Role of dorsal root ganglion FTO, a RNA demethylase, in neuropathic pain

背根神经节 FTO(一种 RNA 去甲基酶)在神经性疼痛中的作用

基本信息

  • 批准号:
    10677805
  • 负责人:
  • 金额:
    $ 50.99万
  • 依托单位:
  • 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:
    2019-07-15 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY: RNA modifications were recently rediscovered as essential regulators of gene expression. N6-methyladenosine (m6A) is identified as the most prevalent internal modification of eukaryotic RNA. The m6A modification controls RNA metabolism including RNA degradation and has been linked to human diseases such as obesity and cancer. However, its role in chronic pain including neuropathic pain is unknown. Our preliminary data suggest that a nerve injury-induced increase in dorsal root ganglion (DRG) FTO (fat mass and obesity-associated protein), a well-characterized RNA demethylase, may participate in neuropathic pain by reducing the level of m6A on Ehmt2 mRNA (encoding G9a, a histone methyltransferase), stabilizing nerve injury-induced G9a upregulation, and, consequently, silencing the expression of mu opioid receptor (MOR) in the injured DRG. Given that the transcriptional and translational changes in DRG gene expression following peripheral nerve injury participate in the development and maintenance of neuropathic pain and that G9a as a repressor of gene expression is a key endogenous contributor to neuropathic pain genesis, we propose that the increased FTO in the injured DRG contributes to neuropathic pain. In Aim 1, we will first determine whether pharmacological inhibition or genetic knockdown of DRG FTO attenuates nerve injury-induced pain hypersensitivity during the development and maintenance periods, and whether mimicking nerve injury-induced increase in DRG FTO leads to major symptoms of neuropathic pain in naive rats. In Aim 2, we will examine whether and how peripheral nerve injury upregulates the expression of FTO in the DRG. Time-dependent changes in the expression of Fto and its transcriptional activator Runx1 mRNAs and their proteins and in the level of m6A on specific RNAs in the DRG after peripheral nerve injury will be examined. We will also define whether nerve injury-induced up-regulation of DRG FTO is attributed to an increase in Runx1 in the injured DRG. In Aim 3, we will examine how DRG FTO participates in neuropathic pain. We will first observe whether FTO binds to Ehmt2 mRNA and whether this binding activity is increased in the injured DRG neurons after the fifth lumbar spinal nerve ligation (SNL). We will then define whether FTO contributes to the SNL-induced upregulation of Ehmt1 mRNA/G9a and the G9a-controlled downregulation of MOR by stabilizing the increased G9a expression in the injured DRG. Finally, we will determine whether blocking the SNL-induced increase in DRG FTO reduces the MOR-controlled primary afferent neurotransmitter release, restores the decrease of opioid analgesia, and attenuates opioid tolerance development. These studies will not only advance our understanding of posttranscriptional mechanisms of neuropathic pain, but will also open a door to develop a new strategy for the prevention and treatment of this disorder.
项目概要: RNA修饰最近被重新发现为基因表达的重要调节因子。N6-甲基腺苷 (m6A)被认为是真核RNA最普遍的内部修饰。M6 A改装控制器 RNA代谢包括RNA降解,并且已经与人类疾病如肥胖症和肥胖症相关。 癌然而,其在慢性疼痛包括神经性疼痛中的作用尚不清楚。我们的初步数据显示 神经损伤诱导背根神经节(DRG)FTO(脂肪量和肥胖相关 蛋白质),一种充分表征的RNA去甲基化酶,可能通过降低蛋白质的水平参与神经性疼痛。 m6 A对Ehmt 2 mRNA(编码G9 a,一种组蛋白甲基转移酶)的作用,稳定神经损伤诱导的G9 a 上调,并因此沉默受损DRG中μ阿片受体(莫尔)的表达。 鉴于外周神经损伤后DRG基因表达的转录和翻译变化, 损伤参与神经病理性疼痛发生和维持及G9 a作为基因阻遏物 表达是神经病理性疼痛发生的关键内源性贡献者,我们认为, 受损的DRG导致神经性疼痛。在目标1中,我们将首先确定药理学是否 抑制或基因敲除背根神经节FTO可减弱神经损伤诱导的疼痛超敏反应 发展和维持期,以及是否模仿神经损伤诱导DRG FTO增加 导致未处理大鼠神经性疼痛的主要症状。在目标2中,我们将研究是否以及如何 周围神经损伤后FTO在DRG中的表达上调。随时间的变化 Fto及其转录激活因子Runx 1 mRNA及其蛋白质的表达,以及m6 A水平, 将检测外周神经损伤后DRG中的特异性RNA。我们还将定义神经 损伤诱导的DRG FTO上调归因于损伤DRG中Runx 1的增加。在目标3中,我们 将研究DRG FTO如何参与神经性疼痛。我们将首先观察FTO是否与Ehmt 2结合 mRNA和这种结合活性是否在第五腰椎后损伤的DRG神经元中增加, 神经结扎(SNL)。然后我们将确定FTO是否有助于SNL诱导的Ehmt 1上调 mRNA/G9 a和G9 a控制的莫尔下调通过稳定G9 a表达的增加, 受伤的DRG最后,我们将确定阻断SNL诱导的DRG FTO增加是否会减少 MOR控制的初级传入神经递质释放,恢复阿片类镇痛的减少, 减弱阿片耐受性的发展。这些研究不仅会增进我们对 神经病理性疼痛的转录后机制,但也将打开一扇大门,以制定一个新的战略, 预防和治疗这种疾病。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Intrathecal administration of the fat-mass and obesity-associated protein inhibitor mitigates neuropathic pain in female rats.
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Yuan-Xiang Tao其他文献

Yuan-Xiang Tao的其他文献

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{{ truncateString('Yuan-Xiang Tao', 18)}}的其他基金

Role of dorsal root ganglion FTO, a RNA demethylase, in neuropathic pain
背根神经节 FTO(一种 RNA 去甲基酶)在神经性疼痛中的作用
  • 批准号:
    10175069
  • 财政年份:
    2019
  • 资助金额:
    $ 50.99万
  • 项目类别:
Role of dorsal root ganglion FTO, a RNA demethylase, in neuropathic pain
背根神经节 FTO(一种 RNA 去甲基酶)在神经性疼痛中的作用
  • 批准号:
    10470094
  • 财政年份:
    2019
  • 资助金额:
    $ 50.99万
  • 项目类别:
Role of dorsal root ganglion FTO, a RNA demethylase, in neuropathic pain
背根神经节 FTO(一种 RNA 去甲基酶)在神经性疼痛中的作用
  • 批准号:
    9978158
  • 财政年份:
    2019
  • 资助金额:
    $ 50.99万
  • 项目类别:
Epigenetic regulation of neuropathic pain: Role of DRG histone methyltransferase G9a
神经性疼痛的表观遗传调控:DRG 组蛋白甲基转移酶 G9a 的作用
  • 批准号:
    9207019
  • 财政年份:
    2016
  • 资助金额:
    $ 50.99万
  • 项目类别:
mTOR, A new target for opioid-induced togerance and hyperalgesia
mTOR,阿片类药物引起的耐受和痛觉过敏的新靶点
  • 批准号:
    8738282
  • 财政年份:
    2013
  • 资助金额:
    $ 50.99万
  • 项目类别:
mTOR, a new target for opioid-induced tolerance and hyperalgesia
mTOR,阿片类药物引起的耐受和痛觉过敏的新靶点
  • 批准号:
    8439671
  • 财政年份:
    2013
  • 资助金额:
    $ 50.99万
  • 项目类别:
Epigenetic regulation of neuropathic pain: Role of native KV1.2 antisense RNA
神经性疼痛的表观遗传调控:天然 KV1.2 反义 RNA 的作用
  • 批准号:
    8687754
  • 财政年份:
    2013
  • 资助金额:
    $ 50.99万
  • 项目类别:
Epigenetic regulation of neuropathic pain: Role of native KV1.2 antisense RNA
神经性疼痛的表观遗传调控:天然 KV1.2 反义 RNA 的作用
  • 批准号:
    8722205
  • 财政年份:
    2013
  • 资助金额:
    $ 50.99万
  • 项目类别:
mTOR, A new target for opioid-induced togerance and hyperalgesia
mTOR,阿片类药物引起的耐受和痛觉过敏的新靶点
  • 批准号:
    8974824
  • 财政年份:
    2013
  • 资助金额:
    $ 50.99万
  • 项目类别:
mTOR, A new target for opioid-induced togerance and hyperalgesia
mTOR,阿片类药物引起的耐受和痛觉过敏的新靶点
  • 批准号:
    9187000
  • 财政年份:
    2013
  • 资助金额:
    $ 50.99万
  • 项目类别:

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