Mechanobiology of Inflammation in the Intervertebral Disc

椎间盘炎症的力学生物学

• 批准号: 10000833
• 负责人: NADEEN O. CHAHINE
• 金额: $ 41.36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000833
• 关键词: Acute; Adult; Affect; Back Pain; Binding; Biochemistry; Biological; Biological Process; Biomechanics; CXCR4 gene; Cells; Chemotactic Factors; Chronic; Clinical; Cytoskeletal Modeling; Cytoskeleton; Data; Disulfides; Etiology; Extracellular Matrix; Family; HMGB1 Protein; Histology; Human; Immune system; Inflammation; Inflammatory; Inflammatory Response; Injections; Injury; Intervertebral disc structure; Lipopolysaccharides; Location; Mechanics; Mediating; Modeling; Modulus; Molecular; Musculoskeletal System; Nuclear Protein; Operative Surgical Procedures; Oxidation-Reduction; Pain; Pattern; Permeability; Population; Post-Translational Protein Processing; Protein Isoforms; Puncture procedure; Rattus; Recovery; Research; Role; Severities; Signal Transduction; Stress; TLR2 gene; TLR4 gene; Therapeutic; Tissues; Toll-like receptors; Trauma; Vertebral column; cell type; cost; cytokine; disability; discogenic pain; extracellular; immune activation; in vivo; inhibitor/antagonist; intervertebral disk degeneration; macrophage; mechanical properties; mechanotransduction; member; nerve supply; novel therapeutics; nucleus pulposus; painful neuropathy; receptor; receptor binding; response; stem

Project Summary: Disability and pain stemming from degenerated intervertebral discs (IVD) affects over 40% of U.S adults and costs >$100 billion annually. The etiology of IVD degeneration (DD) is unknown. There is a significant clinical need for a better mechanistic understanding of DD, and for therapeutic approaches that directly treat the IVD, mitigate DD, and promote recovery of spine function. I nflammation is a key contributor to discogenic pain. High mobility group box 1 ( HMGB1) protein is a ubiquitous nuclear protein that is secreted extracellularly by stressed or dying cells. The biologic function of HMGB1 depends on its cellular location, redox state, and binding partners. Recent studies show that HMGB1 levels increase with DD severity, though the biologic function of HMGB1 in nucleus pulposus (NP) cells and its role in DD are largely unknown. The contributions of HMGB1 to NP cell mechanobiology are similarly unknown, and may be dually related to the pro-inflammatory potential of disulfide HMGB1 and to the chemotactic activity of fully reduced HMGB1. The objective of the proposed studies is to identify the redox dependent function of HMGB1 in DD. Our global hypothesis is that HMGB1 will trigger IVD pro-inflammatory signaling, promote ECM degradation and alter NP cell mechanobiology in a redox dependent manner. Aim 1 studies will quantify the biological and mechanotransduction function of redox isoforms of HMGB1 in human NP cells. We will also identify the specific binding receptors that mediate the pro-inflammatory and mechanobiological activity of HMGB1 isoforms in NP cells. Aim 2 studies will identify the contribution of HMGB1 as a central mediating damage associated molecular pattern (DAMP) in DD inflammation and mechanobiology from acute to chronic stages in vivo. These studies will provide mechanistic evidence about how redox isoforms of HMGB1 contribute to DD and mechanotransduction. Our findings may identify targets for mitigating DD initiation or progression. Since multiple HMGB1 isoforms have the potential to alter the cytoskeleton and thus mechanobiology of NP cells, we predict that our studies will identify strategies for mitigating alterations in IVD mechanotransduction, which are more extensive than regulating inflammatory signaling.

项目概要： 椎间盘退变 (IVD) 造成的残疾和疼痛影响着超过 40% 的美国人 成人每年花费超过 1000 亿美元。 IVD 变性 (DD) 的病因尚不清楚。有 临床上迫切需要更好地了解 DD 的机制以及治疗方法 直接治疗 IVD、减轻 DD 并促进脊柱功能恢复的方法。 我 炎症是椎间盘源性疼痛的关键因素。高机动性组箱1（ HMGB1) 蛋白质是 普遍存在的核蛋白，由应激或垂死细胞分泌到细胞外。生物制剂 HMGB1 的功能取决于其细胞位置、氧化还原状态和结合伙伴。最近的研究 表明 HMGB1 水平随 DD 严重程度而增加，尽管 HMGB1 在细胞核中的生物学功能 髓 (NP) 细胞及其在 DD 中的作用尚不清楚。 HMGB1对NP细胞的贡献 机械生物学同样是未知的，并且可能与促炎潜力双重相关 二硫键HMGB1并完全降低HMGB1的趋化活性。该计划的目标 拟议的研究旨在确定 DD 中 HMGB1 的氧化还原依赖性功能。我们的全球假设 HMGB1 会触发 IVD 促炎信号、促进 ECM 降解并改变 NP 以氧化还原依赖方式的细胞力学生物学。目标 1 研究将量化生物学和 人类 NP 细胞中 HMGB1 氧化还原亚型的机械转导功能。我们还将确定 介导促炎和机械生物学活性的特异性结合受体 NP 细胞中的 HMGB1 亚型。目标 2 研究将确定 HMGB1 作为核心的贡献 介导 DD 炎症和机械生物学中损伤相关分子模式 (DAMP) 在体内从急性阶段到慢性阶段。这些研究将提供关于如何 HMGB1 的氧化还原异构体有助于 DD 和机械转导。我们的研究结果可能会确定 缓解 DD 发生或进展的目标。由于多种 HMGB1 亚型具有潜力 为了改变 NP 细胞的细胞骨架和力学生物学，我们预测我们的研究将确定 减轻 IVD 机械转导改变的策略，其范围比 调节炎症信号传导。