Mechanobiology of Inflammation in the Intervertebral Disc

项目总结： 退行性腰椎间盘(IVD)引起的残疾和疼痛影响着超过40%的美国人 成人和每年花费1000亿美元。IVD变性(DD)的病因尚不清楚。的确有 临床上需要更好地理解DD的机制，并进行治疗 直接治疗IVD，缓解DD，促进脊柱功能恢复的方法。 我 炎症是导致间盘源性疼痛的关键因素。高流动性组框1( HMGB1)是一种 无处不在的核蛋白，由应激或死亡的细胞外分泌。《生物学》 HMGB1的功能取决于其细胞位置、氧化还原状态和结合伙伴。最新研究 HMGB1在核内的生物学功能随DD严重程度的增加而升高 髓(NP)细胞及其在DD中的作用在很大程度上是未知的。HMGB1在NP细胞中的作用 机制生物学也同样未知，可能与血管紧张素转换酶的促炎潜能有关。 二硫键HMGB1和完全还原的HMGB1的趋化活性。该计划的目标是 建议的研究是确定HMGB1在DD中的氧化还原依赖功能。我们的全球假说 HMGB1将触发IVD促炎信号，促进ECM降解，改变NP 细胞机械生物学以氧化还原依赖的方式。目标1研究将量化生物学和 氧化还原亚型HMGB1在人NP细胞中的机械转导功能。我们还将确定 介导血管紧张素转换酶促炎症和机械生物学活性的特异性结合受体 HMGB1在NP细胞中的异构体。目标2研究将确定HMGB1作为一个中心的贡献 介导损伤相关分子模式(DAMP)在DD炎症和机械生物学中的作用 在体内从急性阶段到慢性阶段。这些研究将提供机械证据，说明 HMGB1的氧化还原异构体参与DD和机械转导。我们的发现可能会确定 缓解DD启动或进展的目标。由于多种HMGB1亚型具有潜在的 为了改变NP细胞的细胞骨架从而改变机械生物学，我们预测我们的研究将确定 减轻IVD机械转导中的改变的策略，这些改变比 调节炎症信号。

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.