Exploration of MBD1 as a therapeutic target for chronic pain

项目摘要/摘要 慢性疼痛伴随着长期的感觉、情感和认知障碍。有很多人-- 目前还没有针对慢性疼痛的治疗方法，以解决慢性疼痛的潜在驱动因素，目前的症状- 自动治疗(如阿片类药物)的长期疗效有限，并伴随着不良的副作用。 影响，包括增加阿片类药物使用障碍的风险。迄今为止，确定新的安全和有效的新办法的努力 使用一种药物、一种靶点的治疗模式在很大程度上失败了。在……取得有意义的进展 与慢性疼痛作斗争，需要一个全新的理论框架。 慢性疼痛会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MAL结构和功能。FC与下行痛觉调制有关 以及与疼痛相关的常见并发症，如抑郁、焦虑和认知障碍。DNA冰毒- 甲基化是基因表达长期调控的表观遗传机制。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- 甲基化的DNA结合蛋白(即MeCP2，MBD1-6)识别，这是关键的 将DNA甲基化转化为功能。我们已经证明了MBD1(甲基-CpG结合 结构域蛋白1)在神经损伤后几个月的FC中异常调节，与 机械敏感性，并在神经损伤后2周和6个月下调。我们- 靶向甲基化的DNA阅读器MBD1将同时重置许多功能通路-- 巧妙地，从而超越了一种药物、一个靶点的范式。 这项应用的总体目标是确定MBD1作为药物靶点的潜力 慢性疼痛。我们的中心假设是，在神经病理性疼痛中，MBD1的恢复将发挥主宰作用 切换以减轻与疼痛相关的感觉、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MBD1下调，并精确定位可能异常的基因和功能基因途径。 在慢性疼痛方面落后于MBD1。在目标2中，我们将确定更换MBD1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- 在慢性神经病理性疼痛模型中的优势。 预期的结果是，我们将揭示MBD1在 慢性疼痛、疼痛共病和疼痛相关细胞特异性基因表达的变化。这些都是- SULTS将通过提供非常需要的MBD1作为 用于治疗疼痛和棘上介导的疼痛共病的潜在可用药靶点。

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.