal muscle repair
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批准号:8499263
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项目类别:
-
资助金额:$32.06万
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财政年份:2011
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负责人:Rebecca L Berdeaux
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依托单位:
Dynamic regulation of hepatic SIK1 during fasting and feeding
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批准号:8464093
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项目类别:
-
资助金额:$31.48万
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财政年份:2011
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负责人:Rebecca L Berdeaux
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依托单位:
The role of SIK1 in myogenic differentiation and skeletal muscle repair
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批准号:8875612
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项目类别:
-
资助金额:$33.75万
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财政年份:2011
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负责人:Rebecca L Berdeaux
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依托单位:
Dynamic regulation of hepatic SIK1 during fasting and feeding
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批准号:8162022
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项目类别:
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资助金额:$37.0万
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财政年份:2011
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负责人:Rebecca L Berdeaux
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依托单位:
The role of SIK1 in myogenic differentiation and skeletal muscle repair
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批准号:8302378
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项目类别:
-
资助金额:$33.75万
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财政年份:2011
-
负责人:Rebecca L Berdeaux
-
依托单位:
Dynamic regulation of hepatic SIK1 during fasting and feeding
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批准号:8890142
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项目类别:
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资助金额:$32.63万
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财政年份:2011
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负责人:Rebecca L Berdeaux
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依托单位:
Dynamic regulation of hepatic SIK1 during fasting and feeding
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批准号:8672634
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项目类别:
-
资助金额:$40.23万
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财政年份:2011
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负责人:Rebecca L Berdeaux
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依托单位:
Dynamic regulation of hepatic SIK1 during fasting and feeding
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批准号:8307342
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项目类别:
-
资助金额:$32.63万
-
财政年份:2011
-
负责人:Rebecca L Berdeaux
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依托单位:
The role of SIK1 in myogenic differentiation and skeletal muscle repair
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批准号:8185115
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项目类别:
-
资助金额:$33.3万
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财政年份:2011
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负责人:Rebecca L Berdeaux
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依托单位:
Regulation of hepatic insulin sensitivity by CREB
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批准号:7113915
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项目类别:
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资助金额:$4.88万
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财政年份:2006
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负责人:Rebecca L Berdeaux
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依托单位:
Regulation of hepatic insulin sensitivity by CREB
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批准号:7221900
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项目类别:
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资助金额:$4.04万
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财政年份:2006
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负责人:Rebecca L Berdeaux
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依托单位:
海外基金