Role of Shh/Brachyury axis in the maintenance of the postnatal intervertebral disc
Shh/Brachyury 轴在产后椎间盘维持中的作用
基本信息
- 批准号:10596619
- 负责人:
- 金额:$ 55.17万
- 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:2021-06-17 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:Absenteeism at workAccelerationAdultAffectAgeAge MonthsAgingAgonistAllelesAppearanceBack PainBiological AssayBrachyury proteinCell CountCell Differentiation processCell ProliferationCellsChondrocyte-like CellChondrocytesChronic low back painChronologyDISC componentsDataDevelopmentDifferentiation and GrowthDiseaseEmbryoEpiphysial cartilageExhibitsExtracellular MatrixFinancial HardshipGene ExpressionGenesGeneticGenetic TranscriptionGoalsGrowthHealthHeterogeneityHumanIn VitroIndividualInjuryIntervertebral disc structureKnock-outKnowledgeLearningMaintenanceMicroscopicModelingMolecularMusPainPalliative CarePathologicPathologyPhenotypePopulationPopulation HeterogeneityProcessReporterResearchRisk FactorsRoleSHH geneSignal TransductionStructureTestingTherapeuticTherapeutic UsesTimeVisualizationWagesage relatedagedcartilaginousconditional knockoutdifferential expressioneffective therapyemotional distressin vivoinsightintervertebral disk degenerationknock-downmouse modelneonatal micenotochordnovelnucleus pulposusoverexpressionpostnatalpostnatal developmentpreventsmall moleculesmoothened signaling pathwayspine bone structuretherapeutic developmenttranscription factortranscriptometranscriptome sequencingtranslational study
项目摘要
PROJECT SUMMARY/ ABSTRACT
The goal of this proposal is to identify the role of critical developmental molecules in growth and maintenance
of the postnatal intervertebral disc (IVD, or disc), and how the loss of these molecules with age results in
pathological changes in the disc. The disc is a cartilaginous structure present between each vertebra. The disc
has three components: notochord derived central nucleus pulposus (NP), surrounded by orthogonal layers of
annulus fibrosus (AF), and endplate (EP) adjacent to the growth plate. With age or injury, the disc undergoes
degenerative changes leading to chronic lower back pain (cLBP) affecting almost 80% of the adult US
population. Much remains to be learned about the cellular and molecular basis of disc growth differentiation,
and aging, that has limited development of effective therapies. We will use conditional genetic mouse models,
lineage-tracing, and disc injury models to identify the function(s) of a crucial developmental regulator Brachyury
(Bra) in the disc. Our central hypothesis is that Bra-expression by the NP cells is essential for disc growth and
maintenance, and its loss during aging leads to the pathological changes in the disc. BRA is a T-box
transcription factor and a notochordal marker. Previously, we showed that postnatal NP cells express Bra; but
it’s expression decreases with age. We also found that sonic hedgehog (SHH), an important notochord signal
secreted by NP cells, regulates postnatal disc growth and differentiation, and regulates Bra expression. While
the total number of NP cells decreased with age, the Bra-expressing NP cells also decreased with age and
were replaced by non-Bra-expressing "chondrocyte-like cells" (CLCs). The lineage relationship between CLCs
and the Bra-expressing cells they replace is unknown, nor is it known how (or if) the loss of Bra expression
leads to disc aging. Our preliminary data showed that all NP cells are lost in an aged mouse disc. We also
showed that conditional targeting of Shh in adult mouse accelerates disc aging, along with the loss of Bra
expression. We further showed that haploinsufficiency of Bra accelerates disc aging, providing the logical
premise for this new project. Aim 1 tests the hypothesis that Bra is a primary transcriptional regulator
downstream of SHH signaling, and regulates growth and maintenance of postnatal disc. Aim 2 will test the
hypothesis that NP cells diverge into two molecularly heterogeneous populations, which differ with respect to
Shh and Bra expression. Aim 3 will test the hypothesis that Bra controls the survival of NP cells, and prevents
them from differentiating into "chondrocyte-like" cells. We expect that the findings from this study will provide
insights into the role of developmental molecules in the maintenance of postnatal disc during growth and aging,
and will identify avenues for targeting such molecules to reverse the aging process, aiding the development of
therapeutics for the treatment of disc related disorders and LBP.
项目摘要/摘要
这项建议的目标是确定关键的发育分子在生长和维持中的作用。
以及随着年龄的增长这些分子的丢失是如何导致
椎间盘内的病理改变。椎间盘是存在于每个椎骨之间的软骨结构。这张光盘
有三个组成部分:脊索来源的中央髓核(NP),周围有正交层
纤维环(AF)和与生长板相邻的终板(EP)。随着年龄的增长或受伤,椎间盘会经历
退行性改变导致慢性下腰痛(CLBP),影响近80%的美国成年人
人口。关于视盘生长分化的细胞和分子基础仍有许多需要了解,
以及衰老,这限制了有效治疗方法的开发。我们将使用条件遗传小鼠模型,
血统追踪和视盘损伤模型以确定关键的发育调节因子短臂的功能(S)
(胸罩)在光盘中。我们的中心假设是,NP细胞的Bra表达对于椎间盘的生长和
在老化过程中,它的丢失会导致椎间盘的病理变化。文胸是一种T-box
转录因子和脊索标记。以前,我们发现出生后的NP细胞表达Bra;但是
它的表达随着年龄的增长而减少。我们还发现了一种重要的无弦信号--声波刺猬(SHH
由NP细胞分泌,调节出生后视盘的生长和分化,并调节Bra的表达。而当
NP细胞总数随增龄而减少,表达Bra的NP细胞也随增龄而减少。
取而代之的是不表达Bra的“软骨细胞样细胞”(CLCs)。CLC之间的血统关系
他们取代的表达Bra的细胞是未知的,也不知道Bra表达的丧失是如何(或是否)的
导致光盘老化。我们的初步数据显示,所有的NP细胞在老化的小鼠椎间盘中都消失了。我们也
结果表明,在成年小鼠中有条件地靶向Shh会加速椎间盘的老化,并伴随着Bra的丢失
表情。我们进一步表明,Bra的单倍体不足加速了椎间盘的老化,提供了符合逻辑的
这个新项目的前提。Aim 1验证了Bra是主要转录调节因子的假设
在SHH信号的下游,并调节出生后视盘的生长和维持。目标2将测试
假设NP细胞分化成两个分子上不同的群体,这两个群体在
Shh和Bra的表达。目标3将验证Bra控制NP细胞存活并防止
使其不能分化为“软骨细胞样”细胞。我们预计这项研究的结果将提供
对发育分子在发育和衰老过程中维持出生后视盘的作用的洞察,
并将确定靶向这类分子的途径,以逆转衰老过程,帮助发展
治疗腰椎间盘相关疾病和腰椎管狭窄症。
项目成果
期刊论文数量(0)
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{{ truncateString('Chitra L Dahia', 18)}}的其他基金
Admin Supplement: Role of Shh/Brachyury axis in the maintenance of the postnatal intervertebral disc
管理补充:Shh/Brachyury 轴在产后椎间盘维护中的作用
- 批准号:
10879520 - 财政年份:2023
- 资助金额:
$ 55.17万 - 项目类别:
Role of Developmental Signaling Pathways in Maintenance of Spinal Discs
发育信号通路在椎间盘维护中的作用
- 批准号:
10305941 - 财政年份:2021
- 资助金额:
$ 55.17万 - 项目类别:
Role of Developmental Signaling Pathways in Maintenance of Spinal Discs
发育信号通路在椎间盘维护中的作用
- 批准号:
10609916 - 财政年份:2021
- 资助金额:
$ 55.17万 - 项目类别:
Role of Developmental Signaling Pathways in Maintenance of Spinal Discs
发育信号通路在椎间盘维护中的作用
- 批准号:
10469481 - 财政年份:2021
- 资助金额:
$ 55.17万 - 项目类别:
Role of Shh/Brachyury axis in the maintenance of the postnatal intervertebral disc
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10433845 - 财政年份:2021
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A Wnt/Shh signaling loop controls intervertebral disc growth and differentiation
Wnt/Shh 信号环路控制椎间盘生长和分化
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8759103 - 财政年份:2014
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