Translation Control of Pain Plasticity

在神经元中，突触的可塑性和内在可塑性依赖于mRNA翻译的调控。 在过去的十年里，我们的工作主要集中在翻译调控信号如何参与神经元 导致慢性疼痛的可塑性。我们的研究结果表明，炎症和神经病理性损伤 刺激背根神经节(DRG)伤害性感受器中的翻译调节信号通路 检测有害或潜在有害的刺激。这些通路的激活结果是增加的 伤害性感受器的兴奋性、持续疼痛的行为迹象以及对机械和热的敏化 刺激。这项工作支持这样一种观点，即针对翻译调节信号的治疗 通路可用于慢性疼痛的有效治疗。我们对此的首要假设是 继续的计划是，在伤害感受器中激活MNK1是翻译的关键调控因素 MRNAs的一个子集，其编码的蛋白质可增强引起疼痛的痛觉感受器的兴奋性 表型。我们将使用新的转基因小鼠品系、特定细胞类型的翻译来验证这一假设 核糖体亲和纯化(TRAP)、高度特异的MNK1/2抑制剂和新一代抑制剂 特定于MNK1。我们的初步数据表明，MNK亚型是伤害性行为可塑性的关键亚型 是MNK1。根据我们的电生理学实验，我们推测这种激酶的作用部位是 在背根节神经元中。我们的第一个特定目标将检验这样的假设，即在伤害性感受器中MNK1的表达是关键 慢性疼痛行为表现的驱动因素。我们已经创建了一条表示L10a标记的陷波线 表达Scn10a基因(Scn10aTRAP)的神经元中的核糖体。在我们的第二个具体目标中，我们将检查 在有和没有遗传基因的临床前神经病理性疼痛模型中，特定mRNAs的翻译是如何调节的 或对MNK-eIF4E信号的药理学操作。这将产生前所未有的分子洞察力 可塑性驱动的神经病理性疼痛伤害性感受器基因表达变化。第三个具体目标是 重点关注利用目标1和目标2中的方法发现的药理学或基因靶向机制。 例如，我们的TRAP方法捕捉到了神经病患者mrgrpd受体的翻译上调。 模特。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。拟议的具体目标将突出神经病理性疼痛的关键调控途径，并 为神经病理性疼痛的新治疗靶点提供新的见解。

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.