BIOLOGICAL TREATMENT STRATEGIES FOR GROWTH FACTORS AND CYTOKINES INHIBITORS

生长因子和细胞因子抑制剂的生物治疗策略

• 批准号: 7915747
• 负责人: Howard S An
• 金额: $ 30.82万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915747
• 关键词: 2 year old; Address; Adolescent; Adult; Age; Animal Model; Back; Back Pain; Biochemical; Biological; Biomechanics; Cell Survival; Cells; Chondroitin ABC Lyase; Chronic; Clinical; Equilibrium; Etiology; Exhibits; Funding; Growth Factor; Health Care Costs; Human; Human Pathology; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-1; Intervertebral Disk Chemolysis; Intervertebral disc structure; Low Back Pain; Measures; Mediating; Metabolic; Metabolism; Modeling; Natural regeneration; Needles; Nerve; Nerve Growth Factors; Nutrient; Nutritional; Nutritional status; Oryctolagus cuniculus; Pain; Pathway interactions; Phase I Clinical Trials; Program Research Project Grants; Proteins; Puncture procedure; Research; Research Personnel; Sampling; Source; Staging; Structure; Surrogate Markers; System; Testing; Therapeutic; Translating; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; anakinra; bone morphogenetic protein 7; clinically relevant; cytokine; disc regeneration; growth differentiation factor 5; in vivo; inhibitor/antagonist; intervertebral disk degeneration; mature animal; nucleus pulposus; nutrition; programs; receptor; repaired; socioeconomics; solute; treatment strategy

We have shown that the rabbit disc degeneration model, which is induced by puncturing the annulus fibrosus with needles of defined gauges, resulted in reproducible, degenerative changes that could be quantitatively assessed. Our initial hypothesis that an injection of the growth factor, osteogenic protein-1, is able to regenerate the intervertebral disc was shown to be true using this model. This promising protein injection therapy approach will soon be translated into a Phase I clinical trial as the first injection therapy using a growth factor. The approaches in the proposed funding period are to: (1) test if the injection of a growth factor into a disc also stimulates repair in a more clinically relevant model using adult rabbits; (2) expand therapeutic approaches to the application of cytokine inhibitory molecules; and (3) delineate the limitations of such therapy under conditions where nutrition levels in the disc are compromised. In addition, efforts will be extended to identify changes in nerve-related cytokines, i.e. nerve growth factor, in the rabbit model and in cadaveric samples, as potential surrogate markers of low back pain. Hypothesis 1: Disc degeneration can be delayed or reversed by manipulating the balance between anabolic and catabolic pathways; some manipulations will result in decreased pain associated with disc degeneration. In Specific Aim 1, we will test if growth factors (osteogenic protein-1, growth differentiation factor-5) and/or inhibitory molecules of cytokines (interleukin-1 receptor antagonist, tumor necrosis factor-a soluble receptor) delay the progression of disc degeneration or restore the degenerated disc using an in vivo protein injection in a mature rabbit chronic disc degeneration model. Hypothesis 2: Compromised nutrient transport through the endplate limits cell-mediated disc repair induced by the application of a growth factor. In Specific Aim 2 we will investigate changes in nutrient transport in the rabbit annular puncture model of disc degeneration and identify the presence of a critical level of nutrient transport that is deleterious to matrix metabolism. Low back pain is responsible for enormous human suffering, high health care costs and significant socioeconomic losses. Although the etiology of back pain is often unknown, the intervertebral disc is a significant source of back problems. The results from this study will advance the field of biological treatment for intervertebral disc degeneration.

我们已经证明兔椎间盘退变模型是通过穿刺纤维环诱导的 用规定规格的针刺入纤维组织，导致可重复的退行性变化 进行了定量评估。我们最初的假设是注射生长因子、成骨蛋白-1 使用该模型证明能够再生椎间盘是正确的。这种有前途的蛋白质 注射疗法很快将转化为I期临床试验，作为第一种注射疗法 使用生长因子。建议资助期内的方法是： (1) 测试是否注入 在使用成年兔的更具临床相关性的模型中，将生长因子注入椎间盘中也可以刺激修复； (2) 扩大细胞因子抑制分子应用的治疗方法； (3) 划定 在椎间盘营养水平受损的情况下，这种疗法的局限性。此外， 将进一步努力确定兔子神经相关细胞因子（即神经生长因子）的变化 模型和尸体样本中，作为腰痛的潜在替代标志物。假设1：光盘 通过操纵合成代谢和分解代谢之间的平衡可以延迟或逆转退化 途径；一些操作会减轻与椎间盘退变相关的疼痛。具体来说 目标 1，我们将测试生长因子（成骨蛋白-1、生长分化因子-5）和/或抑制性 细胞因子分子（白细胞介素-1受体拮抗剂、肿瘤坏死因子-a可溶性受体）延迟 椎间盘退变的进展或使用体内蛋白质注射恢复退变的椎间盘 成熟兔慢性椎间盘退变模型。假设 2：通过营养物质运输受损 终板限制了生长因子诱导的细胞介导的椎间盘修复。在具体目标 2 中，我们 将研究兔椎间盘退变环形穿刺模型中营养物质运输的变化和 确定对基质代谢有害的营养物质运输的临界水平的存在。低背 疼痛造成巨大的人类痛苦、高昂的医疗费用和重大的社会经济影响 损失。尽管背痛的病因通常未知，但椎间盘是背痛的重要来源。 背部问题。这项研究的结果将推动椎间孔生物治疗领域的发展 椎间盘退变。