Spatial and Temporal Role of the Runx3 Transcription Factor in Secondary Fracture Healing
Runx3 转录因子在二次骨折愈合中的时空作用
基本信息
- 批准号:10454763
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAgingBiomechanicsBlood VesselsBlood capillariesBone TissueBone callusCartilageCell Differentiation processCell LineageCellsChondrocytesClinicalDataDiabetes MellitusEconomic BurdenEncapsulatedEvaluationEventFemoral FracturesFlow CytometryFractureFrequenciesGelatinHealthcare SystemsHistologicHistologyHydrogelsImageImpairmentIncidenceKnockout MiceLoxP-flanked alleleMediatingMesenchymalMicroRNAsModalityModelingMolecularMolecular AnalysisMolecular TargetMonitorMusNamesOsteoblastsOsteocytesOsteogenesisOsteoporosisOsteoporoticPathway interactionsPatientsPeriosteal CellPeriosteumPharmaceutical PreparationsPopulationProcessRNARUNX3 geneRegulator GenesRegulatory PathwayReporterReportingRepressionRoentgen RaysRoleSiteSmokingSorting - Cell MovementTamoxifenTestingTimeTissuesTorsionTransgenic MiceTranslational ResearchVascular blood supplyVeteransWorkangiogenesisbonebone fracture repairbone healingbone imagingbone massbone repaircartilaginousclinically relevantcomorbidityconditional knockoutexperimental studyhealingineffective therapieslaser capture microdissectionlong bonelost work timemicroCTmultiphoton microscopynanofibernew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsosteogenicosteoporosis with pathological fracturepre-clinicalpreventprogenitorskeletal stem cellstem cellssuccesstranscription factortwo photon microscopy
项目摘要
Clinical Dilemma: The frequency of impaired fracture healing is increased with aging as well as in the
presence of other patient-related factors such as smoking, osteoporosis, and diabetes. Treatment of fractures
in this setting continues to pose a significant economic burden on the US healthcare system due to increases
in time lost from work as well as increases in the expenses associated with fracture-associated complications.
While various bone anabolic drugs are successful in increasing homeostatic bone mass in osteoporotic
patients and decreasing fracture incidence, they have not demonstrated significant success in enhancing
fracture repair. Therefore, identifying novel molecular targets to accelerate secondary fracture healing in this
very common setting remains of paramount importance.
Relevance to the VA: According to the Office of VA Inspector General report in 2010, osteoporotic patients
who suffered a single fracture present a higher incidence of subsequent fractures (20-fold increase) than
unaffected populations. Impaired or delayed bony union following fracture of long bones prevents or delays a
significant percentage of VA patients from resuming their daily activities and returning to work. Ineffective
treatment of these fractures maximizes the economic burden on the VA healthcare system. Identifying novel
molecular targets to enhance secondary bone repair remains of paramount importance. The objective of this
translational research application is to enhance secondary fracture healing by targeting novel regulatory
pathways that enhance periosteal cell-induced osteogenesis and angiogenesis during fracture callus formation.
Scientific premise: We provide compelling preliminary evidence of the following:
1. Runx3 is expressed in chondrocytes, osteoblasts and osteocytes of C57BL6j murine long bones.
2. Runx3 expression levels are increased in soft cartilaginous calluses and subsequently decreased in bony
calluses of murine femoral fractures.
3. Conditional deletion of Runx3 in periosteal cells (cKO) resulted in enhanced secondary bone healing as
evidenced by histological, histomorphometric, and molecular analyses.
4. The cellular mechanisms underlying these positive effects on secondary bone healing implicate increased
osteogenesis as well as angiogenesis of fractured periosteal cells from Runx3 cKO compared to control
mice.
5. Use of multiphoton microscopy demonstrate the feasibility of tracking Prx1+ skeletal progenitor cells during
bone repair and longitudinally monitor the bone healing process for lineage tracing experiments.
Here we hypothesize that Runx3 is a molecular switch that controls the transition from cartilaginous to
bony callus, and its deletion in the chondrogenic cell lineage will accelerate secondary fracture
healing.
To verify this hypothesis, we propose to first establish the effects of stage-specific repression of Runx3 on
secondary fracture healing (Aim 1). We will then determine the mechanisms via which Runx3 controls
mesenchymal cell differentiation into the chondro/osteogenic lineages (Aim 2). Finally, we will assess the
efficacy of Runx3 inhibition during fracture repair in control C57BL6 mice through controlled and sustained
delivery of miRNA encapsulated hydrogel and examine the rate of bone healing and biomechanical strength of
healed bone (Aim 3).
Impact: Defining the pathways that governthe transition from soft to bony callus will help identify new therapies
to accelerate secondary fracture healing. Here, we will establish Runx3 as a novel therapeutic target.
临床困境:骨折愈合受损的频率随着年龄的增长而增加
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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HICHAM M DRISSI其他文献
HICHAM M DRISSI的其他文献
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{{ truncateString('HICHAM M DRISSI', 18)}}的其他基金
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10719356 - 财政年份:2023
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10929243 - 财政年份:2023
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Control of intervertebral disc degeneration via matrix-mediated delivery of platelet-derived growth factors
通过基质介导的血小板衍生生长因子的传递来控制椎间盘退变
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10377961 - 财政年份:2021
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Control of intervertebral disc degeneration via matrix-mediated delivery of platelet-derived growth factors
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10614929 - 财政年份:2021
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CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Novel cell-based therapies to increase functional outcomes and alleviate pain in preclinical models of osteoarthritis
CMA:减轻关节炎疼痛的软骨修复策略 (CaRe AP):基于新型细胞的疗法,可提高骨关节炎临床前模型的功能结果并减轻疼痛
- 批准号:
10514601 - 财政年份:2020
- 资助金额:
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CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Novel cell-based therapies to increase functional outcomes and alleviate pain in preclinical models of osteoarthritis
CMA:减轻关节炎疼痛的软骨修复策略 (CaRe AP):基于新型细胞的疗法,可提高骨关节炎临床前模型的功能结果并减轻疼痛
- 批准号:
10292959 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Spatial and Temporal Role of the Runx3 Transcription Factor in Secondary Fracture Healing
Runx3 转录因子在二次骨折愈合中的时空作用
- 批准号:
10618866 - 财政年份:2020
- 资助金额:
-- - 项目类别:
CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Novel cell-based therapies to increase functional outcomes and alleviate pain in preclinical models of osteoarthritis
CMA:减轻关节炎疼痛的软骨修复策略 (CaRe AP):基于新型细胞的疗法,可提高骨关节炎临床前模型的功能结果并减轻疼痛
- 批准号:
10013786 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Spatial and Temporal Role of the Runx3 Transcription Factor in Secondary Fracture Healing
Runx3 转录因子在二次骨折愈合中的时空作用
- 批准号:
9890844 - 财政年份:2020
- 资助金额:
-- - 项目类别:
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