Hox-Regulated MSCs in Skeletal Development, Growth and Fracture Healing

Hox 调节的 MSC 在骨骼发育、生长和骨折愈合中的作用

基本信息

  • 批准号:
    10566127
  • 负责人:
  • 金额:
    $ 45.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-08 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Although the critical roles Hox genes play in establishing skeletal morphology has been known for decades, virtually nothing is understood regarding the molecular mechanisms by which Hox genes function in the skeleton. Utilizing a unique collection of genetic tools that permit live visualization of Hox expression (Hoxa11eGFP), Cre-mediated lineage labeling and/or conditional deletion (HoxCreERT2, Hoxd11LoxP/LoxP) and assessment of Hox11 chromatin binding sites (unpublished, validated Hoxa113XFLAG and Hoxd113XFLAG alleles), the overall objective of this application is to dissect the pathways and targets regulated by Hox transcription factors in skeletal stem/progenitor cells to regulate osteogenic and chondrogenesis differentiation. Previous work has demonstrated that Hox-expressing stem/progenitors are maintained in the skeleton in the absence of Hox function, and osteo- and chondrogenic lineages continue to emerge (Sox9-, Osx-/Runx2-expressing), but differentiation is incomplete. Osteoblasts do not progress to mature stages, and chondrocytes fail to undergo normal apoptosis and replacement by bony matrix in Hox mutants. This differentiation defect can be recapitulated in vitro. Based on previously published work and preliminary data, the central hypothesis is that Hox transcription factors regulate critical downstream events at the top of the hierarchy during osteochondrogenic differentiation from skeletal stem/progenitor cells in parallel with canonical differentiation factors. This project will utilize the Hoxa11eGFP reporter and Hoxa11CreERT2-mediated lineage labeling in the presence and absence of adult conditional deletion of Hoxd11 to probe the single cell trajectories of Hox11- expressing progenitors as they expand and differentiate into cartilage and bone in response to injury (Aim 1). The recapitulation of osteo- and chondrogenic differentiation defects in Hox11 mutants in vitro permits a comparative assessment of differential gene expression during temporally controlled differentiation (Aim 2). Newly generated and validated Hoxa113XFLAG; Hoxd113XFLAG epitope-tagged alleles will be utilized to interrogate the sites of chromatin binding in Hox-expressing progenitors and early differentiating cells (Aim 3). The research proposal is innovative in its use of sophisticated genetic tools generated by the research team, the combined in vivo and in vitro approaches, and critical inclusion of a co-investigator and her team with biostatistics expertise. The proposed research is significant as it addresses the longstanding and highly significant question of the molecular mechanism of Hox function in the skeleton. As Hox expression is only observed in skeletal stem/progenitors and early differentiation markers initiate as cells exit the Hox lineage, dissecting the downstream targets and pathways regulated by Hox that are critical to complete successful osteogenic and chondrogenic differentiation will provide impactful new knowledge of skeletal biology.
项目总结/文摘

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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Deneen M Wellik其他文献

Deneen M Wellik的其他文献

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{{ truncateString('Deneen M Wellik', 18)}}的其他基金

Hox-Regulated MSCs in Skeletal Development, Growth and Fracture Healing
Hox 调节的 MSC 在骨骼发育、生长和骨折愈合中的作用
  • 批准号:
    10840553
  • 财政年份:
    2022
  • 资助金额:
    $ 45.76万
  • 项目类别:
Hox-Regulated MSCs in Skeletal Development, Growth and Fracture Healing
Hox 调节的 MSC 在骨骼发育、生长和骨折愈合中的作用
  • 批准号:
    10662574
  • 财政年份:
    2022
  • 资助金额:
    $ 45.76万
  • 项目类别:
Hox genes regulate functionally distinct, regionally restricted MSC populations
Hox 基因调节功能不同、区域受限的 MSC 群体
  • 批准号:
    10197314
  • 财政年份:
    2019
  • 资助金额:
    $ 45.76万
  • 项目类别:
Hox5 gene regulation of lung fibroblasts and distal lung extracellular matrix
Hox5基因对肺成纤维细胞和远端肺细胞外基质的调控
  • 批准号:
    9980992
  • 财政年份:
    2018
  • 资助金额:
    $ 45.76万
  • 项目类别:
Hox5 gene regulation of lung fibroblasts and distal lung extracellular matrix
Hox5基因对肺成纤维细胞和远端肺细胞外基质的调控
  • 批准号:
    10202716
  • 财政年份:
    2018
  • 资助金额:
    $ 45.76万
  • 项目类别:
Hox-Expressing Stromal Cells in Muscle Development and Repair
表达 Hox 的基质细胞在肌肉发育和修复中的作用
  • 批准号:
    9530540
  • 财政年份:
    2017
  • 资助金额:
    $ 45.76万
  • 项目类别:
Using BMSC-derived Bone-Ligament-Bone Tissue as a Live Template for ACL Regenerat
使用 BMSC 衍生的骨韧带骨组织作为 ACL 再生的实时模板
  • 批准号:
    8490317
  • 财政年份:
    2012
  • 资助金额:
    $ 45.76万
  • 项目类别:
Using BMSC-derived Bone-Ligament-Bone Tissue as a Live Template for ACL Regenerat
使用 BMSC 衍生的骨韧带骨组织作为 ACL 再生的实时模板
  • 批准号:
    8383131
  • 财政年份:
    2012
  • 资助金额:
    $ 45.76万
  • 项目类别:
Role of Hox Genes in Integration of the Musculoskeletal System in Development
Hox 基因在发育中肌肉骨骼系统整合中的作用
  • 批准号:
    8308416
  • 财政年份:
    2011
  • 资助金额:
    $ 45.76万
  • 项目类别:
Role of Hox Genes in Integration of the Musculoskeletal System in Development
Hox 基因在发育中肌肉骨骼系统整合中的作用
  • 批准号:
    8840889
  • 财政年份:
    2011
  • 资助金额:
    $ 45.76万
  • 项目类别:

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