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

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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.