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FGF signaling during growth and mechanical adaptation of tendon-bone interfaces

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:
10653151
负责人:
MEGAN Leigh KILLIAN
金额:
$40.4万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-08-15 至 2026-05-31

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中文摘要
翻译
摘要 肌腱-骨界面是结构分级的纤维软骨界面,其对于转导至关重要。 从肌肉到骨骼的机械负荷。肌肉负荷减少会导致界面生长受损 和骨骼畸形。最近,我们已经表明,在胚胎肌腱-骨界面的大小, 小鼠肢体受成纤维细胞生长因子9(FGF 9)负调控,骨骼肌特异性敲除 FGF 9的表型模仿了我们在全球FGF 9突变体中看到的效果。这些强有力的初步发现使我们 假设由肌肉特异性FGF 9介导的FGF信号传导有助于非- 细胞自主的方式然而,目前还不清楚相邻肌肉之间是否以及如何发生FGF信号传导, 肌腱和骨骼改变界面祖细胞的行为,或者界面生长是否是次要的 FGF介导的肌肉机械负荷变化。在这个建议中,我们将使用创新的鼠标 组织特异性Cre中FGF配体和受体功能丧失(LOF)和功能获得(GOF)的模型 等位基因来分离FGF诱导的变化所需的细胞群。我们将严格比较结构 (i.e.,微计算机断层摄影术),细胞/ECM(即,组织形态学)和生物力学性质(即, 拉伸,压痕测试)的肌腱-骨界面LOF/GOF基因型和对照。我们将测试FGFR- 使用化学物质的肌肉卸载后界面的依赖性机械反应性结构适应 去神经或使用光遗传学刺激增加肌肉负荷。在这个项目中,我们将使用创新的, 使用脉冲蓝光在新生小鼠中诱导重复骨骼肌收缩的体内光遗传学, 我们在最近的NIH R 03支持下建立了这项技术。这种方法结合新型FGFR LOF/GOF 小鼠模型,将使我们能够确定FGF信号转导在肌肉负荷诱导的适应中的作用, 腱骨界面我们的目的是(1)证明肌肉来源的Fgf 9负责调节肌肉的生长, 腱-骨界面在胚胎和出生后发育过程中的发育和(2)建立机制 细胞特异性FGF信号通过其调节腱-骨界面的负荷诱导的结构适应。 该R 01提案将确定Fgf 9在界面生长中的非细胞自主贡献, 肌腱-骨界面的结构/功能以及FGFR信号传导在界面中的细胞自主作用 生长和机械适应。此外,这项工作的结果将确定保守和独特的 与FGF受体相关的下游信号通路,引导腱-骨的出生后生长 接口。
英文摘要
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.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1126/sciadv.adf4683
发表时间: 2023-06-23
期刊: SCIENCE ADVANCES
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: bioRxiv : the preprint server for biology
影响因子: --
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
FGF signaling during growth and mechanical adaptation of tendon-bone interfaces
FGF signaling during growth and mechanical adaptation of tendon-bone interfaces
Contributions of skeletal muscle loading during rotator cuff maturation and healing
The Role of Scleraxis and Mechanical Loading on Enthesis Maturation
  • 批准号:
    8820068
  • 项目类别:
  • 资助金额:
    $5.51万
  • 财政年份:
    2013
  • 负责人:
    MEGAN Leigh KILLIAN
  • 依托单位:
海外基金