Role of TNFalpha in discogenic pain progression and as a treatment target

总结 背痛是全球残疾的主要原因，椎间盘（IVD）疾病在特定和 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具体原因， 疼痛，或轴性背痛与椎间盘退变作为最常见的诊断，是非特异性的，缺乏有效的 治疗策略。椎间盘源性疼痛的原因很难确定，因为影像学IVD退变是 常见于有症状的患者和无疼痛的对照组，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靶向和新的干预措施，但目前的科学是有限的 由于缺乏关于IVD损伤如何进展为神经炎性病理学的基本信息，以及IVD损伤如何进展为神经炎性病理学的基本信息， 这可以被调制。事实上，令人惊讶的是，很少有人知道IVD和背根神经节（DRG）如何相互作用 尽管涉及肿瘤坏死因子α的慢性炎症 (TNF a）起着关键作用。此外，几乎没有关于椎间盘源性疼痛性别差异的研究， 疼痛传递的性别差异该项目讨论了IVD损伤如何进展为慢性 涉及IVD变性和背根神经节神经炎症的椎间盘源性疼痛，以及如何调节这种疼痛。我们 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， DRG敏感化和重塑;长期椎间盘源性疼痛的治疗是难治性的， 治疗和需要干预的目标都IVD和神经病理。我们开发了一个强大的 特征在于在体内大鼠椎间盘源性疼痛模型和新的跨学科合作。试点成果 表明TNFα是IVD变性和疼痛发作的重要因素，TNFα受体 1（TNFR 1）和TNFR 2在IVD和DRG之间的炎症相互作用中具有不同的作用，需要进一步研究。 研究以了解病理生理学和确定治疗方法。目的1确定肿瘤坏死因子α及其 使用大鼠椎间盘源性疼痛模型， 人IVD细胞。目的2：利用单细胞RNAseq（scRNAseq）技术鉴定IVD和DRG细胞及其分子生物学特性， 在TNFα介导的长期椎间盘源性疼痛中起重要作用的通路，并受到新型药物Atsttrin的影响 阻断TNFR 1相关的催化剂并促进TNFR 2相关的抑制剂。Aim 3治疗慢性椎间盘源性 使用Atsttrin、Duloxastine（一种对神经性疼痛有效的抗抑郁药）和联合治疗的疼痛 以解决IVD变性和神经病理学。目的使用大鼠体内模型和人体外细胞 培养模型系统，包括行为、基因和蛋白质测量，以及下一代测序。 该项目的结果包括确定TNFα及其受体在肿瘤发生和进展中的作用， 椎间盘源性疼痛;识别TNFα调节的细胞和在IVD-DRG串扰中至关重要的分子通路 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;并确定 椎间盘源性疼痛病理生理学和治疗的潜在性别差异。

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.