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
• 负责人: James C. Iatridis
• 金额: $ 66.99万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375766
• 关键词: Address; Adult; Affect; Anabolism; Animal Model; Anterior; Antidepressive Agents; Back Pain; Behavior; Behavior Therapy; Behavioral; Bioinformatics; Biological Models; Biomechanics; Catabolism; Cell Culture Techniques; Cell model; Cells; Chronic; Combined Modality Therapy; Critical Pathways; Data; Defect; Degenerative Disorder; Diagnosis; Disease; Female; Functional disorder; Gene Proteins; Height; Human; In Vitro; Inflammation; Inflammatory; Injections; Injury; Intervention; Intervertebral disc structure; Investigation; Measurement; Measures; Mechanics; Mediating; Molecular; Molecular Analysis; Molecular Target; Nervous system structure; Operative Surgical Procedures; Outcome; PGRN gene; Pain; Pain-Free; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral Nervous System; Pharmaceutical Preparations; Play; Puncture procedure; Rattus; Refractory; Role; Sampling; Science; Sex Differences; Spinal Ganglia; Spinal Stenosis; Spine surgery; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Techniques; Thinking; Time; Tissues; Tumor Necrosis Factor Receptor; allodynia; disability; disability impact; discogenic pain; duloxetine; effective therapy; ganglion cell; healing; human model; in vitro Model; in vivo; in vivo Model; inhibitor; interdisciplinary collaboration; intervertebral disk degeneration; male; molecular marker; monoamine; neuroinflammation; neuropathology; neurovascular; next generation sequencing; novel; novel therapeutics; pain model; painful neuropathy; prevent; radiological imaging; receptor; relating to nervous system; response; single-cell RNA sequencing; skeletal; spinal disk injury; surgical pain; transmission process; treatment strategy

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。 非特异性疼痛和残疾。虽然脊柱手术可以有效解决疼痛的特定原因，但椎间盘源性疼痛 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，因为放射照相 IVD 变性是 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 这是可以调节的。事实上，令人惊讶的是，人们对 IVD 和背根神经节 (DRG) 如何相互作用知之甚少 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 (TNFα) 起着关键作用。此外，几乎没有关于椎间盘源性疼痛的性别差异的研究，尽管 已知疼痛传递的性别差异。该项目探讨 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。我们的 前提是 IVD 损伤通过 TNFα 调节的 IVD 变性进展为慢性椎间盘源性疼痛，并且 DRG敏化和重塑；长期椎间盘源性疼痛的治疗很难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。我们开发了一个强大的 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。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 调查以了解病理生理学并确定治疗方法。目标 1 确定 TNFα 的作用及其 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 人类 IVD 细胞。目标 2 使用单细胞 RNAseq (scRNAseq) 来识别 IVD 和 DRG 细胞以及分子 在长期椎间盘源性疼痛中重要的通路，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。目标 3 治疗慢性椎间盘源性 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 解决 IVD 变性和神经病理学问题。目的是使用大鼠体内模型和人类体外细胞 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 TNFα 调节的细胞和分子通路在 IVD-DRG 串扰中至关重要 长期椎间盘源性疼痛；制定慢性椎间盘源性疼痛的新治疗策略；并确定 椎间盘源性疼痛病理生理学和治疗中潜在的性别差异。