Cellular mechanisms of antidepressant drug actions in neuropathic pain models

项目摘要 神经病理性疼痛是一种以感觉、认知和情感症状为特征的慢性疾病。最 的药物用于治疗这种疾病表现出低疗效和主要的副作用。了解 表观遗传和转录机制，调节传输和维护外周血淋巴细胞， 神经损伤（PNI）症状的治疗将是朝着开发新的治疗方法迈出的重要一步。 我们早期的研究结果确定了表观遗传修饰剂组蛋白脱乙酰酶5（HDAC 5）在细胞凋亡中的关键作用。 抗抑郁药在神经性疼痛模型中的起效和功效。HDAC 5在细胞核中的作用 Accumbens（NAc）与染色质复合物结合，抑制几种影响细胞增殖的基因的表达。 突触功能，包括转录因子MEF 2C。父R 01提案调查了 HDAC 5和下游靶点调节抗抑郁药在NAc中的作用的机制。 这个补充项目的目的是阐明细胞类型特异性表观遗传和转录机制 介导单胺靶向抗抑郁药在神经性疼痛模型中的抗异常性疼痛作用。 单核RNASeq数据的生物信息学分析将补充HDAC 5和MEF 2C的发现 还将提供与抗抑郁疗效相关的转录组学事件的见解。我们 将使用荧光原位杂交、免疫荧光以及Western blot验证关键发现。 印迹分析药理学和遗传学模型将用于检测选定的基因/细胞内途径。 了解介导单胺靶向抗抑郁药作用的分子机制 将有助于开发新的和更有效的治疗神经性疼痛的药物。

PROJECT SUMMARY Neuropathic pain is a chronic condition characterized by sensory, cognitive and affective symptoms. Most of the drugs used to treat this disorder demonstrate low efficacy and major side-effects. Understanding the epigenetic and transcriptional mechanisms that modulate the transmission and maintenance of peripheral nerve injury (PNI) symptoms will be a major step towards the development of novel treatment approaches. Our earlier findings identified a key role of the epigenetic modifier Histone deacetylase 5 (HDAC5) in the onset of action and efficacy of antidepressants in models of neuropathic pain. HDAC5 in the Nucleus Accumbens (NAc) binds to chromatin complexes to suppress the expression of several genes that affect synaptic function, including the transcription factor MEF2C. The parent R01 proposal investigates the mechanism by which HDAC5 and downstream targets modulate the actions of antidepressants in the NAc. This supplement project aims to elucidate cell type-specific epigenetic and transcriptomic mechanisms mediating the antiallodynic effects of monoamine-targeting antidepressants in models of neuropathic pain. Bioinformatic analysis of single nuclei RNASeq data will complement findings on HDAC5 and MEF2C actions and will also provide insight on transcriptomic events associated with antidepressant efficacy. We will validate key findings using fluorescent in situ hybridization, immunofluorescence, as well as western blot analysis. Pharmacological and genetic models will be use to test selected genes/intracellular pathways. Understanding the molecular mechanisms mediating the actions of monoamine-targeting antidepressants will help the development of novel and more efficacious medications for the treatment of neuropathic pain.