Scaffolding the Transition to Chronic Pain

描述（由申请人提供）：本研究项目的长期目标是了解支架蛋白在调节伤害感受器可塑性中的作用。初级传入终末蛋白表达的动态变化显著改变了痛觉。例如，离子通道磷酸化可以调节通道活性，从而影响对有害刺激的急性有害反应。然而，持续疼痛的状态可能依赖于动态蛋白修饰的多种机制来维持外周伤害感受器的敏化。因此，感觉末端的伤害感受器可塑性可能支持持续的痛觉。关于初级传入神经元的神经可塑性变化如何整合到持续疼痛的发展中，存在很大的知识缺口。这代表了一个重要的未满足的需求，因为仔细鉴定持续疼痛的分子协调物将为镇痛药物的开发提供新的外周治疗靶点。本应用的总体目标是确定持续性疼痛的发展依赖于自分泌伤害感受器的致敏，通过a激酶锚定蛋白79/150 （AKAP）协调的前瞻神经可塑性机制。该应用的中心假设是支架蛋白a激酶锚定蛋白79/150 （AKAP）协调伤害受体的可塑性。这一假设将通过三个具体目标来解决：(1)评估AKAP在细胞和行为模型中作为TRP通道敏感性的重要协调者，(2)评估AKAP对前馈伤害感受器致敏的依赖性，以及(3)研究AKAP表达的神经可塑性转录控制。将通过遗传学、分子生物学、生物化学、行为学和电生理学等多种方法对AKAP支架机制进行研究。这项研究的贡献是重要的，因为它是开发针对伤害感受器可塑性关键支架机制的新型外周活性镇痛药的第一步。研究结果将表明，破坏支架蛋白AKAP可以显著破坏伤害感受器兴奋性的神经可塑性变化，这些变化有助于许多临床疼痛状态的发展。

DESCRIPTION (provided by applicant): The long-term goal of this research project is to understand the role of scaffolding proteins in the regulation of nociceptor plasticity. Dynamic changes to proteins expressed in primary afferent terminals significantly alter pain sensation. For instance, ion channel phosphorylation can modulate channel activity, thereby affecting acute nocifensive responses to noxious stimuli. However, states of persistent pain likely rely on multiple mechanisms of dynamic protein modifications to maintain peripheral nociceptor sensitization. Therefore, nociceptor plasticity at the sensory terminal may exist to support persistent pain sensation. A large gap in knowledge exists concerning how neuroplastic changes in primary afferent neurons are integrated to contribute to the development of persistent pain. This represents an important unmet need, since the careful identification of molecular coordinators of persistent pain would provide new, peripheral therapeutic targets for analgesic drug development. The overall objective of this application is to identify that the development of persistent pain depends on autocrine nociceptor sensitization through a feed-forward, neuroplastic mechanism coordinated by A-Kinase Anchoring Protein 79/150 (AKAP). The central hypothesis for this application is that the scaffolding protein A-Kinase Anchoring Protein 79/150 (AKAP) coordinates nociceptor plasticity. This hypothesis will be addressed through three specific aims that (1) evaluate AKAP as an important coordinator of TRP channel sensitivity in cellular and behavioral models, (2) evaluate AKAP-dependence of feed-forward nociceptor sensitization, and (3) examine neuroplastic transcriptional control of AKAP expression. AKAP scaffolding mechanisms will be investigated through a combination of genetic, molecular, biochemical, behavioral and electrophysiology methods. The contribution of this research is significant because it is the first step towards developing novel peripherally active analgesics targeted at a key scaffolding mechanism of nociceptor plasticity. Research results will demonstrate that disrupting the scaffolding protein AKAP can significantly undermine neuroplastic changes in nociceptor excitability that contribute to the development of many clinical pain states.