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REST-mediated epigenomic and transcriptomic signatures in neuropathic pain

REST 介导的神经病理性疼痛的表观基因组和转录组特征

基本信息

批准号：
10472694
负责人：
SADHAN MAJUMDER
金额：
$ 39.46万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472694
关键词：
ATAC-seq Acute Affect Afferent Neurons American Animal Model Attenuated Behavioral Assay Biochemical Biological Markers Biology Cells ChIP-seq Chronic Phase Clinical Clinical Research Collaborations DNA DNA-Directed RNA Polymerase Data Development Disease Down-Regulation Drug Targeting Epigenetic Process Exhibits G9a histone methyltransferase Genes Genetic Genetic Transcription Goals Grant Histones Human Hypersensitivity Immunofluorescence Immunologic Knockout Mice Knowledge Length Malignant neoplasm of brain Mediating Messenger RNA Methods MicroRNAs Molecular Probes Mus Nervous system structure Neurons Pain Patients Peripheral nerve injury Potassium Channel Predisposition Prevention Quality of life Repression Research Resistance Rest Reverse Transcriptase Polymerase Chain Reaction Role Spinal Ganglia System Testing Transcription Repressor Traumatic Nerve Injury United States National Institutes of Health VP 16 Work base chemotherapy chronic neuropathic pain chronic pain conditional knockout epigenetic regulation epigenetic silencing epigenomics experience gender difference gene network genetic corepressor genetic signature genome-wide genome-wide analysis in vivo inhibitor innovation mouse model mu opioid receptors nerve injury novel overexpression pain chronification painful neuropathy preclinical study promoter somatosensory therapeutic target transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Chronic neuropathic pain is difficult to treat and remains a major clinical problem despite numerous clinical and preclinical studies. Our long-term goal is to identify new targets for treatment/prevention of chronic neuropathic pain. Mounting evidence suggests that epigenetic mechanisms and regulation via microRNAs (miRs) are associated with the transition from acute to chronic pain. The goal of this project is to identify REST- and G9a- related transcriptomic and epigenomic regulatory networks in the dorsal root ganglion (DRG) and their roles in the development of neuropathic pain. The transcriptional repressor REST is a major epigenomic regulator. In nerve injury-induced neuropathic pain, epigenetic silencing by REST overexpression in DRG neurons has been implicated in the repression of targets such as Oprm1, Kcnd3, Kcnq2, and scn10a genes. Histone methyl-transferase G9a is also an epigenomic corepressor of many transcription factors including REST. We recently found that G9a is critical in the epigenetic silencing of almost all K+ channel genes in DRG neurons via increased histone H3K9me2 on the genes' promoters during acute-to-chronic pain transition. Accordingly, mice with G9a ablated from DRG neurons do not develop chronic pain after nerve injury. Thus, both REST and G9a present suitable molecular probes to decipher the genetic and epigenetic bases of chronic pain. However, knowledge is limited about the transcriptomic and epigenomic networks associated with REST and G9a in neuropathic pain development. This multiple-PI grant is a collaboration between two labs with complementary expertise. In addition to the G9a mouse model described above, the two labs have developed an innovative experimental system consisting of complementary Rest conditional knock-out (cKO) and new conditional human REST overexpression (cOE) mouse models. Preliminary results indicate that whereas DRG-specific Rest cKO mice show attenuated pain hypersensitivity after nerve injury, DRG-specific REST cOE mice exhibit pain hypersensitivity. Thus, the two contrasting mouse models recapitulate the chronic pain transition, as anticipated based on work in the field, and provide an in vivo system to study transcriptional mechanisms of chronic pain. Here we propose to the test the central hypothesis that REST and G9a are involved in the development of chronic pain after DRG nerve injury via unique transcriptomic and epigenomic signatures. If successful, our proposed research will identify all REST and G9a targets in DRG neurons including mRNAs and miRs, as well as REST- and G9a-mediated epigenomic changes in the development of chronic pain after nerve injury. We will also functionally identify those REST- and G9a-regulated miRs that could be utilized to block REST- and G9a-mediated chronic pain. We will compare our results to those obtained in chemotherapy- induced chronic pain. In summary, the results from this work are likely to generate new signatures and biomarkers that could potentially be utilized to predict patient susceptibility or resistance to chronic pain development. The results could also be used to identify new actionable drug targets in chronic pain.

项目总结