Role of TNFalpha in discogenic pain progression and as a treatment target
TNFα 在椎间盘源性疼痛进展中的作用及其作为治疗靶点
基本信息
- 批准号:10755462
- 负责人:
- 金额:$ 6.58万
- 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:2022-02-01 至 2023-09-01
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAnabolismAnimal ModelAnteriorAntidepressive AgentsBack PainBehaviorBehavioralBioinformaticsBiological ModelsBiomechanicsCatabolismCell Culture TechniquesCell SeparationCell modelCellsChronicCombined Modality TherapyCritical PathwaysDataDefectDegenerative DisorderDiagnosisDiseaseFemaleFunctional disorderGenesGrowthHeightHumanIn VitroInflammationInflammatoryInjectionsInjuryInterventionIntervertebral disc structureInvestigationMeasurementMeasuresMechanicsMediatingMolecularMolecular AnalysisMolecular TargetNervous SystemOperative Surgical ProceduresOutcomePGRN genePainPain FreePathogenesisPathologyPathway interactionsPatientsPeripheral Nervous SystemPharmaceutical PreparationsPlayProteinsPuncture procedureRattusReceptors, Tumor Necrosis Factor, Type IIRefractoryRoleSamplingScienceSex DifferencesSpinal GangliaSpinal StenosisSpine surgeryTNF geneTNFRSF1A geneTNFRSF1B geneTechniquesThinkingTimeTissuesTumor Necrosis Factor Receptorallodyniadisabilitydisability impactdiscogenic painduloxetineeffective therapyganglion cellhealinghuman modelin vitro Modelin vivoin vivo Modelinhibitorinterdisciplinary collaborationintervertebral disk degenerationintervertebral disk surgerymalemolecular markermonoamineneuralneuroinflammationneuropathologyneurovascularnext generation sequencingnovelnovel therapeuticspain modelpainful neuropathypreventradiological imagingreceptorresponsesingle-cell RNA sequencingspinal disk injurysurgical paintransmission processtreatment strategy
项目摘要
Summary
Back pain is a leading cause of global disability and intervertebral disc (IVD) disorders play a role in specific and
non-specific pain and disability. While spinal surgery can effectively address specific causes of pain, discogenic
pain, or axial back pain with IVD degeneration as the most common diagnosis, is non-specific and lacks effective
treatment strategies. Causes of discogenic pain are hard to identify since radiographic IVD degeneration is
common in both symptomatic patients and pain-free controls, and treatment strategies are also non-specific.
Hence, a critical need exists for targeted and novel interventions for discogenic pain, yet current science is limited
by a lack of fundamental information on how IVD injury progresses to neuroinflammatory pathologies, and how
this can be modulated. In fact, surprisingly little is known about how IVDs and dorsal root ganglia (DRGs) interact
in response to IVD injury and degeneration, although chronic inflammation involving tumor necrosis factor alpha
(TNFα) plays a key role. Furthermore, almost no studies on sex differences in discogenic pain exist despite
known sex differences in pain transmission. This project addresses how IVD injury progresses to chronic
discogenic pain involving IVD degeneration and DRG neuroinflammation, and how this can be modulated. Our
premise is that IVD injuries progress to chronic discogenic pain via TNFα-modulated IVD degeneration, and
DRG sensitization and remodeling; and that the treatment of long-term discogenic pain is refractory with simple
treatments and requires interventions that target both IVD and neural pathologies. We developed a robustly
characterized in vivo rat discogenic pain model and novel interdisciplinary collaborations. Pilot results
demonstrate that TNFα is an essential factor in the onset of IVD degeneration and pain, and that TNFα receptor
1 (TNFR1) and TNFR2 have distinct roles in the inflammatory cross-talk between IVDs and DRGs needing further
investigation to understand pathophysiology and identify treatments. Aim 1 determines the role of TNFα and its
receptors in the progression from IVD injury to chronic discogenic pain using a rat discogenic pain model and
human IVD cells. Aim 2 uses single cell RNAseq (scRNAseq) to identify IVD and DRG cells and molecular
pathways important in long-term discogenic pain that are TNFα-mediated and affected by Atsttrin, a novel drug
that blocks TNFR1-related catabolism and promotes TNFR2-related anabolism. Aim 3 treats chronic discogenic
pain using Atsttrin, Duloxetine (an anti-depressant with efficacy for neuropathic pain), and combined treatments
to address both IVD degeneration and neuropathology. Aims use rat in vivo models and human in vitro cell
culture model systems with behavioral, gene and protein measurements, as well as next generation sequencing.
Outcomes of this project include determining the role of TNFα and its receptors in onset and progression of
discogenic pain; identifying TNFα-modulated cells and molecular pathways critical in the IVD-DRG of cross-talk
in long-term discogenic pain; developing novel treatment strategies for chronic discogenic pain; and identifying
potential sex differences in discogenic pain pathophysiology and treatment.
概括
背痛是全球残疾的主要原因,而椎间盘 (IVD) 疾病在特定和特定领域发挥着重要作用。
虽然脊柱手术可以有效解决疼痛、椎间盘源性疼痛的特定原因。
疼痛或轴性背痛(以 IVD 变性为最常见的诊断)是非特异性的且缺乏有效的
治疗策略 椎间盘源性疼痛的原因很难确定,因为放射影像学上的 IVD 变性是很常见的。
在有症状的患者和无痛对照中都很常见,而且治疗策略也是非特异性的。
因此,迫切需要针对椎间盘源性疼痛的有针对性的新颖干预措施,但目前的科学有限
由于缺乏关于 IVD 损伤如何进展为神经炎症病理学的基本信息,以及如何
事实上,令人惊讶的是,人们对 IVD 和背根神经节 (DRG) 的相互作用知之甚少。
尽管慢性炎症涉及肿瘤坏死因子α,但对 IVD 损伤和变性的反应
此外,尽管如此,几乎没有关于椎间盘源性疼痛的性别差异的研究。
该项目探讨了 IVD 损伤如何发展为慢性损伤。
涉及 IVD 变性和 DRG 神经炎症的椎间盘源性疼痛,以及如何调节这种疼痛。
前提是 IVD 损伤通过 TNFα 调节的 IVD 变性进展为慢性异源性疼痛,并且
DRG 敏化和重塑;并且长期椎间盘源性疼痛的治疗难以通过简单的方法治愈。
治疗并需要针对 IVD 和神经病理学的干预措施。
描述了体内大鼠椎间盘源性疼痛模型和新颖的跨学科合作的试点结果。
证明 TNFα 是 IVD 变性和疼痛发生的重要因素,并且 TNFα 受体
1 (TNFR1) 和 TNFR2 在 IVD 和 DRG 之间的炎症串扰中具有不同的作用,需要进一步研究
研究以了解病理生理学并确定治疗方法。目标 1 确定 TNFα 及其作用。
使用大鼠椎间盘源性疼痛模型研究从 IVD 损伤到慢性椎间盘源性疼痛进展中的受体
Aim 2 使用单细胞 RNAseq (scRNAseq) 来识别 IVD 和 DRG 细胞和分子。
长期椎间盘源性疼痛的重要途径,由 TNFα 介导并受新药 Atsttrin 影响
阻断 TNFR1 相关的分解代谢并促进 TNFR2 相关的合成代谢 Aim 3 治疗慢性遗传性疾病。
使用 Atsttrin、度洛西汀(一种对神经性疼痛有效的抗抑郁药)和联合治疗来缓解疼痛
旨在使用大鼠体内模型和人类体外细胞来解决 IVD 变性和神经病理学问题。
具有行为、基因和蛋白质测量以及下一代测序的培养模型系统。
该项目的成果包括确定 TNFα 及其受体在疾病发生和进展中的作用
椎间盘源性疼痛;识别 IVD-DRG 串扰中 TNFα 调节的细胞和分子关键通路
长期椎间盘源性疼痛;开发慢性椎间盘源性疼痛的新治疗策略;
椎间盘源性疼痛病理生理学和治疗中潜在的性别差异。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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James C. Iatridis其他文献
Effect of the CCL5 releasing fibrin gel for intervertebral disc regeneration
CCL5释放纤维蛋白凝胶对椎间盘再生的影响
- DOI:
7.10.1177/1947603518764263 - 发表时间:
2018 - 期刊:
- 影响因子:2.8
- 作者:
Zhiyu Zhou;Stephan Zeiter;Tanja Schmid;Daisuke Sakai;James C. Iatridis;Guangqian Zhou;R. Geoff Richards;Mauro Alini;Sibylle Grad;Zhen Li - 通讯作者:
Zhen Li
Functional cell phenotype induction with TGFβ1 and collagen-polyurethane scaffold for annulus fibrosus rupture repair
功能细胞表型诱导与 TGFβ1 和胶原蛋白聚氨酯支架纤维环破裂修复
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Jie Du;Rose G. Long;Tomoko Nakai;Daisuke Sakai;Lorin M. Benneker;Guangqian Zhou;Bin Li;David Eglin;James C. Iatridis;Mauro Alini;Sibylle Grad;Zhen Li - 通讯作者:
Zhen Li
James C. Iatridis的其他文献
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{{ truncateString('James C. Iatridis', 18)}}的其他基金
Role of TNFalpha in discogenic pain progression and as a treatment target
TNFα 在椎间盘源性疼痛进展中的作用及其作为治疗靶点
- 批准号:
10375766 - 财政年份:2022
- 资助金额:
$ 6.58万 - 项目类别:
Mechanisms for Regenerative Healing in Intervertebral Discs
椎间盘再生愈合机制
- 批准号:
10762672 - 财政年份:2022
- 资助金额:
$ 6.58万 - 项目类别:
Diversity Supplement for: Mechanisms for Regenerative Healing in Intervertebral Discs
多样性补充:椎间盘再生愈合机制
- 批准号:
10631488 - 财政年份:2022
- 资助金额:
$ 6.58万 - 项目类别:
Mechanisms for Regenerative Healing in Intervertebral Discs
椎间盘再生愈合机制
- 批准号:
10551336 - 财政年份:2022
- 资助金额:
$ 6.58万 - 项目类别:
Mechanisms for Regenerative Healing in Intervertebral Discs
椎间盘再生愈合机制
- 批准号:
10344363 - 财政年份:2022
- 资助金额:
$ 6.58万 - 项目类别:
Diversity Supplement for: Role of TNFalpha in discogenic pain progression and as a treatment target
多样性补充:TNFα 在椎间盘源性疼痛进展中的作用以及作为治疗目标
- 批准号:
10631481 - 财政年份:2022
- 资助金额:
$ 6.58万 - 项目类别:
Diversity Supplement for: Mechanisms for Regenerative Healing in Intervertebral Discs
多样性补充:椎间盘再生愈合机制
- 批准号:
10631488 - 财政年份:2022
- 资助金额:
$ 6.58万 - 项目类别:
Role of TNFalpha in discogenic pain progression and as a treatment target
TNFα 在椎间盘源性疼痛进展中的作用及其作为治疗靶点
- 批准号:
10557110 - 财政年份:2022
- 资助金额:
$ 6.58万 - 项目类别:
Diversity Supplement for: Role of TNFalpha in discogenic pain progression and as a treatment target
多样性补充:TNFα 在椎间盘源性疼痛进展中的作用以及作为治疗目标
- 批准号:
10631481 - 财政年份:2022
- 资助金额:
$ 6.58万 - 项目类别:
Diabetes Induced Disc Degeneration and Prevention
糖尿病引起的椎间盘退变及预防
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9293971 - 财政年份:2016
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