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
• 负责人: James C. Iatridis
• 金额: $ 64.46万
• 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/10557110
• 关键词: Address; Adult; Affect; Anabolism; Animal Model; Anterior; Antidepressive Agents; Back Pain; Behavior; Behavioral; Bioinformatics; Biological Models; Biomechanics; Catabolism; Cell Culture Techniques; Cell Separation; Cell model; Cells; Chronic; Combined Modality Therapy; Critical Pathways; Data; Defect; Degenerative Disorder; Diagnosis; Disease; Female; Functional disorder; Genes; Growth; Height; Human; In Vitro; Inflammation; Inflammatory; Injections; Injury; Intervention; Intervertebral disc structure; Investigation; Measurement; Measures; Mechanics; Mediating; Molecular; Molecular Analysis; Molecular Target; Nervous System; Operative Surgical Procedures; Outcome; PGRN gene; Pain; Pain Free; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral Nervous System; Pharmaceutical Preparations; Play; Proteins; Puncture procedure; Rattus; Receptors, Tumor Necrosis Factor, Type II; 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; intervertebral disk surgery; male; molecular marker; monoamine; neural; neuroinflammation; neuropathology; neurovascular; next generation sequencing; novel; novel therapeutics; pain model; painful neuropathy; prevent; radiological imaging; receptor; response; single-cell RNA sequencing; 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.

总结