Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification

机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响

基本信息

  • 批准号:
    10448303
  • 负责人:
  • 金额:
    $ 43.51万
  • 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:
    2021-07-15 至 2026-04-30
  • 项目状态:
    未结题

项目摘要

Project Summary Heterotopic ossification (HO) is the pathologic formation of extra-skeletal bone forming almost exclusively at sites of mechanical stress, that occurs in ~20% of patients after hip arthroplasty, burns or musculoskeletal injury. Currently, no therapeutics or physical therapy-based protocols exist to prevent HO. In this regard, there is a void in our understanding of the causative mechanotransductive pathways behind this debilitating process. Our unbiased transcription profiles in mouse HO-mesenchymal progenitor cells (MPCs) recovered from HO sites in combination with immunostaining of mouse and human HO revealed that a series of mechanotranduction-linked pathways, including discoidin receptor 2 (DDR2), FAK and the Hippo effectors, YAP and TAZ, are highly upregulated in tandem with observed changes in extracellular matrix (ECM) alignment. Using a novel, regional MPC-specific inducible Cre system (Hoxa11-CreERT2), we have compiled preliminary data that support critical roles for DDR2 signaling and stage-specific immobilization in both triggering FAK/YAP/TAZ signaling and MPC lineage commitment, but also an unexpected function in controlling ECM alignment. Together, these observations have led to our central hypothesis that MPC DDR2 signaling is necessary for mobility-induced changes in ECM alignment that trigger aberrant osteochondral differentiation at HO sites and can be blocked by DDR2 inhibition or injury stage-specific immobilization. Aim 1: Define the role of DDR2 as a critical upstream regulator of FAK/YAP/TAZ signaling in controlling the induction and progression of HO. We hypothesize that DDR2-mechanotransductive signaling alters osteochondral differentiation and HO in vivo and can be targeted with cell specific deletion models or translatable clinical therapies. Aim 2: Determine the optimal post-injury timing during which MPCs can be redirected away from aberrant osteochondral fate and pathologic ECM alignment through immobilization-based intervention. We hypothesize that immobilization during the early proliferative phase after injury will block pathologic changes in ECM alignment with disease-ameliorating effects on MPC fate determination and aberrant ossification. Aim 3: Characterize the role of mobilization-induced DDR2 activation on collagen alignment/anisotropy and mechanotransductive signaling. We hypothesize that DDR2 activity drives ECM alignment independently of limb mobility in vivo or cyclic stretch in vitro. Impact: The proposed studies will provide a comprehensive and mechanistic understanding of how DDR2 and joint mobility regulate ECM alignment, cell fate and HO using conditional deletion models and clinical therapies.
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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Benjamin Levi其他文献

Benjamin Levi的其他文献

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{{ truncateString('Benjamin Levi', 18)}}的其他基金

Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification - diversity supplement
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响 - 多样性补充
  • 批准号:
    10533903
  • 财政年份:
    2021
  • 资助金额:
    $ 43.51万
  • 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
  • 批准号:
    10832255
  • 财政年份:
    2021
  • 资助金额:
    $ 43.51万
  • 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
  • 批准号:
    10297550
  • 财政年份:
    2021
  • 资助金额:
    $ 43.51万
  • 项目类别:
Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification
机械感觉和基质结构对创伤性异位骨化细胞命运规范的影响
  • 批准号:
    10613582
  • 财政年份:
    2021
  • 资助金额:
    $ 43.51万
  • 项目类别:
Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification
中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化
  • 批准号:
    10900159
  • 财政年份:
    2020
  • 资助金额:
    $ 43.51万
  • 项目类别:
Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification
中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化
  • 批准号:
    10267729
  • 财政年份:
    2020
  • 资助金额:
    $ 43.51万
  • 项目类别:
Neutrophil Biomarker and neutrophil targeted therapy to predict and prevent heterotopic ossification
中性粒细胞生物标志物和中性粒细胞靶向治疗可预测和预防异位骨化
  • 批准号:
    10081442
  • 财政年份:
    2020
  • 资助金额:
    $ 43.51万
  • 项目类别:
Targeting Molecular and Cellular Mediators of Inflammation to Prevent Pathologic Cell Differentiation and Heterotopic Ossification
靶向炎症的分子和细胞介质以防止病理性细胞分化和异位骨化
  • 批准号:
    9906177
  • 财政年份:
    2017
  • 资助金额:
    $ 43.51万
  • 项目类别:
Targeting Molecular and Cellular Mediators of Inflammation to Prevent Pathologic Cell Differentiation and Heterotopic Ossific
靶向炎症的分子和细胞介质以防止病理性细胞分化和异位骨化
  • 批准号:
    10283122
  • 财政年份:
    2017
  • 资助金额:
    $ 43.51万
  • 项目类别:
Developing New Diagnostic and Timed, TAK1 Specific Treatment Strategies for Trauma Induced Heterotopic Ossification
为创伤引起的异位骨化开发新的诊断和定时 TAK1 特异性治疗策略
  • 批准号:
    9398623
  • 财政年份:
    2017
  • 资助金额:
    $ 43.51万
  • 项目类别:

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