Hox Gene Regulation of Skeletal Repair
Hox 基因对骨骼修复的调控
基本信息
- 批准号:10685496
- 负责人:
- 金额:$ 1.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2024-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdipocytesAdultAllelesAnimal ExperimentsAnimalsAnteriorBehaviorBiologicalBiological AssayBone MarrowBone MatrixBone callusBone remodelingCartilageCell Culture TechniquesCell Differentiation processCell LineageCellsChondrocytesChondrogenesisCollagenCollectionControl AnimalDataDefectDevelopmentDevelopmental ProcessEmbryonic DevelopmentEventExhibitsFractureGene ExpressionGene Expression RegulationGenesGeneticGenetic RecombinationGoalsGrowthHistocytochemistryHistologyHomeobox GenesHomeostasisInjuryKnowledgeLabelLaboratoriesLifeMaintenanceMeasuresMediatingMesenchymalMesenchymal Stem CellsModelingMolecularMusNatural regenerationOrganOsteoblastsOsteocytesOsteogenesisPathway interactionsPatternPopulationProcessProliferatingRadialReporterReportingRoentgen RaysRoleSkeletonSmall Interfering RNASortingStromal CellsTestingTimeTomatoesWorkbonebone cellbone fracture repaircartilage cellconditional mutantdifferential expressionfibulagene functionhealinginjury and repairinsightloss of functionmicroCTmouse modelmutantosteogenicparalogous genepostnatalprogenitorrepairedresponseresponse to injuryself-renewalsingle cell analysissingle cell sequencingskeletalskeletal stem cellstemstem cell populationstem cellstibiatooltranscription factortranscriptome sequencingtranscriptomicsulna
项目摘要
PROJECT SUMMARY/ABSTRACT
Hox genes are a group of evolutionarily conserved transcription factors important for several developmental
processes, including patterning of the anterior-posterior axis of the skeleton. The Hox11 paralogous gene
group, which is expressed in the zeugopod region (radius/ulna and fibula/tibia), are necessary for proper
patterning of the zeugopod. In the past few years, work from the Wellik laboratory has shown that these
developmentally important Hox transcription factors remain expressed in the skeleton throughout life,
specifically in progenitor-enriched mesenchymal stem cells (MSCs). Rigorous genetic lineage labeling from the
lab demonstrated that these cells give rise to all three mesenchymal lineages, osteoblasts, chondrocytes and
adipocytes, and exhibit life-long self-renewal, providing strong evidence that this population of cells are skeletal
stem cells. A key question based on this information is whether Hox gene function is important in these stem
cells throughout life. We recently reported that temporal deletion of Hox11 at adult stages results in defects in
osteoblastogenesis, wherein differentiation is initiated, but osteoblasts and osteocytes fail to mature. Adult
conditional loss of Hox11 function results in a progressively weakened bone matrix where collagen does not
properly assemble in remodeling bone. In this study, I will use a temporally-controlled, conditional loss-of-
function model to assess defects in response to fracture repair (Aim 1). Preliminary data shows that
temporally-deleted, ROSACreERT2/+;Hoxa11eGFP/-;Hoxd11LoxP/LoxP mice are unable to repair after fracture.
Additionally, preliminary data suggest that the populations of osteoblasts and chondrocytes appear to be in
abnormal in mutants. Using Hoxa11CreERT2 to enact both deletion and lineage labeling, I can mark the cells that
have undergone recombination for isolation and transcriptomic analyses (Hoxa11eGFP/CreERT2;Hoxd11LoxP/LoxP;
ROSAtd-Tomato/+, Aim 2). Fracture injury induces an acute response in which stem/progenitor expansion and
differentiation to both skeletal lineages is occurring simultaneously, providing an excellent model to isolate
single cells and identify the pathways and targets Hox genes regulate in these processes. Preliminary data
shows that a large proportion of GFP+ cells are available for collection from the fracture callus, making single
cell sequencing not only possible, but a highly effective tool to investigate transcriptomic change in Hox-
expressing and Hox-lineage cells. The overall goal of this project is to define Hox genetic function in fracture
repair and to identify the molecular mechanisms by which Hox genes regulate skeletal behavior in this process.
项目总结/文摘
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Navigating a research career with a disability.
带着残疾开展研究生涯。
- DOI:10.1242/dev.201906
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Anbuhl,KelseyL;Cazares,Oscar;Hubert,KatharineA;Mahapatra,Riya;Morgan,JackD
- 通讯作者:Morgan,JackD
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Katharine A. Hubert其他文献
Katharine A. Hubert的其他文献
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