Notch signaling and Bone Fracture Healing

Notch信号传导和骨折愈合

基本信息

项目摘要

There is an urgent clinical need to develop new therapeutics to promote healing of bone. While most bone injuries heal, many do not, particularly large defects. Understanding cellular signaling mechanisms that regulate normal healing, can lead us to new therapeutic targets. Notch signaling regulates the expansion and differentiation of mesenchymal progenitor cells (MPC) and regulates vascularization of many tissues, including bone. Our studies, and published studies from other investigators, show that Notch signaling is a key regulatory pathway during bone healing. Indeed, our preliminary and published results show that increasing Notch signaling in MPCs improves bone regeneration, and that global inhibition of Notch using various models, deleteriously impacts healing. To sufficiently advance our understanding of Notch signaling in bone healing, and translate these mechanistic observations, will require robust experimentation, including preclinical studies in relevant injury models. Our long-term goal is to develop a clinically relevant approach to increase Notch signaling that enhances bone healing. We hypothesize that Notch signaling promotes expansion of MPCs and callus vascularization, leading to enhanced bone formation. We will interrogate the Notch signaling pathway during bone healing to reveal a deeper understanding of ligands and receptors that are at play during healing, and the cell-type specific expression of these signaling components. This work will be completed in two specific Aims, using state of the art mouse models. In the first Aim, we will study the role of Notch ligands. Our work has previously demonstrated that Jagged1 is the dominant Notch ligand expressed in MPCs and the osteochondrogenic lineage. We will disrupt Jag1 specifically in MPCs, chondrocytes, osteoblasts and osteocytes in the callus during fracture healing. Additionally, as Jag1 and Dll4 produced by endothelial cells regulate vascularization, we will determine which is the dominant ligand regulating vascularization using conditional deletion of both ligands from endothelial cells using Cdh5-CreER. A spectrum of fracture healing outcomes, including vascularization, as well as effects on endothelial cell and MPC proliferation and MPC differentiation will be determined in vivo. We will capitalize on our extensive experience using inducible Cre mice to ensure normal development thereby by-passing developmental effects of ligand disruption. These studies will be complemented with a translational study in which Jag1 protein, alone or in combination with an existing therapy, BMP2, will be delivered during healing of critical sized femoral defects. In the second Aim, we will examine the role of Notch receptors on MPC and endothelial cells using Notch1 or Notch2 floxed mice. We will determine whether these receptors are critical for defect healing driven by BMP2 or Jag1. This study will significantly advance the field by clarifying the cell-specific role of ligand and receptor during bone healing, and provide the preclinical relevance for local activation Notch signaling to increase bone defect healing.
临床迫切需要开发新的治疗方法来促进骨愈合。虽然大多数

项目成果

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Kurt David Hankenson其他文献

Kurt David Hankenson的其他文献

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{{ truncateString('Kurt David Hankenson', 18)}}的其他基金

FASEB SRC: Matricellular Proteins: Fundamental Concepts and New Directions
FASEB SRC:基质细胞蛋白:基本概念和新方向
  • 批准号:
    10468385
  • 财政年份:
    2022
  • 资助金额:
    $ 56.1万
  • 项目类别:
Rspondin-Lgr Axis in Bone Regeneration
骨再生中的 Rspondin-Lgr 轴
  • 批准号:
    10469469
  • 财政年份:
    2020
  • 资助金额:
    $ 56.1万
  • 项目类别:
Rspondin-Lgr Axis in Bone Regeneration
骨再生中的 Rspondin-Lgr 轴
  • 批准号:
    10260493
  • 财政年份:
    2020
  • 资助金额:
    $ 56.1万
  • 项目类别:
Rspondin-Lgr Axis in Bone Regeneration
骨再生中的 Rspondin-Lgr 轴
  • 批准号:
    10261766
  • 财政年份:
    2020
  • 资助金额:
    $ 56.1万
  • 项目类别:
ORS-ISFR 17th Biennial Conference: Thinking big on fracture repair
ORS-ISFR 第 17 届双年会:对骨折修复的大思考
  • 批准号:
    10066004
  • 财政年份:
    2020
  • 资助金额:
    $ 56.1万
  • 项目类别:
Rspondin-Lgr Axis in Bone Regeneration
骨再生中的 Rspondin-Lgr 轴
  • 批准号:
    10669815
  • 财政年份:
    2020
  • 资助金额:
    $ 56.1万
  • 项目类别:
Regulators of Ischemic Fracture Healing
缺血性骨折愈合的调节因子
  • 批准号:
    9921196
  • 财政年份:
    2015
  • 资助金额:
    $ 56.1万
  • 项目类别:
Notch signaling and Bone Fracture Healing
Notch信号传导和骨折愈合
  • 批准号:
    10363359
  • 财政年份:
    2011
  • 资助金额:
    $ 56.1万
  • 项目类别:
In vivo microcomputed tomography
体内微型计算机断层扫描
  • 批准号:
    7389369
  • 财政年份:
    2008
  • 资助金额:
    $ 56.1万
  • 项目类别:
BMP6 Induction of Human Mesenchymal Stem Cell Osteoblast Differentiation
BMP6 诱导人间充质干细胞成骨细胞分化
  • 批准号:
    7436259
  • 财政年份:
    2006
  • 资助金额:
    $ 56.1万
  • 项目类别:

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