Stressful life events confer risk for chronic posttraumatic musculoskeletal pain through DNA methylation changes at the POMC promoter - Project Summary/Abstract Chronic musculoskeletal pain is a persistent, debilitating condition with high societal costs. Traumatic stress exposures (TSE) often precede the onset of chronic pain, and affect >90% of individuals in their lifetime. While repeated incidents of acute physical injury can lead to chronic pain, many individuals without serious physical injury report enduring musculoskeletal pain following TSE, termed chronic post-traumatic pain (CPTP). Despite high rates of CPTP, risk factors and mechanisms driving CPTP are poorly understood, impeding the development of promising therapeutic strategies to prevent or treat CPTP. To address this knowledge gap, I will perform a series of studies aimed at elucidating biopsychosocial mechanisms underlying the transition from acute pain following TSE to CPTP. Specifically, I will examine how one particularly influential epigenetic mediator type, DNA methylation, influences CPTP development by building on my recently published data showing that increased DNA methylation levels in the pro-opiomelanocortin (POMC) gene predict CPTP development. Through a series of mentored, didactic, and experiential trainings in statistical analysis of large longitudinal datasets, molecular and cell culture studies, and translational research design, I will be well positioned to accomplish two main study aims. One aim will examine whether stressful life events experienced prior to TSE increase POMC promoter methylation levels that prime individuals for CPTP persistence, and the mechanism by which this occurs. The other aim will assess whether increased POMC methylation levels influence downstream gene expression and function, and ultimately CPTP severity. Aims will be accomplished using complementary human cohort and molecular and cell culture studies. Overall, this F31 training award will provide me with a strong foundation in the skills needed to build a successful independent academic research career focused on identifying biopsychosocial mediators of complex human disorders such as CPTP, and the proposed studies have the potential to identify novel therapeutic targets for the prevention of CPTP.
