Identification of a novel DRG-specific long noncoding RNA and its role in neuropathic pain

新型 DRG 特异性长非编码 RNA 的鉴定及其在神经病理性疼痛中的作用

• 批准号: 10605185
• 负责人: Huijuan Hu
• 金额: $ 49.16万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605185
• 关键词: Adverse effects; Attenuated; Binding; Chronic; Clinical Trials; Code; Data; Development; Disease; Disease Management; Distress; Down-Regulation; Enzymes; Gene Expression; Genes; Genetic Transcription; Human; Hypersensitivity; Injury; Ion Channel; Laboratories; Lead; Length; Ligation; Maintenance; Mediating; Messenger RNA; Mus; Names; Neurons; Nucleotides; Opioid Receptor; POU Domain; POU domain factors; Pain; Pain management; Peripheral nerve injury; Proteins; Public Health; RNA I; RNA Polymerase II; Regulation; Role; Spinal Ganglia; Spinal nerve structure; Testing; Time; Transcription Coactivator; Transcription Factor 3; Untranslated RNA; Up-Regulation; Virus; Voltage-Gated Potassium Channel; chemokine; clinical application; cofactor; cytokine; gene therapy; injured; knock-down; nerve injury; next generation; novel; novel strategies; overexpression; pain symptom; painful neuropathy; promoter; receptor; therapeutic target; transcriptome sequencing

Project Abstract Long noncoding RNAs (lncRNAs) regulate gene expression. Peripheral nerve injury dysregulated their expression in the pain-related regions including dorsal root ganglion (DRG). However, the role of most identified lncRNAs in neuropathic pain is still uncertain. Identifying novel lncRNAs and exploring their contribution to neuropathic pain may provide novel strategies for management of this disorder. We recently used a next generation RNA sequencing approach and identified a large, native, full-length non-coding RNA in mice and human. Because it is expressed highly in the DRG, we named it as DRG specific long noncoding RNA (DS-lncRNA). Our preliminary data revealed that peripheral nerve injury downregulated DS-lncRNA likely due to a decrease in the expression of a transcriptional activator Pou4f3 in the injured DRG. Rescuing this downregulation attenuated the nerve injury-induced pain hypersensitivity, likely through blockade of the increased interaction between RALY (a transcription co-factor) and the RNA polymerase II (RNA II) and consequent silence of the RALY/RNA II-triggered expression of Ehmt2 mRNA and its coding protein G9a (a key player in neuropathic pain) in the injured DRG. Given that DS-lncRNA can directly bind to RALY, our preliminary results indicate that DRG DS-lncRNA downregulation is required for neuropathic pain likely through negative regulation of DRG RALY/RNA II-triggered G9a expression. This proposal will further examine whether and how DS-lncRNA contributes to neuropathic pain. In Specific Aim 1, we will first investigate whether rescuing downregulation of DS-lncRNA in the injured DRG attenuates neuropathic pain development and maintenance. We will then examine whether mimicking nerve injury-induced downregulation of DRG DS-lncRNA leads to neuropathic pain symptoms in the absence of nerve injury. In Specific Aim 2, we will examine whether peripheral nerve injury results in time-dependent downregulation of DS-lncRNA and its transcription factor Pou4f3 in the DRG. We will also examine whether DS-lncRNA downregulation is attributed to a decrease of Pou4f3 expression in the injured DRG after peripheral nerve injury. In Specific Aim 3, we will test the effect of DS-lncRNA on the expression of Ehmt2 mRNA, G9a and their downstream pain-related genes in the injured DRG after peripheral nerve injury. We will also determine whether DS-lncRNA downregulation enhances the binding of RALY to RNA II leading to RALY/RNA II-triggered Ehmt2/G9a increase and G9a-controlled pain-related gene decrease in the injured DRG after peripheral nerve injury. Our study will likely identify a previously unknown regulatory mechanism for neuropathic pain. Given that virus- mediated gene therapy has been used in clinical trial, the present study will have a potential clinical application in neuropathic pain management.

项目摘要

项目成果

Sensory neuron-specific long noncoding RNA in small non-peptidergic dorsal root ganglion neurons selectively impairs nerve injury-induced mechanical hypersensitivity.

• DOI: 10.1016/j.lfs.2023.122120
• 发表时间: 2023-09
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Bing Wang;Yingping Liang;Alex Bekker;Huijuan Hu;Yuan-Xiang Tao

A nerve injury-specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression.

• DOI: 10.1172/jci153563
• 发表时间: 2022-07-01
• 期刊: The Journal of clinical investigation
• 作者: Du S;Wu S;Feng X;Wang B;Xia S;Liang L;Zhang L;Govindarajalu G;Bunk A;Kadakia F;Mao Q;Guo X;Zhao H;Berkman T;Liu T;Li H;Stillman J;Bekker A;Davidson S;Tao YX
• 通讯作者: Tao YX

FUS Contributes to Nerve Injury-Induced Nociceptive Hypersensitivity by Activating NF-κB Pathway in Primary Sensory Neurons.

FUS 通过激活初级感觉神经元中的 NF-κB 通路，导致神经损伤引起的伤害性超敏反应。

• DOI: 10.1523/jneurosci.2082-22.2022
• 发表时间: 2023
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Han,Guang;Li,Xiang;Wen,Chun-Hsien;Wu,Shaogen;He,Long;Tan,Cynthia;Nivar,John;Bekker,Alex;Davidson,Steve;Tao,Yuan-Xiang
• 通讯作者: Tao,Yuan-Xiang

Toll-like receptor 4 activation enhances Orai1-mediated calcium signal promoting cytokine production in spinal astrocytes.

• DOI: 10.1016/j.ceca.2022.102619
• 发表时间: 2022-07
• 期刊: CELL CALCIUM
• 影响因子: 4
• 作者: Birla, Hareram;Xia, Jingsheng;Gao, Xinghua;Zhao, Hui;Wang, Fengying;Patel, Shivam;Amponsah, Akwasi;Bekker, Alex;Tao, Yuan -Xiang;Hu, Huijuan
• 通讯作者: Hu, Huijuan

Effect of intrathecal NIS-lncRNA antisense oligonucleotides on neuropathic pain caused by nerve trauma, chemotherapy, or diabetes mellitus.

• DOI: 10.1016/j.bja.2022.09.027
• 发表时间: 2022-11
• 期刊: British journal of anaesthesia
• 影响因子: 9.8
• 作者: C. Wen;Tolga Berkman;Xiang Li;Shibin Du;Gokulapriya Govindarajalu;Hai-jun Zhang;A. Bekker;Steve Davidson;Y. Tao