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 长链非编码RNA（lncRNA）调节基因表达。周围神经损伤失调， 在包括背根神经节（DRG）在内的疼痛相关区域中表达。然而，大多数人的作用 在神经性疼痛中鉴定的lncRNA仍然不确定。识别新的lncRNA并探索其 对神经性疼痛的贡献可能为这种疾病的管理提供新的策略。我们最近 使用下一代RNA测序方法，并确定了一个大的，天然的，全长非编码RNA， 老鼠和人类。由于它在背根神经节中高度表达，我们将其命名为背根神经节特异性长非编码区 RNA（DS-lncRNA）。我们的初步数据显示，周围神经损伤可能下调DS-lncRNA， 这是由于受损DRG中转录激活因子Pou 4f 3的表达减少。拯救这个 下调减弱了神经损伤诱导的疼痛超敏反应，可能是通过阻断神经元的表达。 RALY（转录辅因子）和RNA聚合酶II（RNA II）之间的相互作用增加， 随后RALY/RNA II触发的Ehmt 2 mRNA及其编码蛋白G9 a（a）表达的沉默 神经性疼痛的关键参与者）。考虑到DS-lncRNA可以直接结合RALY，我们的 初步结果表明，DRG DS-lncRNA下调可能是神经病理性疼痛所必需的， 通过负调节DRG RALY/RNA II触发的G9 a表达。该提案将进一步 研究DS-lncRNA是否以及如何促进神经性疼痛。在具体目标1中，我们将首先 研究在受损的DRG中挽救DS-lncRNA的下调是否减轻神经病理性疼痛 开发和维护。然后我们将研究模仿神经损伤是否会引起下调 在没有神经损伤的情况下，背根神经节DS-lncRNA的表达会导致神经性疼痛症状。在具体目标2中， 将检测周围神经损伤是否导致DS-lncRNA的时间依赖性下调， 背根神经节中的转录因子Pou 4f 3。我们还将研究DS-lncRNA下调是否归因于 Pou 4f 3在周围神经损伤后受损DRG中的表达减少。在具体目标3中，我们 检测DS-lncRNA对Ehmt 2 mRNA、G9 a及其下游疼痛相关蛋白表达的影响。 周围神经损伤后受损DRG中的基因。我们还将确定DS-lncRNA 下调增强RALY与RNA II的结合，导致RALY/RNA II触发的Ehmt 2/G9 a G9 a调控的痛相关基因表达减少。我们 研究将可能确定一种以前未知的神经性疼痛的调节机制。如果有病毒- 介导的基因治疗已用于临床试验，本研究将具有潜在的临床应用价值。 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

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