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Growth Factor Based on Enhancement of Bone Repair

基于增强骨修复的生长因子

基本信息

批准号：
9440342
负责人：
IVO Kalajzic
金额：
$ 35.09万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9440342
关键词：
Adverse effects BMP2 gene Bone Regeneration Cell Count Cell Lineage Chondrocytes Clinical Combined Modality Therapy Complex Data Defect Development Dose Evaluation Fracture Fracture Healing Future Gene Expression Genetic Growth Factor Histologic Human In Vitro Luciferases Mechanics Mediating Mesenchymal Stem Cells Mitogens Modeling Molecular Orthopedics Osteoblasts Osteocytes Osteogenesis Outcome Pathway interactions Periodontium Periosteal Cell Phosphorylation Phosphotransferases Platelet-Derived Growth Factor Platelet-Derived Growth Factor alpha Receptor Prevalence Process Recombinants Reporter Role Signal Pathway Signal Transduction Stem cells Testing Tissues Transgenic Model Transgenic Organisms Treatment Protocols base blocking factor bone bone healing cell growth cell motility cell type clinical application cost cytokine dentin matrix protein 1 design dosage effective therapy healing improved in vivo in vivo Model in vivo evaluation inhibitor/antagonist long bone microCT mouse model novel osteogenic platelet-derived growth factor BB prevent receptor repaired research clinical testing targeted treatment

项目摘要

The healing of fractures and bone defects involves complex interactions between cells and growth factors. Currently, recombinant BMP2, a potent inducer of bone formation, is approved for use in a number of orthopedic applications, however it can generate serious side effects likely associated with the high doses used. Combining BMP2 with other modulators of bone formation could improve its efficacy and potency in orthopedic applications. Our preliminary data indicate that PDGF blocks the effects of BMP2 in periosteal progenitor cells and prevents BMP2 induced osteogenesis. PDGF and its receptors are abundant during fracture healing, however the in vivo role of PDGF during healing, and how it interacts with BMP2 signaling, is not well defined. Our hypothesis is that PDGF is a critical regulator of BMP2 signaling during bone healing. We propose three aims: In aim 1 we will define the mechanisms by which PDGF regulates BMP2 signaling. The effects of PDGF on BMP2-induced Smad signaling will be evaluated at the level of Smad phosphorylation, luciferase reporter activity and downstream gene expression in periosteal progenitor cells in vitro. We will evaluate which downstream signaling pathways are involved in the inhibition of BMP signaling by PDGF. In vivo studies will be conducted in Aim 2 and Aim 3. We will utilize models of bone fracture and bone defects. In Aim 2 we will evaluate the effects of disrupting endogenous PDGFRβ signaling using an in vivo conditional deletion approach. We propose to target deletion to mesenchymal progenitor cells, chondrocytes and osteoblast lineages during fracture healing using lineage specific inducible Cre transgenic models. Effects of conditional activation of PDGFRβ signaling on fracture healing will be achieved by tissue specific expression of a constitutively active form of the PDGFRβ kinase domain. In Aim 3 we will evaluate the efficacy of BMP2/PDGF combination treatment delivered locally. In addition, we will evaluate the effects of a PDGFR inhibitor delivered systemically at different stages of healing allowing for precise control of dosage and timing. Combination treatments will be tested with a dose of BMP2 that alone does not induce bridging of the defect. Our project will provide better understanding on the interactions of the PDGF and BMP2 during osteogenesis and bone healing. The potential for an increase in osteogenic repair by modulating PDGF and BMP2 signaling during bone defect healing in vivo will outline the possibility of future clinical evaluation of this treatment.

骨折和骨缺损的愈合涉及细胞和生长因子之间复杂的相互作用。