FGF signaling during growth and mechanical adaptation of tendon-bone interfaces
腱-骨界面生长和机械适应过程中的 FGF 信号传导
基本信息
- 批准号:10653151
- 负责人:
- 金额:$ 40.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:ACTA1 geneAllelesBehaviorBiomechanicsBone GrowthCell SeparationCellsChemicalsChondrocytesClinicalDeformityDenervationDevelopmentDiseaseEmbryoEpiphysial cartilageExtracellular MatrixFGFR1 geneFGFR3 geneFibroblast Growth FactorFibroblast Growth Factor ReceptorsFibrocartilagesGeneticGenotypeGoalsGrowthHypertrophyImpairmentJointsKnock-outKnowledgeLigandsLightLimb structureLoxP-flanked alleleMechanicsMediatingModificationMusMuscleMuscle ContractionMutationOsteoblastsPathological fracturePhenocopyPhenotypePhysiologic pulsePopulationPropertyReporterRoleSecondary toSignal PathwaySignal TransductionSkeletal MuscleSkeletonSourceSpecificityStructureTechniquesTendon structureTestingTissuesUnited States National Institutes of HealthVisualizationWorkbonecomparison controlfibroblast growth factor 9gain of functionhealingin vivoinducible Creinnovationloss of functionmechanical loadmouse modelmutantneonatal miceneonatenerve supplynoveloptogeneticspostnatalprogenitorreceptorresponseskeletalstem cellstendon developmenttherapeutic targettomographytool
项目摘要
ABSTRACT
The tendon-bone interface is a structurally graded fibrocartilage interface that is critical for transducing
mechanical loads from muscle to the skeleton. Reduced muscle loading can lead to impaired interface growth
and skeletal deformities. Recently, we have shown that the size of tendon-bone interfaces in the embryonic
mouse limb are negatively regulated by fibroblast growth factor 9 (FGF9), and skeletal muscle-specific knockout
of FGF9 phenocopies the effects we see in global FGF9 mutants. These strong preliminary findings have led us
to hypothesize that FGF signaling, mediated by muscle specific FGF9, contributes to interface growth in a non-
cell autonomous manner. However, it remains unclear if and how FGF signaling between adjacent muscle,
tendon, and bone alters the behavior of interface progenitor cells, or whether interface growth is secondary to
FGF-mediated changes to mechanical loading from muscle. In this proposal, we will use innovative mouse
models for FGF ligand- and receptor-loss of function (LOF) and gain-of-function (GOF) in tissue-specific Cre
alleles to isolate the cell population required for FGF-induced changes. We will rigorously compare the structural
(i.e., microcomputed tomography), cellular/ECM (i.e., histomorphology) and biomechanical properties (i.e.,
tensile, indentation tests) of the tendon-bone interface in LOF/GOF genotypes and controls. We will test FGFR-
dependent mechanoresponsive structural adaptation of interfaces following muscle unloading using chemical
denervation or increased muscle loading using optogenetic stimulation. In this project, we will use innovative, in
vivo optogenetics to induce repetitive skeletal muscle contraction in neonatal mice using pulsed blue light, a
technique we established with recent NIH R03 support. This approach, combined with novel FGFR LOF/GOF
mouse models, will allow us to determine the role of FGF signaling in muscle loading induced adaptation of the
tendon-bone interface. We aim to (1) demonstrate muscle-derived Fgf9 is responsible for regulating the
development of tendon-bone interfaces during embryonic and postnatal growth and (2) Establish the mechanism
by which cell-specific FGF signaling regulates loading-induced structural adaptations of tendon-bone interfaces.
This R01 proposal will establish the non-cell autonomous contributions of Fgf9 in interface growth and
structure/function of tendon-bone interfaces as well as the cell autonomous roles of FGFR signaling in interface
growth and mechanical adaptation. Additionally, findings from this work will identify both conserved and unique
downstream signaling pathways associated with FGF receptors that guide postnatal growth of tendon-bone
interfaces.
抽象的
肌腱骨界面是一种结构分级的纤维球锥体界面,对于转导至关重要
从肌肉到骨骼的机械载荷。减少肌肉负荷会导致界面增长受损
和骨骼畸形。最近,我们已经证明了胚胎中肌腱骨接口的大小
小鼠肢体由成纤维细胞生长因子9(FGF9)和骨骼肌肉特异性敲除负面调节
FGF9表,我们在全球FGF9突变体中看到的影响。这些强大的初步发现导致了我们
假设由肌肉特异性FGF9介导的FGF信号传导有助于非 -
细胞自主方式。但是,尚不清楚邻近肌肉之间的FGF信号是否以及如何
肌腱,骨骼改变界面祖细胞的行为,或者界面生长是否继发于
FGF介导的肌肉机械负荷的变化。在此提案中,我们将使用创新的鼠标
组织特异性CRE中FGF配体和受体功能(LOF)和功能获得(GOF)的模型
等位基因分离出FGF诱导的变化所需的细胞群。我们将严格比较结构
(即微型层析成像),细胞/ECM(即组织形态学)和生物力学特性(即,
LOF/GOF基因型和对照中肌腱骨界面的拉伸测试)。我们将测试FGFR-
使用化学的肌肉卸载后界面的依赖机械响应性结构适应
使用光遗传学刺激进行神经支配或增加肌肉负荷。在这个项目中,我们将使用创新的
使用脉冲蓝光,A
我们在最近的NIH R03支持下建立的技术。这种方法与新颖的FGFR LOF/GOF结合
小鼠模型将使我们能够确定FGF信号在肌肉负荷中的作用
肌腱骨接口。我们的目标是(1)证明肌肉衍生的FGF9负责调节
胚胎和产后生长过程中肌腱骨界面的发展,(2)建立机制
通过哪种细胞特异性FGF信号传导调节肌腱骨界面的负载诱导的结构适应。
该R01提案将确定FGF9在接口增长和
肌腱骨接口的结构/功能以及FGFR信号在界面中的细胞自主作用
生长和机械适应。此外,这项工作的发现将确定保守和独特
与FGF受体相关的下游信号通路,引导肌腱骨的产后生长
接口。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Optogenetic-induced muscle loading leads to mechanical adaptation of the Achilles tendon enthesis in mice.
- DOI:10.1126/sciadv.adf4683
- 发表时间:2023-06-23
- 期刊:
- 影响因子:13.6
- 作者:Ganji, Elahe;Lamia, Syeda N.;Stepanovich, Matthew;Whyte, Noelle;Goulet, Robert W.;Abraham, Adam C.;Killian, Megan L.
- 通讯作者:Killian, Megan L.
Bone quality following peripubertal growth in a mouse model of transmasculine gender-affirming hormone therapy.
跨男性性别肯定激素治疗小鼠模型中青春期周围生长后的骨质量。
- DOI:10.1101/2023.12.08.570840
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Henry,BrandonW;Cruz,CynthiaDela;Goulet,RobertW;Nolan,BonnieT;Locke,Conor;Padmanabhan,Vasantha;Moravek,MollyB;Shikanov,Ariella;Killian,MeganL
- 通讯作者:Killian,MeganL
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MEGAN Leigh KILLIAN其他文献
MEGAN Leigh KILLIAN的其他文献
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{{ truncateString('MEGAN Leigh KILLIAN', 18)}}的其他基金
FGF signaling during growth and mechanical adaptation of tendon-bone interfaces
腱-骨界面生长和机械适应过程中的 FGF 信号传导
- 批准号:
10469630 - 财政年份:2021
- 资助金额:
$ 40.4万 - 项目类别:
FGF signaling during growth and mechanical adaptation of tendon-bone interfaces
腱-骨界面生长和机械适应过程中的 FGF 信号传导
- 批准号:
10271685 - 财政年份:2021
- 资助金额:
$ 40.4万 - 项目类别:
Contributions of skeletal muscle loading during rotator cuff maturation and healing
骨骼肌负荷在肩袖成熟和愈合过程中的贡献
- 批准号:
10141920 - 财政年份:2018
- 资助金额:
$ 40.4万 - 项目类别:
The Role of Scleraxis and Mechanical Loading on Enthesis Maturation
巩膜和机械负荷对附着点成熟的作用
- 批准号:
8820068 - 财政年份:2013
- 资助金额:
$ 40.4万 - 项目类别:
The Role of Scleraxis and Mechanical Loading on Enthesis Maturation
巩膜和机械负荷对附着点成熟的作用
- 批准号:
8525519 - 财政年份:2013
- 资助金额:
$ 40.4万 - 项目类别:
The Role of Scleraxis and Mechanical Loading on Enthesis Maturation
巩膜和机械负荷对附着点成熟的作用
- 批准号:
8839713 - 财政年份:2013
- 资助金额:
$ 40.4万 - 项目类别:
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