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 长的非编码RNA（LNCRNA）调节基因表达。周围神经损伤失调 包括背根神经节（DRG）在内的与疼痛相关区域的表达。但是，大多数的作用 神经性疼痛中鉴定出的LNCRNA仍然不确定。识别新颖的lncrnas并探索他们的 对神经性疼痛的贡献可能为治疗这种疾病提供新的策略。我们最近 使用了下一代RNA测序方法，并确定了一个大型，天然的，全长的非编码RNA 老鼠和人类。因为它在DRG中表达很高，所以我们将其命名为DRG特定的长期不编码 RNA（DS-LNCRNA）。我们的初步数据表明，外周神经损伤可能下调DS-LNCRNA 由于受伤的DRG中转录激活剂POU4F3的表达降低。营救这个 下调减弱了神经损伤引起的疼痛超敏反应，可能通过阻碍 RALY（转录co因子）和RNA聚合酶II（RNA II）和 因此，EHMT2 mRNA及其编码蛋白G9A的RALY/RNA II触发的表达的静音（a） 受伤的DRG中的神经性疼痛的关键人物。鉴于ds-lncrna可以直接与raly结合， 初步结果表明，神经性疼痛可能需要DRG DS-LNCRNA下调 通过DRG raly/RNA II触发的G9a表达的负调节。该提议将进一步 检查DS-LNCRNA是否有助于神经性疼痛。在特定目标1中，我们将首先 调查受伤的DRG中DS-LNCRNA的下调是否减轻神经性疼痛 开发和维护。然后，我们将检查是否模仿神经损伤引起的下调 在没有神经损伤的情况下，DRG DS-LNCRNA导致神经性疼痛症状。在特定的目标2中，我们 将检查周围神经损伤是否导致DS-LNCRNA及其ITS的时间依赖性下调 DRG中的转录因子POU4F3。我们还将检查DS-LNCRNA下调是否归因于 周围神经损伤后受伤的DRG中POU4F3表达的降低。在特定的目标3中，我们将 测试DS-LNCRNA对EHMT2 mRNA，G9A及其下游疼痛相关的表达的影响 周围神经损伤后受伤的DRG中的基因。我们还将确定ds-lncrna是否 下调增强了RALY与RNA II的结合，导致RALY/RNA II触发的EHMT2/G9A的结合 周围神经损伤后受伤的DRG的增加和与G9a控制的疼痛相关基因减少。我们的 研究可能会确定以前未知的神经性疼痛的调节机制。鉴于病毒 - 介导的基因疗法已用于临床试验，本研究将具有潜在的临床 在神经性疼痛管理中的应用。

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

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

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

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