Circadian rhythms in the ageing spine: implications in intervertebral disc degeneration and stem-cell based regeneration

Low back pain is amongst the most prevalent spinal diseases, causing severe pain and loss of mobility. Progressive degeneration of the intervertebral disc (IVD) tissue is a major cause, with ageing as a major risk factor. Stem cell-based therapies provide hope for tissue regeneration of the IVD and restoration of function. The Hoyland and Meng labs have r shown, for the first time, an autonomous circadian (24 hourly) rhythm in mouse IVD tissue explants and human IVD cells (Dudek et al., Annals Rheum Dis 2016). We have generated a conditional BMAL1 (a core clock factor) knockout mouse model that selectively disrupts circadian rhythm in the IVD, and a BMAL1-Venus knock-in mouse model using CRISPR-CAS technique (Yang et al., PLoS Gen 2020). These exciting novel discoveries and animal models place us in a unique position internationally and provide an unprecedented new opportunity to further our understanding of the pathogenesis of IVD degeneration and low back pain. We therefore hypothesize that disruption to the circadian clock (for example, during ageing) may be a critical risk factor in human disc degeneration. Consequently, enhancing circadian rhythms may slow down tissue degeneration and promote stem-cell based regenerative therapies.

In this PhD project, we will utilize state of the art "-omics" techniques (RNAseq deep sequencing), bio-informatics, high-end imaging, biochemistry and monitoring of clock gene activities, to elucidate roles of circadian rhythm in human disc degeneration and cell-based therapy for treatment of disc degeneration. This project will provide fresh new insights into the function of a core circadian clock factor BMAL1 in IVD physiology and pathogenesis and establish a mechanistic link between ageing and IVD circadian rhythm disruption. More importantly, the project will directly demonstrate the relevance of circadian clocks in human degenerative discs and mesenchymal stem-cell differentiation protocols being currently developed for cell based regenerative strategies for the treatment of disc degeneration and low back pain.