Translation Control of Pain Plasticity

 描述(申请人提供)：慢性疼痛影响着数千万美国人，其治疗不当给我们的医疗保健系统、患者和临床医生带来了巨大的负担。对驱动慢性疼痛的基本机制有更好的理解，有可能导致可以逆转慢性疼痛的疗法，而不是目前可用的姑息治疗。外周感觉神经元基因表达的变化将最初的损伤与慢性疼痛的发展联系起来。这一领域的工作主要集中在转录调节的事件上。然而，感觉神经元是一种大细胞，其外周末端与转录部位--核--相距甚远。因此，对蛋白质的控制 翻译可能为这些细胞提供了一种快速改变基因表达的机制，直接对局部信号因子做出反应。通过前一期的赠款支持，我们已经证明，翻译控制确实在推动向慢性疼痛过渡的基因表达变化中发挥着至关重要的作用。这一发现创造了一个重要的治疗机会 由于翻译是由许多蛋白激酶(如MNK1/2)控制的，它们向蛋白质(如eIF4E)发出信号，参与蛋白质合成的限速步骤，即翻译启动。我们将检验翻译控制信号对伤害性感受器变化至关重要这一中心假设。 在接触促进疼痛化合物后的兴奋性，以及在向慢性疼痛过渡期间介导伤害感受器的表型变化。具体地说，我们将研究一种新的疼痛可塑性信号通路：eIF4E的MNK1/2激酶磷酸化。我们的假设将通过三个特定的目标来验证：1)MNK1/2信号转导eIF4E，作为导致慢性疼痛的行为可塑性的关键信号枢纽；2)MNK1/2信号转导eIF4E，作为伤害性感受器兴奋性可塑性的关键步骤；以及3)BDNF作为MNK1/2-eIF4E信号的关键翻译靶点，在促进慢性疼痛的伤害性感受器表型变化中。完成这些目标的结果将是深入了解翻译调控如何促进伤害性可塑性，确定特定的机制(eIF4E磷酸化)和靶点(MNK1/2激酶)作为潜在的疼痛治疗和BDNF翻译的新调控机制，以及这一过程在向慢性疼痛过渡中的作用。

 DESCRIPTION (provided by applicant): Chronic pain affects tens of millions of Americans and its inadequate treatment creates an enormous burden on our health care system, its patients and its clinicians. Gaining a better understanding of the basic mechanisms driving chronic pain has the potential to lead to therapeutics that can reverse chronic pain as opposed to currently available palliative treatments. Changes in gene expression in peripheral sensory neurons link initial injury to the development of chronic pain. Work in this area has focused on transcriptionally-mediated events. However, sensory neurons are large cells with peripheral terminals at great distances from the site of transcription, the nucleus. Hence, control of protein translation potentially affords these cells a mechanism to rapidly change gene expression in direct response to local signaling factors. We have demonstrated, through the previous period of grant support, that translation control indeed plays a vital role in changes in gene expression driving the transition to chronic pain. This discovery creates an important therapeutic opportunity because translation is controlled by a number of kinases (e.g. MNK1/2) which signal to proteins (e.g. eIF4E) involved in the rate-limited step of protein synthesis, translation initiation. We wil test the central hypothesis that translation control signaling is crucial for changes in nociceptor excitability after exposure to pain promoting compounds and for mediating phenotypic changes in nociceptors during the transition to chronic pain. Specifically we will examine a novel signaling pathway for pain plasticity: MNK1/2 kinase phosphorylation of eIF4E. Our hypotheses will be tested through 3 specific aims: 1) MNK1/2 signaling to eIF4E as a key signaling hub for behavioral plasticity leading to chronic pain, 2) MNK1/2 signaling to eIF4E as a critical step for plasticity in nociceptor excitability and 3) BDNF as a key translational target of MNK1/2 - eIF4E signaling in nociceptor phenotypic changes that promote chronic pain. The outcome of the completion of these aims will be an in-depth understanding of how translation regulation promotes nociceptive plasticity, the identification of a specific mechanism (eIF4E phosphorylation) and target (MNK1/2 kinase) as a potential pain therapeutic and novel regulatory mechanisms of BDNF translation and the role of this process in the transition to chronic pain.