Epigenetic Drivers of Chronic Low Back Pain

PROJECT SUMMARY / ABSTRACT Chronic Low Back Pain (LBP) is a leading cause of disability worldwide and one of the most common reasons patients are prescribed opioids, despite their poor ability to improve function. LBP threatens our economic health due to high rates of health care utilization and disability, our security due to high rates of

medical discharge from armed services, and our quality of life due to pain-related suffering, pain-associ- ated opioid misuse, depression, and anxiety. The primary driver in 40% of all LBP cases is estimated to be pain resulting from intervertebral disc (IVD) degeneration, referred to as discogenic LBP. Improved

understanding of this degenerative process is needed to address this global problem. Epigenetic mecha- nisms, such as DNA methylation, dynamically regulate gene expression in response to local, systemic and environmental influences. However, very little is known about the role of DNA methylation in dis-

cogenic LBP. This application will address this knowledge gap by determining the role of DNA methyla- tion in the pathological expression of genes involved in IVD degeneration and discogenic LBP. Our central hypothesis is that widespread and persistent reprogramming of gene expression by DNA methylation drives IVD degeneration and can be targeted for the treatment of discogenic LBP. Since

DNA methylation is potentially a mechanism underlying the chronicity of pain, elucidation of the role of DNA methylation in IVD degeneration is likely to provide a strong scientific framework for innovative new treatment approaches for discogenic LBP. In Aim 1 we will identify the DNA methylation and gene ex-

pression landscape of IVD degeneration and discogenic LBP in humans. In Aim 2, we will identify the DNA methylation and gene expression landscape of IVD degeneration and discogenic LBP in animal models and delineate correlated DNA methylation and gene expression profiles. In Aim 3, we will explore the role of DNA methylation on IVD degeneration and discogenic LBP in animal models by manipulating

methylation using non-pharmacological (home cage voluntary running wheels) and pharmacological in- terventions. These results will be significant because scientific evidence of a role for epigenetic reprogramming in IVD degeneration and discogenic LBP may contribute to a paradigm shift in understanding, prevention, and

treatment of chronic LBP.