Phenotypes of pathologic vertebral endplate degeneration

病理性椎体终板退变的表型

• 批准号: 10021158
• 负责人: JEFFREY C. LOTZ
• 金额: $ 66.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021158
• 关键词: Address; Anaerobic Bacteria; Animal Model; Animals; Architecture; Astronauts; Back; Back Pain; Bacteria; Biological; Biological Assay; Bone Marrow; Catabolic Process; Cells; Characteristics; Chemistry; Chronic Care; Chronic low back pain; Clinical; Data; Diagnostic; Edema; Enrollment; Etiology; Female; Fluoroscopy; Funding; Future; Goals; Harvest; Histology; Human; Image; Imaging Device; Infection; Inflammation; Inflammatory; Inflammatory Response; Informed Consent; Injections; Injury; Intervertebral disc structure; Ischemia; Lesion; Link; Longitudinal Studies; Lordosis; Low Back Pain; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mechanics; Methods; Modeling; Morbidity - disease rate; Motion; Muscle; Muscular Atrophy; Musculoskeletal; Natural History; Operative Surgical Procedures; Pain; Pathologic; Pathology; Patient Care; Patient Recruitments; Patients; Phenotype; Population; Posture; Prevention strategy; Propionibacterium acnes; Protocols documentation; Questionnaires; Rattus; Reporting; Research; Research Personnel; Resolution; Role; Saline; Scanning; Seeds; Series; Severities; Site; Source; Spinal; Sprague-Dawley Rats; Sterility; Stimulus; Structure; Symptoms; Tail; Testing; Time; United States National Aeronautics and Space Administration; Vertebral Bone; Vertebral column; Work; base; clinically relevant; cohort; cost; cytokine; disability; experience; healing; imaging biomarker; improved; improved outcome; in vivo; insight; nucleus pulposus; pain patient; recruit; spine bone structure; tool; working group

Chronic low back pain (CLBP) is a significant cause of morbidity and societal expense. The intervertebral disc is thought to be a primary pain source, but mechanisms by which discs degenerate and hurt are poorly understood. Historical data suggest that the endplate can be a significant source of pain in some ‘discogenic’ patients due to pathological crosstalk between discs and adjacent vertebra. Further, our studies with NASA astronauts indicate that pathologic crosstalk is exacerbated by paraspinal muscle atrophy that alters spinal mechanics and endplate loading. Over the past funding period, we focused our efforts on developing new evidence for disc pain mechanisms, and based on these, advanced imaging tools that are sensitive and specific for low back pathology. We established imaging biomarkers for key aspects of pathologic crosstalk: 1) endplate damage (UTE MRI); bone marrow edema and paraspinal muscle atrophy (IDEAL MRI); and disc chemistry/infection (MRS). We also investigated cellular mechanisms by which crosstalk triggers vertebral bone marrow lesions (Modic changes; MC) that our data indicate are a common pain generator in CLBP patients. To further clarify the mechanisms and clinical relevance of endplate damage and MC, we now propose to characterize MC natural history in relation to etiology (inflammation versus infection) in an animals and humans. We will use our established imaging biomarkers to link architectural and biological data from MC induced in rats, to pain severity in association with MC progression and paraspinal muscle atrophy in humans. We will test the hypothesis that imaging biomarkers of endplate damage, disc chemistry, and muscle atrophy forecast MC progression and symptom severity. Three aims are proposed. In Aim 1 we will characterize MC mechanisms and natural history in relation to etiology (inflammation or infection) using a rat-tail model. In Aim 2 we will conduct a longitudinal study of CLBP patients to test the hypothesis that MC severity and progression is proportional to the extent of endplate damage (which facilitates crosstalk), and the presence of an adjacent ‘Modic disc’, where ischemia drives the expression of inflammatory cytokines and pain-related factors (ischemic, sterile inflammation), or where inflammatory factors are upregulated by Propionibacteria acnes (infectious inflammation). In Aim 3 we will investigate the role paraspinal muscle atrophy toward exacerbating endplate damage, MC, and patient symptoms via altered segmental alignment (lordosis) and intersegmental mechanics (dynamic motion). Overall, we hypothesize that MC and symptom natural history will vary depending on both disc and paraspinal muscle condition - MC due to a sterile inflammation will resolve over time when paraspinal muscle quality is good. Alternatively, MC due to an infections stimulus will progress (since the underlying infection is ongoing). Through this work, we will validate an imaging suite that researchers can use to study the spine pathologies in clinical cohorts, and clinicians can use to localize pain generators, predict the future course of symptoms, and improve care of CLBP patients.

慢性下腰痛（CLBP）是一个重要的原因，发病率和社会费用。椎间盘是 被认为是主要的疼痛来源，但椎间盘退化和受伤的机制知之甚少。 历史数据表明，终板可能是一些“椎间盘源性”患者疼痛的重要来源， 椎间盘和相邻椎骨之间的病理性串扰。此外，我们对NASA宇航员的研究表明， 椎旁肌萎缩改变了脊柱力学和终板， 加载中在过去的资助期间，我们集中精力开发椎间盘疼痛的新证据 机制，并基于这些，先进的成像工具，是敏感和具体的下背部病理。 我们建立了病理性串扰关键方面的影像学生物标志物：1）终板损伤（UTE MRI）; 骨髓水肿和椎旁肌肉萎缩（IDEAL MRI）;和椎间盘化学/感染（MRS）。我们也 研究串扰触发脊椎骨髓病变的细胞机制（Modic变化; MC），我们的数据表明是CLBP患者中常见的疼痛发生器。进一步澄清机制 以及终板损伤和MC的临床相关性，我们现在建议描述MC的自然史， 病因学（炎症与感染）在动物和人类。我们会用现有的成像技术 生物标志物，以将大鼠中诱导的MC的结构和生物学数据与 人类MC进展和椎旁肌萎缩。我们将检验成像生物标志物 终板损伤、椎间盘化学和肌肉萎缩预测MC进展和症状严重程度。 提出了三个目标。在目标1中，我们将描述MC机制和自然历史， 病因学（炎症或感染）使用鼠尾模型。在目标2中，我们将对CLBP进行纵向研究 患者来检验MC严重程度和进展与终板损伤程度成正比的假设 （这有助于串扰），以及相邻的“Modic盘”的存在，其中缺血驱动表达 炎性细胞因子和疼痛相关因素（缺血性，无菌性炎症），或炎性因素 受痤疮丙酸杆菌（感染性炎症）上调。在目标3中，我们将研究 椎旁肌萎缩通过改变而加剧终板损伤、MC和患者症状 节段对齐（脊柱前凸）和节段间力学（动态运动）。总的来说，我们假设 MC和症状自然史将根据椎间盘和椎旁肌肉状况而变化- MC是由于 当脊柱旁肌肉质量良好时，无菌性炎症将随着时间的推移而消退。或者，MC由于 感染刺激将进展（因为潜在的感染正在进行）。通过这项工作，我们将验证 一个成像套件，研究人员可以使用它来研究临床队列中的脊柱病理，临床医生可以 用于定位疼痛发生器，预测症状的未来进程，并改善CLBP患者的护理。