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，通过穿刺环诱导的兔椎间盘退变模型 纤维组织的针具有固定的规格，导致可重复的、退行性的变化 定量评估。我们最初的假设是，注射生长因子成骨蛋白-1是 使用该模型证明能够再生椎间盘是正确的。这种很有希望的蛋白质 作为第一次注射疗法，注射疗法将很快转化为I期临床试验 使用一种生长因子。拟议资助期的方法是：(1)测试是否注入 在使用成年兔的临床相关模型中，将生长因子注入椎间盘也能刺激修复；(2) 扩大应用细胞因子抑制分子的治疗方法；以及(3)描述 在椎间盘内营养水平受损的情况下，这种治疗的局限性。此外, 将继续努力确定与神经相关的细胞因子，即神经生长因子在兔体内的变化 在模型和身体样本中，作为下腰痛的潜在替代标记。假设1：光盘 通过调节合成代谢和分解代谢之间的平衡，可以延缓或逆转退化。 一些手法可以减少与椎间盘退变相关的疼痛。具体而言 目的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 细胞因子分子(白介素1受体拮抗剂、肿瘤坏死因子-a可溶性受体)延缓 椎间盘退变的进展或使用体内蛋白注射修复退变的椎间盘 成熟兔慢性椎间盘退变模型。假设2：营养物质通过 终板限制了应用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 将研究兔腰椎间盘退变环形穿刺术模型中营养物质转运的变化。 确定是否存在有害于基质新陈代谢的营养物质转运的临界水平。腰背 疼痛造成了巨大的人类痛苦、高昂的医疗费用和巨大的社会经济 损失。虽然背部疼痛的病因通常不清楚，但椎间盘是腰痛的一个重要来源。 背部有问题。本研究的结果将推动生物治疗领域的发展。 椎间盘退变。