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
基本信息
- 批准号:10709661
- 负责人:
- 金额:$ 50.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-22 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdultAffectAgeAgingAgonistAnabolismAntibodiesAttenuatedBack PainBehaviorBehavioral ModelBindingBiophysicsBone structureCell ProliferationCellsChildCollagenCollectionDataDehydrationDoseEarly treatmentEconomic BurdenElderlyEnsureEstrogen Receptor alphaEstrogensEtiologyExtracellular MatrixFDA approvedFemaleGenerationsGeneticGenetic RecombinationGlycine decarboxylaseHeightHistologyHomeostasisHydration statusImpairmentIndividualInflammationInjectionsIntervertebral disc structureKnowledgeLacZ GenesLigandsLow Back PainLoxP-flanked alleleMagnetic Resonance ImagingMaintenanceMechanicsMediatingMetabolismModelingMolecularMusNatural regenerationOccupationsOperative Surgical ProceduresOsteogenesisOutcomeOvariectomyPainPalliative CarePathway interactionsPersonsPopulationPositioning AttributePostmenopausePreventionPropertyProteoglycanRaloxifeneRecording of previous eventsReporterSignal PathwaySignal TransductionStatistical Data InterpretationStrenuous ExerciseStructureSubstance PTailTamoxifenTestingTherapeuticTimeVertebral columnWNT Signaling PathwayWaterWomanage relatedagedaging populationanalogantagonistbeta cateninbonebone masschronic paindisabilityimprovedinhibitorintervertebral disk degenerationmalemechanical forcemennucleus pulposusoverexpressionpain behaviorpalliativepharmacologicpreventprophylacticresponsesecond harmonicsexsocioeconomicsspinal disk injurystemtranscription factortranscriptome sequencingyoung adult
项目摘要
Project Summary
Intervertebral disc degeneration is a major etiological factor of low back pain, which is the #1 cause of job
disability worldwide that affects 80% of people at least once in their lifetime. Older individuals are prone to
intervertebral disc degeneration by a loss of disc height and hydration. Pain can worsen intervertebral disc
degeneration by limiting mobility and reducing the mechanical forces necessary for homeostasis. Therefore,
there is an unmet need to safely protect older individuals from intervertebral disc degeneration and, here, we
intend to repurpose existing bone therapeutics to reduce/prevent intervertebral disc loss and consequently back
pain in the aging population. Intervertebral disc degeneration remains a growing problem because (1) the US
geriatric population is projected to outnumber children for the first time in history, (2) the early treatment of
intervertebral disc degeneration remains palliative and (3) the ballooning socioeconomic burden. We are
uniquely positioned to bridge the knowledge gap in the molecular mechanisms of bone therapeutics to stem
intervertebral disc degeneration. Aging and mechanical injury of the intervertebral disc by compression both
exacerbate breakdown of the extracellular matrix, but compression stimulates inflammation more so than aging.
By contrast, we recently found that deletion of the inhibitor of Wnt/β-Catenin signaling sost, a bone formation
anabolic mechanism and the genetic analog approach to anti-sclerostin antibody injection, increases the
structural properties and hydration of the intervertebral disc. Another bone therapeutic that shows benefits to the
intervertebral disc is anti-resorptive raloxifene, a non-uterine-targeting estrogen agonist, that also increases
binding of water to collagen. Use of raloxifene in postmenopausal women is associated with relieving back pain
and greater intervertebral disc height than non-treated women. Our studies show that raloxifene increases
intervertebral disc height in male and female mice, reduces sex- and age-related intervertebral disc degeneration
in female mice, improves metrics of pain-related behavior in old mice and stimulates Wnt and estrogen signaling.
Here, we hypothesize that currently available therapeutics will stimulate extracellular matrix anabolism and
prevent compression-induced intervertebral disc degeneration in young and aged mice. To test this hypothesis,
we propose two aims using aged mice and catabolic compression as models of intervertebral disc degeneration.
In aim 1, we will determine whether therapeutics known to activate Wnt signaling will prevent IVD degeneration
by injurious mechanical compression in young and aged mice. In aim 2, we will determine whether estrogen
signaling prevents IVD degeneration via Wnt signaling and whether prevention can be safely improved by
combining the signaling pathways in aged mice. This proposal will repurpose current FDA-approved bone
prophylactics that target pathways consistently impacted by intervertebral disc degeneration in variable
conditions and may be specifically beneficial to intervertebral disc degeneration in the elderly.
项目概要
椎间盘退变是腰痛的主要病因,也是导致工作的第一大原因
全球 80% 的人一生中至少会患上一次残疾。
由于椎间盘高度和水合作用的丧失而导致椎间盘退变,疼痛会使椎间盘恶化。
通过限制活动性和减少体内平衡所需的机械力来实现退化。
安全保护老年人免受椎间盘退变的需求尚未得到满足,在这里,我们
打算重新利用现有的骨疗法,以减少/防止椎间盘丢失,从而恢复
椎间盘退变的疼痛仍然是一个日益严重的问题,因为 (1) 美国
预计老年人口数量将在历史上首次超过儿童人数,(2) 早期治疗
椎间盘退变仍然是姑息治疗;(3) 社会负担不断增加。
具有独特的优势,可以弥合骨治疗分子机制的知识差距
椎间盘退变和椎间盘受压造成的机械损伤。
加剧细胞外基质的分解,但压力比衰老更能刺激炎症。
相比之下,我们最近发现,Wnt/β-Catenin 信号传导抑制剂的缺失(骨形成过程)
合成代谢机制和抗硬化素抗体注射的遗传模拟方法,增加了
另一种对椎间盘的结构特性和水合作用有益的骨治疗方法。
雷洛昔芬是一种抗椎间盘吸收的药物,它是一种非子宫靶向雌激素激动剂,它也会增加
水与胶原蛋白的结合在绝经后妇女中使用雷洛昔芬与缓解背痛有关。
我们的研究表明,雷洛昔芬会增加椎间盘高度。
雄性和雌性小鼠的椎间盘高度,减少与性别和年龄相关的椎间盘退变
在雌性小鼠中,改善老年小鼠疼痛相关行为的指标并刺激 Wnt 和雌激素信号传导。
在这里,我们追求当前可用的治疗方法将刺激细胞外基质合成代谢和
防止年轻和老年小鼠受压引起的椎间盘退变为了检验这一假设,
我们提出了两个目标,使用老年小鼠和分解代谢压缩作为椎间盘退变的模型。
在目标 1 中,我们将确定已知激活 Wnt 信号传导的疗法是否可以预防 IVD 退化
在目标 2 中,我们将确定雌激素是否对年轻和老年小鼠造成伤害。
信号传导通过 Wnt 信号传导预防 IVD 变性,以及是否可以通过以下方式安全地改善预防效果:
结合老年小鼠的信号通路,该提案将重新利用目前 FDA 批准的骨骼。
针对不同情况下持续受到椎间盘退变影响的通路的预防剂
条件,可能特别有益于老年人的椎间盘退变。
项目成果
期刊论文数量(0)
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Nilsson Holguin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:
$ 50.71万 - 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:
8716377 - 财政年份:2014
- 资助金额:
$ 50.71万 - 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:
$ 50.71万 - 项目类别:
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