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.

项目总结