AUTOCRINE AND PARACRINE OF HOMEOSTASIS OF THE INTERVERTEBRAL DISC

椎间盘稳态的自分泌和旁分泌

• 批准号: 7486864
• 负责人: Koichi Masuda
• 金额: $ 27.14万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486864
• 关键词: Animals; Back; Back Pain; Biological; Biological Models; Bos taurus; Cattle; Cell Nucleus; Cells; Collagen; Condition; Data; Development; Elderly; Environment; Enzymes; Equilibrium; Etiology; Funding; Future; Gene Expression; Growth Factor; Health Care Costs; Homeostasis; Human; Hypoxia; In Situ; In Vitro; Interleukin-1; Intervertebral disc structure; Low Back Pain; Maintenance; Metabolism; Metalloproteases; Patients; Physiological; Play; Production; Proteins; Proteoglycan; Reagent; Receptor Inhibition; Research Personnel; Role; Signal Transduction; Source; Specificity; Staging; System; Therapeutic; Therapeutic Agents; Tissue Engineering; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Wound Healing; age related; anakinra; autocrine; biglycan; bone morphogenetic protein 7; cytokine; feeding; growth differentiation factor 5; human TNF protein; human tissue; in vivo; in vivo Model; inhibitor/antagonist; intervertebral disk degeneration; paracrine; programs; receptor; repaired; response; socioeconomics

We have documented age-related and degeneration-related changes in the metabolism of collagens, proteoglycans, and matrix-degrading enzymes in the human intervertebral disc. Our studies (i) confirmed the pivotal roles that cytokines and growth factors play in intervertebral disc degeneration and repair, (ii) demonstrated that certain growth factors inhibit the autocrine production of cytokines and that cytokine inhibitors can change basal levels of synthesis of matrix molecules and metalloproteinases, and (iii) found that biglycan was expressed in greater amounts than other small proteoglycans during late stages of disc degeneration and in the discs of old donors and plays an important regulatory role in matrix homeostasis. Our data suggest that an intricate balance of growth factors, cytokines and regulatory molecules is important for the maintenance of tissue homeostasis. Over the next five years, we propose to investigate the mechanisms of action and the interplay between growth factors, cytokines and various regulatory molecules in order to determine their respective roles in tissue homeostasis and their potential use in promoting tissue repair. Hypothesis 1: The effects of growth factors on the intervertebral disc are regulated by the production of cytokines by intervertebral disc cells and by the presence of inhibitory factors; growth factors have a negative feed back on the production of these cytokines. Hypothesis 2: The regulatory mechanisms of matrix homeostasis by cytokines and growth factors vary at different stages of disc degeneration because of changes in the cellular microenvironment in situ within the disc. The response to cytokines and growth factors and the production and activation of matrix-degrading enzymes will be different at advanced stages of disc degeneration. Hypothesis 3: The inhibition of cytokine action by cytokine blockers and the inhibition of cytokine production by growth factors can delay or reverse the degenerative status of intervertebral disc cells in the cellular microenvironment that can be observed in the early and middle stages of disc degeneration. 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 and tissue engineering for intervertebral disc degeneration.

我们已经记录了胶原代谢中与年龄相关和与变性相关的变化， 蛋白聚糖和基质降解酶。我们的研究（i）证实了 细胞因子和生长因子在椎间盘退变和修复中发挥的关键作用，（ii） 表明某些生长因子抑制细胞因子的自分泌产生， 抑制剂可以改变基质分子和金属蛋白酶合成的基础水平，和（iii）发现 双糖蛋白聚糖在椎间盘的晚期表达量高于其他小的蛋白聚糖， 退变和老年供体的椎间盘中，并在基质稳态中起重要的调节作用。 我们的数据表明，生长因子、细胞因子和调节分子的复杂平衡是重要的 来维持组织的稳态在未来五年内，我们建议调查 作用机制以及生长因子、细胞因子和各种调节分子之间的相互作用 为了确定它们各自在组织内稳态中的作用以及它们在促进组织内稳态中的潜在用途， 修复.假设1：生长因子对椎间盘的影响是由生长因子的产生来调节的。 细胞因子的椎间盘细胞和抑制因子的存在;生长因子具有 对这些细胞因子的产生产生负反馈。假设2：监管机制 细胞因子和生长因子的基质稳态在椎间盘退变的不同阶段不同， 椎间盘内原位细胞微环境的变化。对细胞因子和生长的反应 在后期，基质降解酶的产生和活化将不同 椎间盘退变假设3：细胞因子阻断剂对细胞因子作用的抑制以及细胞因子对细胞因子作用的抑制。 通过生长因子产生的细胞因子的减少可以延缓或逆转椎间盘的退变状态 细胞微环境中的细胞，可以在椎间盘的早期和中期观察到 退化下背痛是造成人类巨大痛苦、高昂医疗费用和 重大社会经济损失。虽然背痛的病因往往是未知的，椎间 椎间盘是背部问题的重要来源。这项研究的结果将推动生物学领域的发展。 椎间盘退变的治疗和组织工程。