Cellular mechanisms of antidepressant drug actions in neuropathic pain models

神经病理性疼痛模型中抗抑郁药物作用的细胞机制

• 批准号: 10526787
• 负责人: Venetia Zachariou
• 金额: $ 7.52万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526787
• 关键词: Affect; Affective Symptoms; Antidepressive Agents; Binding; Bioinformatics; Brain; Cell Nucleus; Chromatin; Chronic; Complement; Complex; Data; Development; Disease; Drug usage; Epigenetic Process; Event; Fluorescent in Situ Hybridization; Genes; Genetic Models; Genetic Transcription; HDAC5 gene; Immunofluorescence Immunologic; Maintenance; Mediating; Modeling; Molecular; Neurobehavioral Manifestations; Nucleus Accumbens; Parents; Pathway interactions; Peripheral nerve injury; Pharmaceutical Preparations; Pharmacology; Rewards; Sensory; Symptoms; Testing; Western Blotting; Work; cell type; drug action; insight; monoamine; novel; pain model; painful neuropathy; side effect; synaptic function; transcription factor; transcriptome sequencing; transcriptomics; transmission process

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.

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。大部分 用于治疗这种疾病的药物表现出低的功效和严重的副作用。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）在糖尿病发病中的关键作用。 抗抑郁药在神经性疼痛模型中的作用和功效。HDAC5在伏隔核（NAc）中的表达 与染色质复合物结合以抑制影响突触功能的几种基因的表达， 包括转录因子MEF2C。父R01提案调查了 HDAC5和下游靶点调节抗抑郁药在NAc中的作用。这个补充项目 目的是阐明细胞类型特异性的表观遗传和转录机制介导的抗异常性疼痛， 单胺靶向抗抑郁药在神经性疼痛模型中的作用。生物信息学分析 核RNASeq数据将补充HDAC5和MEF2C作用的发现，并将提供有关 与抗抑郁药疗效相关的转录组学事件。我们将使用荧光技术验证关键发现， 原位杂交、免疫荧光以及蛋白质印迹分析。药理学和遗传学模型 将用于测试选定的基因/细胞内途径。了解介导 单胺靶向抗抑郁药的作用将有助于开发新的和更有效的抗抑郁药。 用于治疗神经性疼痛的药物。