Bone anabolic effects of osteoclast-produced phospho-Wnt5a
破骨细胞产生的磷酸化 Wnt5a 的骨合成代谢作用
基本信息
- 批准号:10929243
- 负责人:
- 金额:$ 31.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-18 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:BiologicalBiological AssayBone MarrowBone ResorptionBone remodelingCRISPR/Cas technologyCalvariaCellsClinicalCoculture TechniquesDataData SetDefectEncapsulatedEvaluationFemaleFractureFutureGenesGenotypeGoalsHarvestHistologicHomeostasisHydrogelsImageIn VitroLoxP-flanked alleleMacrophageMediatingModelingMolecularMolecular AnalysisMusMyeloid CellsOsteoblastsOsteoclastsOsteogenesisOsteoporoticOutcome MeasureOvariectomyParacrine CommunicationPeptidesPharmaceutical PreparationsPhenocopyPhenotypePhosphorylationPost-Translational Protein ProcessingProductionProteinsRoleSignal PathwaySite-Directed MutagenesisSkeletal DevelopmentSurfaceSystemTNFSF11 geneTamoxifenTransgenic MiceVisualizationWorkZebrafishbonebone fragilitybone lossbone massbone repaircost effectiveexperimental studyfracture riskgain of functiongenome editingin vivoinduced pluripotent stem celllaser capture microdissectionloss of functionmalemicroCTmimeticsmutantnovel therapeutic interventionosteoclastogenesisosteogenicoverexpressionparacrinephenotypic biomarkerpreventresponseskeletalsubstantia spongiosatraffickingtranscriptome sequencing
项目摘要
Project Summary
There is still a need to identify new efficacious and cost effective anabolic bone drugs to treat osteopenic
conditions, bone fragility and repair. The goal of this application is to establish a phosphorylated form of Wnt5a
produced by osteoclasts as a clastokine, capable of enhancing bone formation in vivo. This comes with the
translational promise to deliver phosphomimetic Wnt5a peptide as an anabolic drug to promote osteogenesis in
the future. The proposed work is premised on our compelling preliminary evidence that conditional deletion of
Wnt5a from osteoclasts (OCLs) resulted in decreased bone mass, which was concomitant with decreased bone
formation rate in vivo. We further discovered a specific Ser phosphorylation of Wnt5a in osteoclastic cells. This
phospho-Wnt5a or its mimetic mutant proteins promoted osteogenesis. We therefore hypothesize that a
phosphorylated form of Wnt5a, produced by OCL but not OBs, serve as a clastokine to promote anabolic
bone formation. To verify this hypothesis, we will: first establish the in vivo control of OB function by OCL-
produced Wnt5a and determine the skeletal consequences of Wnt5a over-expression in OCL-precursors (First
Aim). We will then reveal the cellular and molecular mechanisms via which a post-translationally modified form
of Wnt5a produced by OCL control OB function in vitro and in vivo. Finally, we will generate induced pluripotent
stem cells expressing phospho-defective and -mimetic Wnt5a mutants via genome editing to promote bone
formation in a murine critical sized calvarial defect (Second Aim).
项目总结
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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Spatial and Temporal Role of the Runx3 Transcription Factor in Secondary Fracture Healing
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10618866 - 财政年份:2020
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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
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$ 31.3万 - 项目类别:
Spatial and Temporal Role of the Runx3 Transcription Factor in Secondary Fracture Healing
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9890844 - 财政年份:2020
- 资助金额:
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