Exploration of MBD1 as a therapeutic target for chronic pain

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PROJECT SUMMARY / ABSTRACT Chronic pain is accompanied with long-term sensory, affective and cognitive disturbances. There are cur- rently no therapies for chronic pain that address the underlying drivers of chronic pain, and current symp- tomatic treatments (e.g., opioids) have limited long-term efficacy and are associated undesired side ef- fects, including increased risk of opioid use disorder. To date, efforts to identify new safe and effective treatments using the one-drug, one-target paradigm have largely failed. To make meaningful progress in the fight against chronic pain, a dramatically new theoretical framework is needed. Chronic pain results in long-term changes throughout the central nervous system (CNS), including abnor- mal structure and function of the frontal cortex (FC). The FC is implicated in descending pain modulation and the common pain-related comorbidities of depression, anxiety and cognitive impairment. DNA meth- ylation is an epigenetic mechanism for long-term regulation of gene expression. Peripheral nerve injury results in wide-spread and long-lasting changes in DNA methylation in the FC. Sites where DNA is meth- ylated are recognized by methylated-DNA binding proteins (i.e. MeCP2, MBD1-6), which are critical for the translation of DNA methylation to function. We have demonstrated that MBD1 (Methyl-CpG Binding Domain Protein 1) is dysregulated in the FC many months after nerve injury, is positively correlated to mechanical sensitivity, and is downregulated in the FC 2-weeks and 6-months after nerve injury. We hy- pothesize that targeting the methylated DNA reader MBD1 will reset many functional pathways simulta- neously, thus moving beyond the one-drug, one-target paradigm. The overall objective for this application is to determine the potential of MBD1 as a druggable target for chronic pain. Our central hypothesis is that restoration of MBD1 in neuropathic pain will act as a master switch to attenuate pain-related sensory, affective and cognitive disturbances and will reset dysregulated molecular molecular pathways in the FC. In Specific Aim 1, we will identify the cellular subpopulations driving MBD1 downregulation and pinpoint genes and functional gene pathways that may be dysregu- lated by MBD1 in chronic pain. In Aim 2 we will determine if replacement of MBD1 protects against the development and maintenance of molecular, cellular, sensory, motor, affective and cognitive disturb- ances in a model of chronic neuropathic pain. The expected outcomes are that we will reveal a role for MBD1 in the development and persistence of chronic pain, pain co-morbidities and pain-related cell-specific changes in gene expression. These re- sults will have an important positive impact by providing the much needed initial validation of MBD1 as a potential druggable target for the treatment of pain and supraspinally-mediated pain comorbidities.