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: 8131120
• 负责人: Howard S An
• 金额: $ 29.41万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8131120
• 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; 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，这是由穿刺环诱导， 用规定规格的针进行纤维化，导致可重复的退行性变化， 定量评估。我们最初的假设是，注射生长因子，成骨蛋白-1， 能够再生椎间盘被证明是真实的使用这个模型。这种有前途的蛋白质 注射治疗方法将很快转化为第一次注射治疗的I期临床试验 使用生长因子。拟议供资期内的方法是：（1）测试是否注入 生长因子注入椎间盘也能刺激成年兔临床相关模型的修复;（2） 将治疗方法扩展到细胞因子抑制分子的应用;和（3）描绘 在椎间盘营养水平受到损害的情况下，这种治疗的局限性。此外，本发明还提供了一种方法， 将努力扩大到确定神经相关细胞因子，即神经生长因子，在兔中的变化 模型和尸体样本，作为潜在的替代标记物的腰痛。假设1：椎间盘 通过控制合成代谢和分解代谢之间的平衡， 一些手法将导致减少与椎间盘退变相关的疼痛。在特定 目的1，我们将测试是否生长因子（成骨蛋白-1，生长分化因子-5）和/或抑制因子（成骨蛋白-1，生长分化因子-5）， 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：营养物质通过 终板限制了由应用生长因子诱导的细胞介导的椎间盘修复。具体目标2 将研究兔椎间盘退变环形穿刺模型中营养转运的变化， 确定是否存在对基质代谢有害的营养物质转运的临界水平。腰背 疼痛是造成巨大人类痛苦、高医疗保健成本和重大社会经济影响的原因。 损失虽然背痛的病因往往是未知的，椎间盘是一个重要的来源， 背部问题。本研究的结果将推动椎间融合器生物治疗领域的发展。 椎间盘退变