Translation Control of Pain Plasticity

在神经元中，突触和内在可塑性依赖于mRNA翻译的调节控制。 在过去的十年里，我们的工作集中在翻译调节信号如何参与神经元的 导致慢性疼痛的可塑性我们的研究结果表明，炎症和神经性损伤 刺激背根神经节（DRG）伤害感受器中的翻译调节信号传导途径，所述神经元 检测有害或潜在有害的刺激。这些途径激活的结果是增加 伤害感受器的兴奋性，持续疼痛的行为体征以及对机械和热的敏感性 刺激.这项工作的主体，支持的想法，治疗靶向翻译调节信号 这些通路可用于有效治疗慢性疼痛。我们对此的总体假设是 一个持续的项目是，伤害感受器中的MNK 1激活是翻译一个 编码增加伤害感受器兴奋性的蛋白质的mRNA的子集，引起增强的疼痛 表型我们将使用新的转基因小鼠品系，细胞类型特异性翻译， 核糖体亲和纯化（TRAP），MNK 1/2的高度特异性抑制剂和新一代抑制剂， MNK 1的特异性。我们的初步数据表明，伤害性行为可塑性的关键MNK亚型 是MNK 1基于我们的电生理学实验，我们假设该激酶的作用位点是 背根神经节神经元我们的第一个具体目标是检验伤害感受器中MNK 1的表达是伤害感受器的关键的假设。 慢性疼痛行为表达的驱动因素。我们已经创建了表达L10 a标记的TRAP系， 核糖体在神经元中表达Scn 10a基因（Scn 10aTRAP）。在我们的第二个具体目标中，我们将研究 临床前神经性疼痛模型中特异性mRNA的翻译是如何被调节的， 或MNK-eIF 4 E信号传导的药理学操作。这将产生前所未有的分子洞察力， 神经性疼痛中伤害感受器基因表达的可塑性驱动变化。第三个具体目标是 侧重于利用目标1和目标2中的方法发现的基因或遗传靶向机制。 例如，我们的TRAP方法捕获了神经病性胶质瘤中Mrgrpd受体的翻译上调。 模型我们将使用基因敲除小鼠来研究这种受体在感觉神经元兴奋性中的作用， 神经性疼痛提出的具体目标将突出神经性疼痛的关键调节途径， 为神经性疼痛的新治疗靶点提供了新的见解。

In neurons, synaptic and intrinsic plasticity is dependent on the regulated control of mRNA translation. Over the past decade our work has focused on how translation regulation signaling is involved in neuronal plasticity that drives chronic pain. Our findings demonstrate that inflammatory and neuropathic injuries stimulate translation regulation signaling pathways in dorsal root ganglion (DRG) nociceptors, neurons that detect injurious or potentially injurious stimuli. The result of activation of these pathways is increased excitability of nociceptors, behavioral signs of ongoing pain and sensitization to mechanical and thermal stimulation. This body of work, supports the idea that therapeutics targeting translation regulation signaling pathways can be used for the efficacious treatment of chronic pain. Our overarching hypothesis for this continuing project is that MNK1 activation in nociceptors is the key regulatory factor for the translation of a subset of mRNAs that encode proteins that augment the excitability of nociceptors causing enhanced pain phenotypes. We will test this hypothesis using new transgenic mouse lines, cell type-specific translating ribosome affinity purification (TRAP), highly specific inhibitors of MNK1/2 and new generation inhibitors that are specific for MNK1. Our preliminary data indicates that the key MNK isoform for nociceptive behavioral plasticity is MNK1. Based on our electrophysiology experiments we hypothesize that the site of action for this kinase is in DRG neurons. Our first specific aim will test the hypothesis that MNK1 expression in nociceptors is a key driver of behavioral expression of chronic pain. We have created a TRAP line that expresses L10a-tagged ribosomes in neurons that express the Scn10a gene (Scn10aTRAP). In our second specific aim we will examine how translation of specific mRNAs is regulated in preclinical neuropathic pain models with and without genetic or pharmacological manipulations of MNK-eIF4E signaling. This will yield unprecedented molecular insight into plasticity-driven changes in gene expression in nociceptors in neuropathic pain. The third specific aim will focus on pharmacologically or genetically targeting mechanisms discovered using approaches in aims 1 and 2. For instance, our TRAP approach captures translational upregulation of the Mrgrpd receptor in a neuropathic model. We will use knockout mice to investigate the role of this receptor in sensory neuron excitability in neuropathic pain. The proposed specific aims will highlight a key regulatory pathway for neuropathic pain and give new insight into novel therapeutic targets for neuropathic pain.