Immune-modulation in canine models of painful intervertebral disc degeneration

疼痛性椎间盘退变犬模型的免疫调节

• 批准号: 10042520
• 负责人: Devina Purmessur (Walter)
• 金额: $ 17.16万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042520
• 关键词: 3-Dimensional; Address; Allergic Disease; Animal Model; Area; Behavior; Behavior assessment; Behavioral; Bioreactors; Blood Vessels; Canis familiaris; Catabolism; Cell Communication; Cell physiology; Cells; Cellular biology; Cellularity; Chronic low back pain; Chymase; Client; Clinical Trials; Coculture Techniques; Communities; Cromolyn Sodium; Degenerative polyarthritis; Diffusion; Disease; Disease model; Economic Burden; Electrophysiology (science); FDA approved; Fibrosis; Functional disorder; GAG Gene; Generations; Goals; Health; Histology; Human; Hyperalgesia; Image; Immune; Immunologist; Immunomodulators; In Vitro; Inflammation; Inflammatory; Intervertebral disc structure; Knowledge; Lead; Low Back Pain; Magnetic Resonance Imaging; Mechanics; Mediating; Mediator of activation protein; Medical; Modeling; Musculoskeletal Diseases; Nature; Nerve; Neurons; Operative Surgical Procedures; Organ; PAR-2 Receptor; Pain; Pain Measurement; Pathogenesis; Pathologic; Pathologist; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Physiological; Posture; Proteoglycan; Publishing; Quality of life; Regulation; Research; Rheumatoid Arthritis; Rodent; Role; Sensory; Sepharose; Signal Transduction; Societies; Spinal Ganglia; Structure; Symptoms; Testing; Therapeutic; Therapeutic Effect; Translating; Tryptase; Validation; Vertebral column; Work; chronic pain; chronic pain patient; clinically relevant; disability; discogenic pain; high reward; high risk; immunomodulatory strategy; immunoregulation; improved; in vivo; inflammatory pain; innovation; interdisciplinary approach; intervertebral disk degeneration; mast cell; multidisciplinary; neuronal excitability; neurovascular; novel; novel therapeutics; nucleus pulposus; opioid epidemic; pain behavior; patient population; pre-clinical; screening; socioeconomics; ward

Project Summary/Abstract Chronic low back pain continues to exert a significant socio-economic burden on society as its contribution to the opioid crisis grows. This is because studies have failed to address the underlying mechanisms associated with pain generation. Intervertebral disc (IVD) degeneration is highly associated with low back pain (LBP), and neurovascular ingrowth into this usually avascular and aneural organ, has been identified in patients with chronic pain. However, the specific pathways propagating ingrowth and pain have yet to be identified. Mast cells regulate inflammation and pain in musculoskeletal diseases such as rheumatoid arthritis and osteoarthritis. Both our published and supportive work have demonstrated significantly increased levels of mast cell marker tryptase in the IVDs of human and canine patients with painful disc degeneration suggesting that mast cells function to enhance catabolism, inflammation and pain pathways in discogenic back pain. The overall goal of this proposal is to use clinically relevant and novel chondrodystrophic canine in vitro and in vivo animal models, to determine the role of mast cells and down-stream pathway protease-activated receptor 2 in LBP and how they can be modulated for therapeutic effect. This goal aligns well with high risk, high reward nature of the proposal as immune-modulation has never been applied to the IVD as a non-addictive strategy to treat LBP. Furthermore, the chondrodystrophic dog is currently under-utilized as an intermediate animal model of LBP despite its similarities to painful disc degeneration in humans and its relevance as a client-owned “patient” population; this is largely because robust validation of behavioral assessments of pain are lacking. Our studies aim to address this gap while catalyzing innovation and improving scientific knowledge in this area. The first specific aim uses a novel high-through Bioreactor to investigate how co-culture of canine mast cell-nucleus pulposus under dynamic physiological load regulates catabolism, inflammation and neurovascular ingrowth in painful disc degeneration. In addition, mechanistic inhibition studies will be conducted to determine efficacy of FDA-approved drug Cromolyn sodium and protease-activated rector 2 antagonist on these mast cell induced effects. The second specific aim involves deep phenotyping the chondrodystrophic dog model of painful disc degeneration using a comprehensive assessment of pain behaviors (hyperalgesia, activity, posture and neuronal excitability) in addition to IVD structure/functional changes using histology, mechanics and MRI followed by screening with immune-modulatory drugs. These studies are both significant and innovative because they combine a unique multi-disciplinary team of medical and veterinary clinicians, a spine biologist, a neuroscientist, veterinary immunologist and histo-pathologist, and a biostatistician to investigate the role of the unexplored mast cell in the pathophysiology of LBP and in vitro and in vivo chondrodystrophic dog models for LBP. The broader impact of this proposal involves a pathway to clinical trials in client-owned dogs with LBP.

项目概要/摘要 慢性腰痛继续对社会造成重大的社会经济负担，因为它对 这是因为研究未能解决相关的潜在机制。 椎间盘（IVD）退变与腰痛（LBP）高度相关，并且 已在患有以下疾病的患者中发现神经血管向这个通常无血管和神经的器官内生长 然而，肥大向内生长和疼痛的具体传播途径尚未确定。 细胞调节肌肉骨骼疾病（例如类风湿性关节炎）的炎症和疼痛 我们发表的和支持性的工作都表明骨关节炎的水平显着增加。 患有疼痛性椎间盘退变的人类和犬类患者 IVD 中肥大细胞标记物类胰蛋白酶提示 肥大细胞的功能是增强椎间盘源性背痛的分解代谢、炎症和疼痛途径。 该提案的总体目标是使用临床相关的新型软骨营养不良药物 犬体外和体内动物模型，以确定肥大细胞和下游的作用 LBP 中的途径蛋白酶激活受体 2 以及如何调节它们以达到治疗效果。 这一目标与该提案的高风险、高回报性质非常吻合，因为免疫调节从未被 应用于IVD作为治疗LBP的非成瘾策略此外，软骨营养不良的狗是。 尽管 LBP 与疼痛椎间盘相似，但目前尚未充分利用作为 LBP 的中间动物模型 人类的退化及其作为客户拥有的“患者”群体的相关性，这在很大程度上是因为强大； 我们的研究旨在在促进的同时解决这一差距。 创新和提高该领域的科学知识。 第一个具体目标使用新型高通量生物反应器来研究犬肥大的共培养 动态生理负荷下的细胞-髓核调节分解代谢、炎症和神经血管 此外，将进行机械抑制研究以确定疼痛性椎间盘退变的向内生长。 FDA 批准的药物色甘酸钠和蛋白酶激活的 Rector 2 拮抗剂对这些肥大细胞的功效 第二个具体目标涉及对软骨营养不良狗模型进行深度表型分析。 通过综合评估疼痛行为（痛觉过敏、活动、姿势 和神经元兴奋性）以及使用组织学、力学和 MRI 进行 IVD 结构/功能变化 随后用免疫调节药物进行筛选，这些研究既重要又具有创新性。 因为他们结合了独特的多学科团队，其中包括医学和兽医长辈、脊柱生物学家、 神经科学家、兽医免疫学家和组织病理学家以及生物统计学家来研究 未探索的肥大细胞在 LBP 的病理生理学以及体外和体内软骨营养不良狗模型中 该提案的更广泛影响涉及在客户拥有的患有 LBP 的狗中进行临床试验的途径。