Regulation and function of PlexinA2 forward signaling in persistent pain

持续性疼痛是一个重要的临床和公共卫生问题。一旦确立，持续性疼痛通常对现有治疗无效，并与不良健康结果相关。当孤立芽在失神经组织中形成神经瘤时，持续性疼痛在外周神经损伤后发展，神经瘤变得电过度兴奋并产生自发和诱发的异位动作电位。这些反应可能是表观遗传机制的结果。表观遗传机制负责细胞表型的改变，其不涉及DNA序列的改变，并且通常作为环境因素影响基因组行为的途径。因此，表观遗传机制是各种生理和病理过程的公认调节剂。然而，外周神经损伤后持续性疼痛的表观遗传参与仍然在很大程度上未被探索。这个COBRE研究项目的中心假设是，改变了的脑信号蛋白-丛蛋白信号传导的表观遗传调节 感觉神经元中的神经传导通路在轴突引导中起功能性作用并促进持续性疼痛状态。此外，我们推测，在神经元发育过程中感觉环境的变化可能在表观遗传学上引发伤害感受器，以促进在以后的生活中改变伤害感受阈值。我们的研究将：1）提供关于神经损伤后和慢性炎症中周围神经系统中重要调节元件的细胞类型特异性位置和活性的新信息; 2）确定 semaphorin-plexin家族基因对神经突生长、排斥和疼痛行为的影响;以及3）确定早期生活压力如何影响感觉神经元的表观基因组并改变基因表达以增加晚年对疼痛相关行为的易感性。对神经元再生和神经元过度兴奋中重要基因表达的调节变化的更好理解可能为预防和治疗神经病理性疼痛的新策略提供治疗靶点。

Persistent pain is a significant clinical and public health problem. Once established, persistent pain is often refractory to existing treatments and associated with adverse health outcomes. Persistent pain develops following peripheral nerve injury when orphan sprouts form neuromas in denervated tissues which become electrically hyperexcitable and generate spontaneous and evoked ectopic action potentials. These responses may be the result of epigenetic mechanisms. Epigenetic mechanisms are responsible for alterations in cellular phenotype that do not involve changes to the DNA sequence and generally serve as an avenue for environmental factors to influence behavior of the genome. Accordingly, epigenetic mechanisms are well established regulators of a wide variety of physiological and pathological processes. However, epigenetic involvement in persistent pain after peripheral nerve injury remains largely unexplored. The central hypothesis for this COBRE Research Project is that altered epigenetic regulation of the semaphorin-plexin signaling pathway in sensory neurons plays a functional role in axon guidance and promotes persistent pain states. In addition, we hypothesize that changes to the sensory environment during neuronal development may epigenetically prime nociceptors to promote altered nociceptive thresholds later in life. Our study will: 1) provide novel information regarding cell-type specific position and activity of important regulatory elements in peripheral nervous system after nerve injury and in chronic inflammation; 2) determine the effects of semaphorin-plexin family genes on neurite outgrowth, repulsion and pain behaviors; and 3) identify how early life stress may affect the epigenome of sensory neurons and alter gene expression to increase susceptibility to pain-related behaviors in later life. An improved understanding of the regulatory changes in the expression of genes important in neuron regeneration and neuronal hyperexcitability may provide therapeutic targets for novel strategies toward the prevention and treatment of neuropathic pain.