Exploration of MBD1 as a therapeutic target for chronic pain

项目总结/摘要 慢性疼痛伴有长期的感觉、情感和认知障碍。有狗- 目前还没有针对慢性疼痛的治疗方法来解决慢性疼痛的潜在驱动因素，而目前的症状是， 抗肿瘤治疗（例如，阿片类药物）具有有限的长期功效并且与不期望的副作用相关。 包括增加阿片类药物使用障碍的风险。到目前为止，努力确定新的安全和有效的 使用一种药物、一种靶标范例的治疗在很大程度上失败了。取得有意义的进展 与慢性疼痛的斗争，需要一个全新的理论框架。 慢性疼痛导致整个中枢神经系统（CNS）的长期变化，包括异常。 额叶皮质（FC）的结构和功能异常。FC与下行疼痛调制有关 以及抑郁、焦虑和认知障碍等常见疼痛相关合并症。DNA冰毒 化是基因表达长期调节的表观遗传机制。周围神经损伤 导致FC中DNA甲基化的广泛和持久的变化。DNA是冰毒的地方 被甲基化DNA结合蛋白（即MeCP 2，MBD 1 -6）识别，这对于 将DNA甲基化转化为功能。我们已经证明MBD 1（甲基-CpG结合） 结构域蛋白1）在神经损伤后许多个月在FC中失调， 机械敏感性，并下调FC神经损伤后2周和6个月。我们- 推测靶向甲基化DNA阅读器MBD 1将同时重置许多功能途径， 因此，超越了单一药物、单一靶点的范式。 该应用的总体目标是确定MBD 1作为药物靶点的潜力 慢性疼痛我们的中心假设是MBD 1在神经病理性疼痛中的恢复将作为一个主导因素， 切换到减弱疼痛相关的感觉，情感和认知障碍，并将重置失调 FC中的分子分子途径。在具体目标1中，我们将确定细胞亚群 驱动MBD 1下调和精确定位基因和功能基因途径，可能是发育不良， MBD 1在慢性疼痛中的作用。在目标2中，我们将确定替换MBD 1是否可以防止 分子、细胞、感觉、运动、情感和认知障碍的发展和维持- 在慢性神经性疼痛模型中的表现。 预期的结果是，我们将揭示MBD 1在发展和持续的作用， 慢性疼痛、疼痛共病和疼痛相关的细胞特异性基因表达变化。这些重新 结果将通过提供急需的MBD 1初步验证， 治疗疼痛和棘上介导的疼痛合并症的潜在药物靶点。

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.