Role of Vitamin C in Low back Pain and Intervertebral Disc Degeneration

维生素 C 在腰痛和椎间盘退变中的作用

• 批准号: 10741198
• 负责人: LAURA S STONE
• 金额: $ 42.12万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741198
• 关键词: Address; Analgesics; Anxiety; Ascorbic Acid; Attenuated; Azacitidine; Back Pain; Behavioral; Biological; Chronic low back pain; Clinic; Clinical; Collagen; Consumption; DNA Methylation; DNA Methylation Regulation; Data; Data Correlations; Disease; Down-Regulation; Elderly; Epigenetic Process; Exercise; Exhibits; Extracellular Matrix; Gene Expression; Genes; Goals; Health; Health Care Rationing; Histology; Human; Individual; Intervertebral disc structure; Low Back Pain; Magnetic Resonance Imaging; Measures; Mental Depression; Methylation; Monitor; Mus; Musculoskeletal; Musculoskeletal Pain; Neck; Operative Surgical Procedures; Organ Culture Techniques; Outcome; Pain; Pathology; Patients; Play; Pre-Clinical Model; Prevalence; Prevention; Production; Property; Proteoglycan; Quality of life; Risk; Rodent; Role; Running; Serum; Severities; Spinal Injections; Supplementation; Surgical complication; Testing; Therapeutic; Therapeutic Effect; Therapeutic exercise; Toxic effect; Translating; Treatment Efficacy; Vertebral column; Water; Work; age related; cancer therapy; chronic back pain; demethylation; dietary; dietary supplements; disability; effective therapy; efficacy evaluation; functional improvement; genome wide methylation; health care service utilization; health economics; improved; improved outcome; intervertebral disk degeneration; leukemia treatment; mRNA Expression; mouse model; opioid misuse; opioid overdose; pharmacologic; pre-clinical; prescription opioid; programs; promoter; prophylactic; protein expression; pyrosequencing; response; side effect; symptomatic improvement; therapy outcome

PROJECT SUMMARY / ABSTRACT Persistent back pain is a leading cause of disability worldwide and one of the most common reasons pa- tients are prescribed opioids, despite their poor ability to improve function. Chronic back pain threatens our economic health due to high rates of health care utilization and disability and our quality of life due to pain-related suffering, pain-associated opioid misuse, depression, and anxiety. The primary driver in 40% of all low back pain (LBP) cases is estimated to be pain from intervertebral disc (IVD) degeneration. Ex- isting symptomatic (e.g., analgesics) or invasive (e.g., spinal injections, surgery) treatments have limited efficacy and are associated with risk for opioid misuse or surgical complications, respectively. There is an urgent need for safe and effective treatments for chronic LBP that can be rapidly translated to the clinic. Disc degeneration is associated with decreased production of extracellular matrix (ECM) components including collagen and proteoglycans. DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified in response to local, environmental, or pharmacological factors. We have previously shown that a non-invasive treatment (running exercise) attenuates behavioral signs of chronic LBP, increases IVD collagen production, and decreases IVD global methylation. Ascorbic acid (vitamin C) is essential for collagen production and is involved in the regulation of DNA methylation. Ascorbic acid is safe for daily consumption and its deficiency is correlated with musculoskeletal pain in elderly. Although ascorbic acid exhibits analgesic properties in some conditions and is essential for colla- gen synthesis and musculoskeletal health, its therapeutic potential for LBP has not been studied. The overall objective for this application is to determine the therapeutic outcomes of ascorbic acid treat- ment in discogenic LBP and IVD degeneration using a pre-clinical model of progressive IVD degenera- tion associated with LBP. Our central hypothesis is that ascorbic acid reprograms expression of ECM genes by decreasing DNA methylation in degenerated IVDs, thereby attenuating discogenic LBP. In Spe- cific Aim 1, we will examine the therapeutic efficacy of long-term ascorbic acid supplementation (4 months) on the prevention and treatment of LBP and disc degeneration using a mouse model. In Specific Aim 2, we will determine the effects of vitamin C on DNA methylation and mRNA expression of ECM genes, with emphasis on collagens and proteoglycans, and will correlate these data to disc pathology and behavioral signs of LBP. The expected outcomes are that we will observe therapeutic effects of ascorbic acid on LBP and IVD degeneration (Aim 1) associated with reprogramming of IVD DNA methyl- ation (Aim 2). These results will provide critical proof-of-concept data for using noninvasive, safe, dietary vitamin C supplementation as a treatment for discogenic LBP.

项目概要/摘要 持续性背痛是全世界残疾的主要原因，也是最常见的原因之一。 尽管阿片类药物改善功能的能力较差，但仍给患者开了阿片类药物。慢性背痛威胁 由于医疗保健利用率高和残疾率高，我们的经济健康；由于医疗保健利用率高，我们的生活质量高 与疼痛相关的痛苦、与疼痛相关的阿片类药物滥用、抑郁和焦虑。 40% 的主要驱动力 据估计，所有腰痛 (LBP) 病例中的疼痛是由椎间盘 (IVD) 退变引起的。前任- 目前的对症治疗（例如镇痛药）或侵入性治疗（例如脊髓注射、手术）治疗效果有限 疗效和分别与阿片类药物滥用或手术并发症的风险相关。有一个 迫切需要能够快速转化为临床的慢性腰痛的安全有效的治疗方法。 椎间盘退变与细胞外基质 (ECM) 成分的产生减少有关 包括胶原蛋白和蛋白聚糖。 DNA甲基化是调节基因的表观遗传机制 表达，并且可以根据局部、环境或药理因素进行修改。我们 之前已经表明，非侵入性治疗（跑步锻炼）可以减轻行为症状 慢性 LBP，增加 IVD 胶原蛋白的产生，并降低 IVD 整体甲基化。抗坏血酸 （维生素 C）对于胶原蛋白的生成至关重要，并参与 DNA 甲基化的调节。 抗坏血酸日常食用是安全的，其缺乏与肌肉骨骼疼痛有关 老年。尽管抗坏血酸在某些情况下表现出镇痛特性，并且对于胶原蛋白来说是必需的。 基因合成和肌肉骨骼健康，其治疗腰痛的潜力尚未被研究。 本申请的总体目标是确定抗坏血酸治疗的治疗结果 使用进行性 IVD 变性的临床前模型来治疗椎间盘源性 LBP 和 IVD 变性 与 LBP 相关的灰化。我们的中心假设是抗坏血酸重新编程 ECM 的表达 通过减少退化 IVD 中的 DNA 甲基化，从而减弱椎间盘基因 LBP。在斯佩- 具体目标1，我们将检查长期补充抗坏血酸的治疗效果（4 月）使用小鼠模型预防和治疗 LBP 和椎间盘退变。具体来说 目标2，我们将确定维生素C对ECM DNA甲基化和mRNA表达的影响 基因，重点是胶原蛋白和蛋白聚糖，并将这些数据与椎间盘病理学相关联 和 LBP 的行为体征。预期结果是我们将观察治疗效果 抗坏血酸对与 IVD DNA 甲基重编程相关的 LBP 和 IVD 变性（目标 1） 化（目标 2）。这些结果将为使用无创、安全、饮食疗法提供关键的概念验证数据。 补充维生素 C 作为椎间盘源性 LBP 的治疗方法。