Developing temperature and osmolarity based therapeutic approaches to modulate circadian rhythm in degenerative intervertebral disc and promote repair

下背痛（LBP）是由脊柱中称为椎间盘的软组织变性引起的，是最常见的脊柱疾病之一。它影响着全世界数百万人，造成严重的疼痛和行动能力丧失，目前没有长期的治愈方法。老龄化是一个主要的风险因素。然而，我们并不完全理解为什么年龄增加椎间盘退变和LBP的易感性。生物钟负责在行为和生理上产生24小时（昼夜）节律。老龄化或轮班工作造成的节律紊乱会显著增加疾病风险。至关重要的是，我们的团队首次在椎间盘中发现了一个功能性生物钟。这种外周生物钟随着年龄的增长而减弱，其破坏导致椎间盘退变的组织损伤特征，例如软组织内的骨样变化。该项目将确定生物钟中断如何导致椎间盘退变和椎间盘骨样变化。我们还将探索使用药物或温度靶向生物钟的治疗潜力，以恢复组织功能并促进修复。具体来说，我们将使用我们的新型椎间盘“无时钟”小鼠模型、椎间盘外植体培养物和患者样本来解决以下具体问题：1）24小时节律失调如何导致椎间盘中的骨样变化，我们能否通过身体时钟作用药物调节这一过程？2），我们能否利用周期性的热脉冲来提高脊柱的日常节奏，作为一种新的手段来增强组织修复？3）渗透压循环如何影响IVD的昼夜节律，我们能否使用药理学化合物作为模拟物来调节IVD的昼夜节律？这项研究建立在我们最近由MRC资助的新发现的基础上，具有很大的潜力来确定新的腰痛治疗策略，因此具有改善健康和生活质量的巨大潜力。此外，我们的研究结果强调了通过健康的生活方式保持强健的生物钟的重要性，这将对老龄化人口的健康和福祉产生长期的影响。这一点尤其重要，因为人口老龄化和我们现代24/7社会不断增长的需求经常扰乱我们的生物钟，这会显着增加许多疾病的风险，包括腰痛。

Low back pain (LBP), caused by degeneration of the soft tissue called intervertebral disc in the spine, is amongst the most prevalent spinal diseases. It affects millions of individuals worldwide, causing severe pain and loss of mobility, with currently no long-term cure. Ageing is a major risk factor. However, we do not fully understand why age increases susceptibility to disc degeneration and LBP. Body clocks are responsible for generating 24 hour (circadian) rhythms in behaviour and physiology. Rhythm disruptions by ageing or shift work can significantly increase disease risks. Crucially, our group, for the first time, have discovered a functional body clock in the intervertebral disc. This peripheral body clock weakens with age and its disruption leads to tissue damage characteristic of disc degeneration, such as bone-like changes within the soft tissue. This project will establish how body clock disruption leads to disc degeneration and bone-like changes in the spinal disc. We will also explore the therapeutic potential of targeting the body clocks using drugs or temperature in order to restore tissue function and promote repair. Specifically, we will use our novel disc "clockless" mouse model, intervertebral disc explant culture and patient samples to address the following specific questions: 1), How dysregulation of the 24 hour rhythm leads to bone-like changes in the spinal disc and can we modulate this process by body clock-acting drugs? 2), Can we utilise periodic heat pulses to boost the daily rhythm in the spine as a new means to enhance tissue repair? 3), How the osmolarity cycle entrains the IVD circadian rhythm and can we use pharmacological compounds as mimetics to modulate circadian rhythms in the IVD? This research builds on our recent MRC-funded novel discoveries and holds strong potential to identify new therapeutic strategies for low back pain and therefore has an enormous potential for improving health and quality of life. Moreover, our findings emphasize the importance of maintaining robust body clocks through healthy life styles, which will have a long lasting impact on the health and well-being of the ageing population. This is particularly important because the greying of the population and the ever-increasing demands of our modern 24/7 society frequently disrupt our body clocks which can significantly increase risk of many diseases, including low back pain.