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 背痛是全球残疾和椎间盘（IVD）疾病的主要原因，在特定和 非特异性疼痛和残疾。虽然脊柱手术可以有效地解决疼痛的特定原因 作为最常见的诊断，疼痛或IVD变性的轴向背痛是非特异性的，并且缺乏有效 治疗策略。由于射线照相IVD变性为 在有症状的患者和无疼痛对照中常见，治疗策略也是非特异性的。 因此，对析生性疼痛的有针对性和新颖的干预措施的关键需要，但当前的科学却有限 由于缺乏有关IVD损伤如何发展为神经炎症病理的基本信息，以及如何 这可以调制。实际上，对于IVD和背根神经（DRG）如何相互作用，知之甚少 响应IVD损伤和变性，尽管涉及肿瘤坏死因子α的慢性感染 （TNFα）起关键作用。此外，几乎没有关于目的地的腹腔痛苦性别差异的研究 疼痛传播中已知的性别差异。该项目解决了IVD损伤如何发展为慢性 涉及IVD变性和DRG神经炎症以及如何调节的椎间盘性疼痛。我们的 前提是，IVD损伤通过TNFα调节的IVD变性而发展为慢性椎间盘痛疼痛，并且 DRG敏感性和重塑；而且，长期的椎间基因痛的治疗是难治性的 治疗和需要针对IVD和神经病理的干预措施。我们开发了一个健壮的 体内大鼠二心痛疼痛模型和新型跨学科合作的特征。飞行员结果 证明TNFα是IVD变性和疼痛发作的重要因素，并且TNFα受体 1（TNFR1）和TNFR2在需要进一步的IVD和DRG之间的炎症串扰中具有不同的作用 研究以了解病理生理并识别治疗。 AIM 1确定TNFα及其的作用 使用大鼠盘源性疼痛模型和 人IVD细胞。 AIM 2使用单细胞RNASEQ（SCRNASEQ）识别IVD和DRG细胞以及分子 TNFα介导并受Atstrin影响的长期椎间盘疼痛的途径很重要，Atstrin是一种新型药物 这阻断了TNFR1相关的分解代谢并促进与TNFR2相关的合成代谢。 AIM 3治疗慢性盘源 使用atsttrin的疼痛，杜洛西汀（一种具有神经性疼痛效率的抗抑制剂）和综合治疗 解决IVD变性和神经病理学。目的是在体内模型中使用大鼠和人体体外细胞 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。 该项目的结果包括确定TNFα及其受体在发作和进展中的作用 椎间盘痛；鉴定TNFα调节的细胞和分子途径在IVD-DRG中至关重要 在长期的椎间盘疼痛中；制定新的治疗策略，以缓解慢性椎间盘痛；并确定 椎间盘止痛病理生理学和治疗中的潜在性别差异。