Regulation of Satellite Cell Development, Programming and Differentiation by Myogenic Factors
成肌因子对卫星细胞发育、编程和分化的调节
基本信息
- 批准号:10222571
- 负责人:
- 金额:$ 45.17万
- 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:2020-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptedAdultAllelesAnatomyBioinformaticsBiological AssayCRISPR/Cas technologyCandidate Disease GeneCell LineageCell TherapyCell physiologyCellsClustered Regularly Interspaced Short Palindromic RepeatsDNADataDegenerative DisorderDevelopmentDifferentiation and GrowthDistalElementsEmbryoEmbryonic DevelopmentEnhancersEnvironmentExhibitsFiberGene TargetingGenesGeneticGenetic Enhancer ElementGenetic RecombinationGenetic TranscriptionHeterogeneityImmunofluorescence ImmunologicInjuryKnock-outLeadMediatingMessenger RNAMethodologyMicroRNAsMolecularMusMuscleMuscle satellite cellMutagenesisMyoD ProteinMyoblastsMyogenic Regulatory FactorsNatural regenerationNeonatalNucleic Acid Regulatory SequencesPathway interactionsPhenotypePolymerasePopulationPositioning AttributePropertyProteinsRegenerative capacityRegulationRegulator GenesRegulatory ElementRegulatory PathwayReporter GenesResearchRunningSkeletal MuscleSkeletal muscle injuryTestingTissuesTranscriptional RegulationTransfectionTransgenic MiceTransgenic Organismsbasecell typeconditional knockoutdosageembryo cellexperimental studyfetalgenetic regulatory proteingenome-widein vivoinjuredinsightmuscle regenerationmutantnovelprenatalprogramspromoterresponsesatellite cellself-renewalsingle-cell RNA sequencingskeletal muscle growthstem cell functionstem cellstibialis anterior muscletooltranscriptometranscriptome sequencing
项目摘要
Project Summary
Satellite cells are muscle-specific stem cells that are responsible for skeletal muscle growth and regeneration.
The myogenic regulatory factors (MRFs) MYOD and MYF5 are essential for muscle lineage determination in
the embryo and are induced in activated satellite cells as an early response to muscle injury. Recent gene-
targeting studies using a new MyoD conditional knockout allele (MyoDcKO) showed that either MyoD or Myf5 is
essential for muscle regeneration; satellite cells lacking both genes (dKO) accumulate in injured muscle but are
unable to undergo myogenic differentiation. In this proposal, new genetic tools and strategies are used to
determine the functions of MyoD and Myf5 in satellite cell development, lineage determination, differentiation
and self-renewal. In addition, transcriptional control mechanisms that regulate MyoD expression in satellite
cells and during embryogenesis are interrogated. In Aim 1, cell type identification by immunofluorescence and
single-cell RNA sequencing (scRNA-seq) will establish whether dKO satellite cells adopt non-myogenic cell
fates, the extent to which they retain myogenic programming, and their capacity for self-renewal. Experiments
will also distinguish cell-autonomous and non-autonomous effects of MRF deficiency. Aim 2 will utilize RNA-
seq to define the transcriptome of mutant satellite cells in uninjured and injured skeletal muscle, which will
identify direct and indirect transcriptional targets of MYOD and MYF5 as well as regulatory pathways and
cellular processes impacted by the loss of these MRFs. In addition, Pro-seq (genome-wide Precision Run-On)
analyses will quantify changes in active gene transcription, will identify candidate genes regulated by promoter-
proximal polymerase pausing, and will identify potential enhancer targets of MYOD and MYF5. Aim 3 will
determine whether the function of MyoD or Myf5 is required for satellite cell development by producing dKO
satellite cell precursors at embryonic, fetal and neonatal stages and testing their capacity to generate adult
satellite cells, as assessed by molecular and anatomical criteria. Recent data demonstrate that the only
enhancer elements known to regulate MyoD expression (the core enhancer and distal regulatory region) are
not necessary for MyoD transcription during embryogenesis or in satellite cells. Aim 4 will utilize transfection,
transgenic and CRISPR-based knockout methodologies to define the regulatory functions of novel putative
enhancer elements identified by PRO-seq and bioinformatic analyses. The proposed research will contribute
significantly to an understanding of fundamental gene regulatory mechanisms that control satellite cell stem
cell functions and may lead to the development of new cell types and strategies for cell-based therapies for
muscle degenerative diseases.
项目总结
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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{{ truncateString('DAVID J GOLDHAMER', 18)}}的其他基金
Regulation of Satellite Cell Development, Programming and Differentiation by Myogenic Factors
成肌因子对卫星细胞发育、编程和分化的调节
- 批准号:
10451732 - 财政年份:2020
- 资助金额:
$ 45.17万 - 项目类别:
Regulation of Satellite Cell Development, Programming and Differentiation by Myogenic Factors
成肌因子对卫星细胞发育、编程和分化的调节
- 批准号:
10670113 - 财政年份:2020
- 资助金额:
$ 45.17万 - 项目类别:
A new therapeutic approach for fibrodysplasia ossificans progressiva based on ACVR1 over-expression
基于ACVR1过表达的进行性骨化性纤维发育不良的新治疗方法
- 批准号:
9977124 - 财政年份:2019
- 资助金额:
$ 45.17万 - 项目类别:
Function of Fibro-Adipogenic Progenitors in Heterotopic Ossification of Skeletal Muscle
纤维脂肪祖细胞在骨骼肌异位骨化中的功能
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9975094 - 财政年份:2017
- 资助金额:
$ 45.17万 - 项目类别:
Function of Fibro-Adipogenic Progenitors in Heterotopic Ossification of Skeletal Muscle
纤维脂肪祖细胞在骨骼肌异位骨化中的功能
- 批准号:
9366782 - 财政年份:2017
- 资助金额:
$ 45.17万 - 项目类别:
Function of Fibro-Adipogenic Progenitors in Heterotopic Ossification of Skeletal Muscle
纤维脂肪祖细胞在骨骼肌异位骨化中的功能
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10218059 - 财政年份:2017
- 资助金额:
$ 45.17万 - 项目类别:
FASEB Science Research Conference on Skeletal Muscle Satellite and Stem Cells
FASEB 骨骼肌卫星和干细胞科学研究会议
- 批准号:
8719376 - 财政年份:2014
- 资助金额:
$ 45.17万 - 项目类别:
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