Promotion of satellite cell proliferation by cAMP signaling
cAMP 信号传导促进卫星细胞增殖
基本信息
- 批准号:10583531
- 负责人:
- 金额:$ 37.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-04 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:Activator AppliancesAcuteAdultAgingAreaBiochemicalBiochemical GeneticsCREB1 geneCell NucleusCell ProliferationChIP-seqComplexCoupledCyclic AMPCyclic AMP-Responsive DNA-Binding ProteinElderlyEmbryoEmbryonic DevelopmentG-Protein-Coupled ReceptorsGene ActivationGenesGeneticGenetic TranscriptionGenomicsGoalsHealthIn VitroIndividualInjuryKnock-inKnockout MiceLigandsMaintenanceMass Spectrum AnalysisMolecularMusMuscleMuscle FibersMuscle functionMuscle satellite cellMuscular DystrophiesMyoblastsMyopathyNatural regenerationPathway interactionsPatientsPopulationPost-Translational Protein ProcessingProliferatingRegulationRoleSignal InductionSignal PathwaySignal TransductionSkeletal MuscleSkeletal Muscle Satellite CellsStimulation of Cell ProliferationTestingTranscription Coactivatorage relatedchemical geneticsdesigner receptors exclusively activated by designer drugsgain of functionimprovedin vitro testingin vivoin vivo regenerationinnovationinsightmuscle formmuscle regenerationmutantnew therapeutic targetoverexpressionpharmacologicpreservationprogenitorprogramspromoterrecruitrelease factorresponseresponse to injurysarcopeniasatellite cellskeletal disorderskeletal muscle wastingstem cell populationstem cell proliferationstem cellstooltranscription factortranscriptome sequencingtranscriptomics
项目摘要
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.
摘要:
--
骨骼肌干细胞的再生需要大量已知的干细胞的激活和增殖。
作为卫星细胞,卫星细胞不仅是损伤后肌肉再生所需的细胞,而且也被认为是损伤后肌肉再生所必需的细胞。
为正在进行的肌肉和质量的日常维护做出贡献。但不幸的是,这些祖先的数量和活动能力都下降了。
随着年龄的增长和肌肉营养不良而下降。因此,需要制定药物治疗策略,以更好地促进心脏功能的扩张。
成肌性的卫星干细胞有可能被用来进一步改善肌肉再生能力,保护肌肉的功能。
在一些患有肌肉萎缩疾病的人或一些高龄的人中,他们的信号通过训练营的途径传递出去。
在胚胎发育过程中刺激肌源性神经前体细胞增殖,这是足够的刺激。
这些细胞的增殖能力是在体外进行的。这一途径也是在成年小鼠的细胞再生过程中被激活的。然而,它并没有被激活。
目前尚不清楚,在肌源性神经前体细胞中释放信号以应对损伤是否足以增强免疫功能。
体内的增殖速度加快。我们之前的研究表明,在体内,与cAMP反应的转录调控因子CREB被激活。
在小鼠的急性骨骼肌损伤后,发现了细胞增殖的区域,并发现小鼠表达了一种激活的CREB基因突变基因。
已经增强了损伤后成肌细胞的增殖能力。这个新项目将使用生化测试和化学-遗传测试工具。
为了更好地确定营地信号的化学遗传和遗传调控机制是否在卫星上有明确规定。
在体内,细胞通过调控CREB/CRTC转录调控基因,改变细胞增殖和肌肉再生能力。
建筑群。我们将继续审问由阵营监管的CREB和共同激活者协会(CRTC)在中国的监管制度和职能。
卫星细胞增殖控制和使用一种无偏见的转录转录技术方法来进一步识别CREB/CRTC的靶向基因。
为支持阵营驱动的增殖性核反应做出贡献。我们将继续进行机械性的核反应研究,以确定其特征。
CRTC的分子调控机制,以及CRTC招募机制的调控机制,都是将阵营调控的CRTC基因整合在一起。
卫星细胞的增殖。这一项目的成果报告将为推动这一进程的基本机制提供更多的见解。
卫星细胞的增殖加速和细胞的扩张。我们的长期目标是进一步确定需要进一步改进的新的生物药理作用靶点。
患有肌肉萎缩疾病和老年性骨骼肌减少症的患者肌肉再生能力和肌肉功能不佳。
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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Rebecca L Berdeaux其他文献
Rebecca L Berdeaux的其他文献
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{{ truncateString('Rebecca L Berdeaux', 18)}}的其他基金
Promotion of satellite cell proliferation by cAMP signaling
cAMP 信号传导促进卫星细胞增殖
- 批准号:
9884731 - 财政年份:2019
- 资助金额:
$ 37.18万 - 项目类别:
Promotion of satellite cell proliferation by cAMP signaling
cAMP 信号传导促进卫星细胞增殖
- 批准号:
10363649 - 财政年份:2019
- 资助金额:
$ 37.18万 - 项目类别:
Dynamic regulation of hepatic SIK1 during fasting and feeding
禁食和进食期间肝脏SIK1的动态调节
- 批准号:
8798882 - 财政年份:2014
- 资助金额:
$ 37.18万 - 项目类别:
The role of SIK1 in myogenic differentiation and skeletal muscle repair
SIK1在生肌分化和骨骼肌修复中的作用
- 批准号:
8499263 - 财政年份:2011
- 资助金额:
$ 37.18万 - 项目类别:
Dynamic regulation of hepatic SIK1 during fasting and feeding
禁食和进食期间肝脏SIK1的动态调节
- 批准号:
8464093 - 财政年份:2011
- 资助金额:
$ 37.18万 - 项目类别:
The role of SIK1 in myogenic differentiation and skeletal muscle repair
SIK1在生肌分化和骨骼肌修复中的作用
- 批准号:
8875612 - 财政年份:2011
- 资助金额:
$ 37.18万 - 项目类别:
Dynamic regulation of hepatic SIK1 during fasting and feeding
禁食和进食期间肝脏SIK1的动态调节
- 批准号:
8162022 - 财政年份:2011
- 资助金额:
$ 37.18万 - 项目类别:
The role of SIK1 in myogenic differentiation and skeletal muscle repair
SIK1在生肌分化和骨骼肌修复中的作用
- 批准号:
8302378 - 财政年份:2011
- 资助金额:
$ 37.18万 - 项目类别:
Dynamic regulation of hepatic SIK1 during fasting and feeding
禁食和进食期间肝脏SIK1的动态调节
- 批准号:
8890142 - 财政年份:2011
- 资助金额:
$ 37.18万 - 项目类别:
Dynamic regulation of hepatic SIK1 during fasting and feeding
禁食和进食期间肝脏SIK1的动态调节
- 批准号:
8672634 - 财政年份:2011
- 资助金额:
$ 37.18万 - 项目类别:
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