Pathogenesis of Inflammation-driven Intervertebral Disc Herniation: The Role of Syndecan 4
炎症驱动的椎间盘突出症的发病机制:Syndecan 4 的作用
基本信息
- 批准号:9754682
- 负责人:
- 金额:$ 46.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:ADAMTSAddressAmericanAnimal ModelAnimalsApoptosisBackBack PainBiomechanicsCXCL12 geneCatabolismCell AgingCell surfaceCellsChronicCollagenDefectDiseaseEtiologyFibronectinsFoundationsFutureGenesGoalsHeparan Sulfate ProteoglycanHeparitin SulfateHumanIL8 geneImmuneImmune Cell ActivationIncidenceIndividualInfiltrationInflammationInflammatoryInterleukin-1 betaInterventionIntervertebral disc structureInvestigationLeadLearningLinkLow Back PainMMP3 geneMacrophage ActivationMagnetic Resonance ImagingMatrix MetalloproteinasesMeasuresMediatingMediator of activation proteinMolecularMolecular StructureMotionMusNeck PainOccupationsOutcome StudyPainPathogenesisPathway interactionsPhasePlayProcessProductionPropertyProteoglycanRANTESRegulationRoleSideSignal TransductionSlipped DiskSolidStromal Cell-Derived Factor 1Stromelysin 1StructureTNF geneTestingTimeTissuesTransgenic MiceTraumaUnspecified or Sulfate Ion SulfatesVertebral columnWorkaggrecanaggrecanasecell motilitychemokinecytokinedisabilitydiscogenic painexperiencehuman tissuein vivoinflammatory milieuintervertebral disk degenerationloss of functionmacrophagemigrationmutantnew therapeutic targetnovelnucleus pulposusoverexpressionpreventprotein degradationstemsyndecan-4syndecan4synergismtherapy developmenttranscriptome sequencing
项目摘要
The relationship between the etiology of intervertebral disc degeneration and low back pain has been subjected
to considerable scrutiny. Degeneration is thought to be initiated by the abnormal production of a number of
pro-inflammatory cytokines, in particular TNF-α and IL-1β. While these studies have shown involvement of
cytokines in pathogenesis of disc degeneration and herniation, progress has been slow in delineating new
therapeutic targets to block inflammation. This deficit stems from our lack of understanding of molecular
mediators that regulate and link cytokine-dependent matrix degradation with immune cell migration into the
disc through annular defects. Interestingly, our ongoing work has found an unexpected synergism between
heparan sulfate (HS) proteoglycan syndecan4 (SDC4) and these two key inflammatory cytokines. The goal of
the proposed investigations is to build on the central role of SDC4 in the pathogenesis of the disc herniation
and inflammation. We have formulated two interrelated hypotheses each of which addresses a separate but
linked phase of the disease process. The first phase relates to the effect of the inflammatory cytokines on the
regulation of aggrecan rich matrix degradation. We will test the hypothesis that SDC4 through HS side chains
promotes cytokine-dependent aggrecan rich matrix degradation through ADAMTS and MMP activation. Using
gain and loss-of-function studies of SDC4 in NP cells treated with cytokines and RNA-Seq approach we will
identify novel SDC4 responsive genes. We will also measure the contribution of MMPs, ADAMTS-1 and
ADAM17 produced by NP cells in SDC4 shedding. In addition, we will determine how changes in SDC4 levels
relate to aggrecan and collagen turnover in human tissues. The second stage of the disease process is
characterized by structural changes in the NP and AF and formation of annular tears and herniations. We
propose to test the hypothesis that that in inflammatory milieu of the herniated disc, SDC4 plays an important
role in macrophage activation and migration by controlling the activity of select chemokines (CCL5, IL-8 and
SDF-1) secreted by the disc cells. This will be achieved using primary macrophages isolated from SDC4-/- mice.
Using well characterized painful human disc tissues, we will link changes in chemokines and SDC4 levels to
immune cell activation, infiltration and matrix degradation. Finally, to explore the in vivo importance of SDC4
in pathogenesis of TNF--driven disc herniation, we will cross hTNFtg mice with SDC4 -/- animals to generate
hTNFtg,SDC4-/- mice. To establish if a deficiency in SDC4 provides protection against cytokine-dependent disc
herniation, we will compare molecular, structural and biomechanical properties of the motion segments with
that of hTNFtg. To our knowledge, this would be the first attempt to address the contribution of SDC4 to
mechanisms linking initiation and propagation of the degenerative cascade and herniation driven by
inflammatory cytokines. These studies will provide a foundation for future development of interventional
strategies to target SDC4 dependent catabolic and inflammatory phases of degenerative disc disease.
椎间盘退变的病因学与腰痛之间的关系一直受到关注
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Makarand V Risbud', 18)}}的其他基金
2021 ORS/PSRS 6th International Spine Research Symposium
2021 ORS/PSRS第六届国际脊柱研究研讨会
- 批准号:
10540609 - 财政年份:2022
- 资助金额:
$ 46.25万 - 项目类别:
Targeting cell senescence in a novel model of spontaneous disc degeneration
在自发性椎间盘退变的新模型中靶向细胞衰老
- 批准号:
10277819 - 财政年份:2021
- 资助金额:
$ 46.25万 - 项目类别:
Targeting cell senescence in a novel model of spontaneous disc degeneration
在自发性椎间盘退变的新模型中靶向细胞衰老
- 批准号:
10839574 - 财政年份:2021
- 资助金额:
$ 46.25万 - 项目类别:
Targeting cell senescence in a novel model of spontaneous disc degeneration
在自发性椎间盘退变的新模型中靶向细胞衰老
- 批准号:
10471403 - 财政年份:2021
- 资助金额:
$ 46.25万 - 项目类别:
Epigenetic Mechanisms of Spontaneous Disc Degeneration in SM/J Mice
SM/J 小鼠椎间盘自发退变的表观遗传机制
- 批准号:
10757531 - 财政年份:2021
- 资助金额:
$ 46.25万 - 项目类别:
Targeting cell senescence in a novel model of spontaneous disc degeneration
在自发性椎间盘退变的新模型中靶向细胞衰老
- 批准号:
10634637 - 财政年份:2021
- 资助金额:
$ 46.25万 - 项目类别:
Pathogenesis of Inflammation-driven Intervertebral Disc Herniation: The Role of Syndecan 4
炎症驱动的椎间盘突出症的发病机制:Syndecan 4 的作用
- 批准号:
10553254 - 财政年份:2019
- 资助金额:
$ 46.25万 - 项目类别:
Pathogenesis of Inflammation-driven Intervertebral Disc Herniation: The Role of Syndecan 4
炎症驱动的椎间盘突出症的发病机制:Syndecan 4 的作用
- 批准号:
9895623 - 财政年份:2019
- 资助金额:
$ 46.25万 - 项目类别:
Pathogenesis of Inflammation-driven Intervertebral Disc Herniation: The Role of Syndecan 4
炎症驱动的椎间盘突出症的发病机制:Syndecan 4 的作用
- 批准号:
10091307 - 财政年份:2019
- 资助金额:
$ 46.25万 - 项目类别:
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