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。一旦确定，持续性疼痛通常对现有治疗无效，并与不良健康结果相关。当孤儿芽在去神经组织中形成神经瘤时，周围神经损伤后发生持续疼痛，神经瘤变得电兴奋并产生自发和诱发异位动作电位。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，不涉及DNA序列的改变，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良好调节机制。然而，外周神经损伤后持续疼痛的表观遗传参与仍未得到充分研究。这个COBRE研究项目的中心假设是改变了信号素丛信号的表观遗传调控

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.