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

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
负责人:
Yuan-Xiang Tao
金额:
$50.99万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-15 至 2024-04-30

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中文摘要
翻译
项目总结: 最近,RNA修饰被重新发现为基因表达的重要调节因子。N6-甲基腺苷 (M6A)被认为是真核生物RNA最普遍的内部修饰。M6A修改控件 RNA代谢包括RNA降解,并与人类疾病有关,如肥胖和 癌症。然而,它在包括神经病理性疼痛在内的慢性疼痛中的作用尚不清楚。我们的初步数据显示 神经损伤导致背根神经节(DRG)FTO(脂肪量和肥胖相关)增加 蛋白质),一种具有良好特性的RNA去甲基酶,可能通过降低 M6A在Ehmt2mRNA(编码G9a,一种组蛋白甲基转移酶)上的表达,稳定神经损伤诱导的G9a 上调mU阿片受体(MOR)的表达,从而抑制损伤的DRG中MU阿片受体的表达。 鉴于周围神经后DRG基因表达的转录和翻译变化 损伤参与神经病理性疼痛的发生和维持以及G9a作为基因抑制物 表达是神经病理性疼痛发生的关键内源性因素,我们认为在神经病理性疼痛中FTO增加 受损的背根神经节导致神经病理性疼痛。在目标1中,我们将首先确定药理作用 DRG FTO的抑制或基因敲除可减轻神经损伤所致的痛过敏 发育和维持期,以及模拟神经损伤是否导致DRG FTO增加 导致幼龄大鼠神经病理性疼痛的主要症状。在目标2中,我们将研究是否以及如何 周围神经损伤可上调背根神经节FTO的表达。中的随时间变化 FTO及其转录激活因子RUNX1mRNAs及其蛋白的表达及其在M6A水平的表达 将检测周围神经损伤后背根神经节中的特定RNA。我们还将定义神经是否 损伤诱导的DRG FTO上调归因于损伤的DRG中RUNX1的增加。在目标3中,我们 将研究DRG FTO如何参与神经病理性疼痛。我们将首先观察FTO是否绑定到Ehmt2 5腰椎损伤后背根神经节神经元中这种结合活性是否增加 神经结扎术(SNL)。然后我们将定义FTO是否有助于SNL诱导的Ehmt1上调 MRNA/G9a和G9a通过稳定增加的G9a表达控制MOR的下调 受伤的背根节。最后,我们将确定阻断SNL诱导的DRG FTO增加是否会减少 吗啡控制的初级传入神经递质释放,恢复阿片类镇痛作用的减少 抑制阿片类药物耐受性的发展。这些研究不仅将增进我们对 转录后机制的神经病理性疼痛,但也将打开一扇门,开发新的战略 这种疾病的预防和治疗。
英文摘要
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.
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Role of dorsal root ganglion FTO, a RNA demethylase, in neuropathic pain
  • 批准号:
    10175069
  • 项目类别:
  • 资助金额:
    $50.99万
  • 财政年份:
    2019
  • 负责人:
    Yuan-Xiang Tao
  • 依托单位:
Role of dorsal root ganglion FTO, a RNA demethylase, in neuropathic pain
Role of dorsal root ganglion FTO, a RNA demethylase, in neuropathic pain
  • 批准号:
    9978158
  • 项目类别:
  • 资助金额:
    $50.99万
  • 财政年份:
    2019
  • 负责人:
    Yuan-Xiang Tao
  • 依托单位:
Epigenetic regulation of neuropathic pain: Role of DRG histone methyltransferase G9a
  • 批准号:
    9207019
  • 项目类别:
  • 资助金额:
    $39.9万
  • 财政年份:
    2016
  • 负责人:
    Yuan-Xiang Tao
  • 依托单位:
海外基金