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:
- 金额:$ 35.09万
- 依托单位:
- 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:
- 关键词:Adverse effectsBMP2 geneBone RegenerationCell CountCell LineageChondrocytesClinicalCombined Modality TherapyComplexDataDefectDevelopmentDoseEvaluationFractureFracture HealingFutureGene ExpressionGeneticGrowth FactorHistologicHumanIn VitroLuciferasesMechanicsMediatingMesenchymal Stem CellsMitogensModelingMolecularOrthopedicsOsteoblastsOsteocytesOsteogenesisOutcomePathway interactionsPeriodontiumPeriosteal CellPhosphorylationPhosphotransferasesPlatelet-Derived Growth FactorPlatelet-Derived Growth Factor alpha ReceptorPrevalenceProcessRecombinantsReporterRoleSignal PathwaySignal TransductionStem cellsTestingTissuesTransgenic ModelTransgenic OrganismsTreatment Protocolsbaseblocking factorbonebone healingcell growthcell motilitycell typeclinical applicationcostcytokinedentin matrix protein 1designdosageeffective therapyhealingimprovedin vivoin vivo Modelin vivo evaluationinhibitor/antagonistlong bonemicroCTmouse modelnovelosteogenicplatelet-derived growth factor BBpreventreceptorrepairedresearch clinical testingtargeted 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。
项目成果
期刊论文数量(0)
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{{ truncateString('IVO Kalajzic', 18)}}的其他基金
CGRP-CLR mediated regulation of bone healing
CGRP-CLR 介导的骨愈合调节
- 批准号:
10659882 - 财政年份:2023
- 资助金额:
$ 35.09万 - 项目类别:
Anti TNF-alpha approach to treat Osteogenesis Imperfecta
抗 TNF-α 方法治疗成骨不全症
- 批准号:
9033816 - 财政年份:2015
- 资助金额:
$ 35.09万 - 项目类别:
Defining a myofibroblast/pericyte as a mesenchymal progenitor cell
将肌成纤维细胞/周细胞定义为间充质祖细胞
- 批准号:
8214496 - 财政年份:2011
- 资助金额:
$ 35.09万 - 项目类别:
Defining a myofibroblast/pericyte as a mesenchymal progenitor cell
将肌成纤维细胞/周细胞定义为间充质祖细胞
- 批准号:
8442384 - 财政年份:2011
- 资助金额:
$ 35.09万 - 项目类别:
Mechanisms underlying commitment and differentiation of progenitor cells during bone healing
骨愈合过程中祖细胞定向和分化的潜在机制
- 批准号:
9463209 - 财政年份:2011
- 资助金额:
$ 35.09万 - 项目类别:
Defining a myofibroblast/pericyte as a mesenchymal progenitor cell
将肌成纤维细胞/周细胞定义为间充质祖细胞
- 批准号:
8040238 - 财政年份:2011
- 资助金额:
$ 35.09万 - 项目类别:
Evaluation of Osteocyte Dedifferentiation Process
骨细胞去分化过程的评价
- 批准号:
8111100 - 财政年份:2010
- 资助金额:
$ 35.09万 - 项目类别:
Evaluation of Osteocyte Dedifferentiation Process
骨细胞去分化过程的评价
- 批准号:
7874902 - 财政年份:2010
- 资助金额:
$ 35.09万 - 项目类别:
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Grant-in-Aid for Scientific Research (C)