Role of Mechanical Forces on Beta-Catenin of Aged Intervertebral Discs
机械力对老化椎间盘β-连环蛋白的作用
基本信息
- 批准号:8716377
- 负责人:
- 金额:$ 5.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AgeAgingAnabolismAnimalsApoptosisBack PainBiochemicalBiological MarkersBiologyCanis familiarisCatabolismCell CountCellsChondrocytesChronicDataDevelopmentDiseaseExhibitsExtracellular Matrix DegradationFailureFelis catusFoundationsGene TargetingGenesGeneticGenetic ModelsGenetic Predisposition to DiseaseHealthHumanHydration statusImmobilizationIn Situ Nick-End LabelingInflammatoryIntervertebral disc structureKnee jointKnockout MiceLeadLiftingLigandsLinkMechanicsMediatingModelingMolecularMorphologyMusMusculoskeletalNormal CellOutcomePathway interactionsPhysiologicalPlayProteinsPublishingReporterReportingResearchRiskRodentRoleSignal TransductionSourceSpinalStaining methodStainsStructureSurfaceTailTechniquesTestingTherapeuticTissuesTransgenic MiceUnited StatesWeight-Bearing stateWestern BlottingWorkage relatedagedaggrecanasearticular cartilagebeta cateninboneclinically relevantcytokineexperienceextracellularin vivoinsightinstrumentinternal controlintervertebral disk degenerationnovel therapeuticspreventresponsesocioeconomicsspine bone structuretooltranscription factoryoung adult
项目摘要
DESCRIPTION (provided by applicant): Supra-physiological activity, aging and genetic factors may initiate intervertebral disc degeneration, which is characterized by, but not limited to, loss f hydration, altered concentrations of matrix constituents, mechanical stiffening and ultimately back pain. Excessive mechanical loads on tail discs, as analogous to those engendered by strenuous lifting, induce aspects of disc degeneration. However, studies of degeneration using mechanical loading focus on describing the consequences to disc structure and its matrix constituents with little insight into the underlying mechanism(s). Further, the risk of disc degeneration increases with age and therefore, it is important to evaluate the influence of aging on the response to deleterious loading. beta-Catenin is regulated by the canonical Wnt pathway and is putatively involved in the catabolism of intervertebral discs. Extracellular Wnt ligands are
upstream regulators of transcription factor beta-catenin, which accumulates in the cells of human degenerated discs, and cells from canines known to have an age-related propensity for degeneration. Suppression of beta-catenin signaling in chondrocytes immersed in inflammatory cytokines mitigates the expression of catabolic markers, suggesting that targeting this pathway may have therapeutic potential. We will combine our experience with murine loading models and genetic tools to determine the role of beta-catenin activation in disc degeneration induced by mechanical loading. The structural-, cellular- and molecular- level consequences of mechanical overloading in a reporter mouse of beta-Catenin activation and a conditional knockout mouse of beta-catenin in young-adult and aged mice. This research will impact the field of intervertebral disc mechano-biology by identifying the involvement of beta-catenin in a model of disc degeneration and help provide a mechanism upon which to develop treatments capable of curbing or preventing disc degeneration.
描述(由申请人提供):超生理活动、衰老和遗传因素可能引发椎间盘退变,其特征包括但不限于水合作用丧失、基质成分浓度改变、机械僵硬和最终背痛。尾椎间盘上的过度机械负荷(类似于剧烈举升所产生的机械负荷)会导致椎间盘退化。然而,使用机械载荷进行退变的研究侧重于描述对椎间盘结构及其基质成分的影响,而很少深入了解潜在的机制。此外,椎间盘退变的风险随着年龄的增长而增加,因此,评估老化对有害负荷反应的影响非常重要。 β-连环蛋白受经典 Wnt 通路调节,推测参与椎间盘的分解代谢。细胞外 Wnt 配体是
转录因子β-连环蛋白的上游调节因子,在人类退化的椎间盘细胞和已知具有与年龄相关的退化倾向的犬科动物的细胞中积累。抑制浸入炎症细胞因子的软骨细胞中的β-连环蛋白信号传导可减轻分解代谢标记物的表达,这表明针对该途径可能具有治疗潜力。我们将把我们的经验与小鼠负荷模型和遗传工具相结合,以确定 β-连环蛋白激活在机械负荷引起的椎间盘退变中的作用。 β-连环蛋白激活的报告小鼠和年轻成年和老年小鼠的 β-连环蛋白条件性敲除小鼠中机械超载的结构、细胞和分子水平后果。这项研究将通过确定β-连环蛋白在椎间盘退变模型中的参与来影响椎间盘力学生物学领域,并有助于提供一种机制来开发能够抑制或预防椎间盘退变的治疗方法。
项目成果
期刊论文数量(0)
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Nilsson Holguin其他文献
Nilsson Holguin的其他文献
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{{ truncateString('Nilsson Holguin', 18)}}的其他基金
Repurpose bone therapeutics for intervertebral disc degeneration in aged mice
重新利用骨疗法治疗老年小鼠椎间盘退变
- 批准号:
10445485 - 财政年份:2022
- 资助金额:
$ 5.78万 - 项目类别:
Repurpose bone therapeutics for intervertebral disc degeneration in aged mice
重新利用骨疗法治疗老年小鼠椎间盘退变
- 批准号:
10709661 - 财政年份:2022
- 资助金额:
$ 5.78万 - 项目类别:
Role of Mechanical Forces on Beta-Catenin of Aged Intervertebral Discs
机械力对老化椎间盘β-连环蛋白的作用
- 批准号:
8850697 - 财政年份:2014
- 资助金额:
$ 5.78万 - 项目类别:
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