Back to the Beginning: Understanding mechanisms regulating human intervertebral disc development and their dysregulation in degenerative disease using an integrated multi-omic approach

Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain and disability, impacting millions of people worldwide. The IVD is made up of a central nucleus pulposus (NP) surrounded by an annulus fibrosus and is essential for flexibility and movement. During development, the NP is populated by notochordal cells, and these are replaced by chondrocyte cells by adolescence. Loss of notochordal cells coincides with the onset of degeneration, suggesting that early signals are essential for disc homeostasis. While most research focuses on end-stage degeneration, early events driving the onset of disease in humans remain poorly understood. As a result, current therapies lack long-term efficacy, and we need better treatments for disc degeneration. Preliminary transcriptomic data revealed that specific genes are upregulated during development, repressed in maturation and reactivated during degeneration, suggesting a dysregulation of developmental mechanisms. SPP1 (secreted phosphoprotein-1) is one such gene and has been selected as a candidate for analysis. This proposal aims to elucidate the function and mechanisms regulating SPP1 in human IVD development and how dysregulation contributes to degeneration. I will apply an integrated workflow combining long-read sequencing, ATAC-sequencing, proteomics, bioinformatics, gene-editing and biofabrication to define these mechanisms, revealing potential targets for regeneration.