Stem Cell Dysfunction in Aged Skeletal Muscle
老年骨骼肌干细胞功能障碍
基本信息
- 批准号:10736449
- 负责人:
- 金额:$ 57.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:ADP Ribose TransferasesADP ribosylationAddressAdenosine Diphosphate RiboseAdultAffectAgeAgingAutomobile DrivingBiology of AgingCell CycleCell surfaceClinicConsumptionDataDeteriorationElderlyEnzymesEventExerciseFunctional disorderGene ActivationGene TargetingGenesGeneticHealthHourImmunohistochemistryInjuryKnockout MiceLaboratoriesLacZ GenesLeftMass Spectrum AnalysisMeasuresMedicalMolecularMusMuscleMuscle satellite cellMuscular AtrophyMutateNatural regenerationNicotinamide adenine dinucleotideOncogenesOrganOrganoidsPHEMX genePathway interactionsPatternPopulationPost-Translational Protein ProcessingProcessProteinsProtocols documentationReporterSignal TransductionSiteSkeletal MuscleSpeedSupplementationSystemTestingTherapeuticTissuesTranscription Factor AP-1TraumaWorkadult stem cellagedaging populationcofactorconditional knockoutdietary supplementsextracellularfunctional declinegain of functionhealingimprovedin vivoloss of functionmouse modelmuscle agingmuscle formmuscle strengthmuscular systemnicotinamide-beta-ribosidenovel therapeutic interventionnovel therapeuticsosteosarcomaoverexpressionpharmacologicprogramsregeneration potentialregenerativeregenerative tissuerepairedresponseskeletal preservationstem cell functionstem cellstissue repairtranscription factorvirtualyoung adult
项目摘要
Abstract
One of the greatest mysteries in ageing biology is to understand why many tissues and organs in our body,
including skeletal muscle, decline in function as we get older? Recent studies suggest that the inability of
muscle stem cells (MuSCs) to turn on the repair program after trauma is a major factor leading to the loss of
muscle mass and strength observed in the elderly. However, given that the signals driving MuSCs into the
regenerative state remains a mystery even in young adults, we are left with virtually no therapeutic options for
boosting the repair potential of aging MuSCs in the clinic. To address this unmet need, my laboratory recently
discovered a new “Super-Healing” adult stem cell activation program, driven by the transcription factor, FBJ
osteosarcoma oncogene (FOS), that speeds up adult stem cell activation and enhances muscle repair.
Intriguingly, a key downstream target gene of FOS in adult MuSCs is the NAD-consuming, cell surface
enzyme, ADP-Ribosyl-Transferase 1 (Art1), which attaches an understudied post-translational modification
(PTM), mono-ADP-Ribosylation (MARylation), to protein substrates. Excitingly, our preliminary data suggests
that the FOS/ART1-MARylation pathway is disrupted in aged MuSCs, and thus, representing one of the
earliest molecular alterations that diminish the regenerative potential of aged skeletal muscle. Thus, in this
proposal, we will test the hypothesis that the FOS/AP-1 tissue regenerative program (including the ART1
pathway) is mis-regulated in aged skeletal muscle, triggering a cascade of molecular events that dampen stem
cell activation potential and lead to the progressive deterioration of skeletal muscle with increasing age; and
most importantly, that reversal of this molecular dysfunction will correct the stem cell activation and
regenerative deficits seen in aged skeletal muscle. In Aim1, we will determine the expression patterns and
functional significance of FOS/AP-1 gene targets in adult and aged MuSCs. In Aim2, we will determine the
expression dynamics, functional requirements, and MARylated protein substrates of the newly discovered
NAD/ART1-MARylation stem cell activation pathway in adult and aged MuSCs. Collectively, this work will
highlight a new FOS/NAD/ART1-MARylation stem cell activation pathway that has been largely ignored in
aging biology until now and whose further study will open new therapeutic avenues for improving muscle
health in the elderly population.
摘要
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Protocol for the isolation of mouse muscle stem cells using fluorescence-activated cell sorting.
- DOI:10.1016/j.xpro.2023.102656
- 发表时间:2023-12-15
- 期刊:
- 影响因子:0
- 作者:Elizalde, Gabriel;Munoz, Alma Zuniga;Almada, Albert E.
- 通讯作者:Almada, Albert E.
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