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: 7223265
• 负责人: Koichi Masuda
• 金额: $ 27.96万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7223265
• 关键词: autocrine; cytokine; growth factor; homeostasis; intervertebral disk; paracrine

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蛋白代谢中与年龄相关和退化相关的变化， 人类椎间盘中的蛋白多糖和基质降解酶。我们的研究(I)证实了 细胞因子和生长因子在椎间盘退变修复中的关键作用(II) 证明某些生长因子抑制细胞因子的自分泌，而细胞因子 抑制剂可以改变基质分子和金属蛋白酶合成的基础水平，以及(Iii)发现 在椎间盘的晚期阶段，该二聚糖比其他小分子蛋白多糖的表达量更大。 在老年供者的盘中和退行性变中，并在基质稳态中起着重要的调节作用。 我们的数据表明，生长因子、细胞因子和调节分子之间错综复杂的平衡很重要。 用来维持组织的动态平衡。在未来五年，我们建议调查 生长因子、细胞因子和多种调控分子的作用机制及相互作用 为了确定它们在组织动态平衡中各自作用以及它们在促进组织中的潜在用途 修理。假说1：生长因子对椎间盘的影响是由生产调节的 通过椎间盘细胞和抑制因子的存在；生长因子具有 负反馈作用于这些细胞因子的产生。假设2：调节机制 细胞因子和生长因子所致的基质动态平衡在椎间盘退变的不同阶段有所不同 间盘内原位细胞微环境的变化。对细胞因子和生长的反应 在晚期，基质降解酶的产生和激活的因素和活性将有所不同。 椎间盘退变的可能性。假设3：细胞因子阻滞剂对细胞因子作用的抑制及其抑制作用 生长因子产生的细胞因子可以延缓或逆转椎间盘的退变状态 在椎间盘早期和中期可观察到的细胞微环境中的细胞 退化。腰痛给人类带来了巨大的痛苦，高昂的医疗费用和 造成重大社会经济损失。虽然背部疼痛的病因通常不清楚，但椎间 椎间盘是背部问题的一个重要来源。这项研究的结果将推动生物学领域的发展。 腰椎间盘退变的治疗和组织工程学。