Translation Control of Pain Plasticity

 慢性疼痛影响着数千万美国人，其治疗不足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。更好地了解驱动慢性疼痛的基本机制有可能导致可以逆转慢性疼痛的治疗方法，而不是目前可用的姑息治疗。外周感觉神经元中基因表达的变化将初始损伤与慢性疼痛的发展联系起来。这方面的工作集中在转录介导的事件。然而，感觉神经元是大细胞，其外周末梢距离转录位点（细胞核）很远。因此，控制蛋白质 翻译潜在地为这些细胞提供了直接响应局部信号传导因子而快速改变基因表达的机制。我们已经证明，通过前一时期的赠款支持，翻译控制确实在基因表达的变化中起着至关重要的作用，从而推动向慢性疼痛的转变。这一发现创造了一个重要的治疗机会 因为翻译是由许多激酶（例如MNK 1/2）控制的，这些激酶向参与蛋白质合成的限速步骤（翻译起始）的蛋白质（例如eIF 4 E）发出信号。我们将检验翻译控制信号对伤害感受器的变化至关重要这一中心假设 暴露于疼痛促进化合物后的兴奋性和在向慢性疼痛转变期间介导伤害感受器的表型变化。具体来说，我们将研究一种新的疼痛可塑性信号通路：MNK 1/2激酶磷酸化eIF 4 E。我们的假设将通过3个具体目标进行测试：1）MNK 1/2信号传导至eIF 4 E，作为导致慢性疼痛的行为可塑性的关键信号中枢，2）MNK 1/2信号传导至eIF 4 E，作为伤害感受器兴奋性可塑性的关键步骤，3）BDNF作为促进慢性疼痛的伤害感受器表型变化中MNK 1/2 -eIF 4 E信号传导的关键翻译靶点。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，确定特定机制（eIF 4 E磷酸化）和靶点（MNK 1/2激酶）作为潜在的疼痛治疗和BDNF翻译的新调控机制，以及该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.