Notch signaling and Bone Fracture Healing

Notch信号传导和骨折愈合

• 批准号: 10589870
• 负责人: Kurt David Hankenson
• 金额: $ 56.1万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589870
• 关键词: Acceleration; Agonist; BMP2 gene; Bone Injury; Bone Regeneration; Bone callus; Bypass; Cell Differentiation process; Cell Lineage; Cells; Cephalic; Chondrocytes; Clinical; Complement; Complex; Data; Defect; Development; Endothelial Cells; Endothelium; Ensure; Environment; Femoral Fractures; Femur; Fracture; Gene Expression; Generations; Goals; Histology; Impaired healing; Impairment; Injury; Joints; Laboratories; Laboratory Study; Ligands; LoxP-flanked allele; Mechanics; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modeling; Molecular Analysis; Molecular Target; Mus; Natural regeneration; Notch Signaling Pathway; Osteoblasts; Osteocytes; Osteogenesis; Outcome; Periosteum; Play; Process; Proliferating; Proteins; Publications; Publishing; Receptor Inhibition; Regulation; Regulatory Pathway; Research Personnel; Role; Signal Transduction; Source; Testing; Therapeutic; Time; Tissues; Translating; Vascularization; Work; bone; bone fracture repair; bone healing; cell type; clinically relevant; efficacy evaluation; experience; healing; improved; in vivo; inducible Cre; jagged1 protein; long bone; mouse model; new therapeutic target; notch protein; novel therapeutics; pre-clinical; preclinical study; promoter; receptor; skeletal regeneration; stem cell proliferation; translational study

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