Epigenetic and genetic contributors to chronic neuropathic pain

描述（由申请人提供）：神经损伤后从急性神经性疼痛转变为慢性神经性疼痛，在许多方面是由神经系统的适应不良可塑性引起的，即它是一种神经系统疾病。可塑性表现在分子、结构、生物化学和生理水平上，所有这些都导致存在持续的强烈自发性疼痛、响应于正常无害刺激的疼痛（异常性疼痛）和响应于正常疼痛刺激的过度疼痛（痛觉过敏）的状况。神经性疼痛的起始和维持涉及受损神经回路的重塑、当疼痛信息通过脊髓和大脑处理时突触强度的变化以及在“疼痛”通路的所有水平上的信号传导过程的扰动。然而，这些变化中的许多是基因表达长期改变的产物和/或原因。由于基因表达程序的最稳定调节是在表观遗传调控控制下进行的，因此我们将进行研究以检验神经损伤诱导神经元表观基因组显著改变的假设，最重要的是，这些变化中的一些有助于神经性疼痛状况的产生和持续。换句话说，我们将剖析慢性神经病理性疼痛的表观遗传景观。我们最初的研究将集中在神经损伤后脊髓中发生的变化，在神经性疼痛的标准啮齿动物模型中。我们的目标是更好地了解这种适应不良过程的分子基础，这是确定治疗干预新靶点的关键第一步。

DESCRIPTION (provided by applicant): The transition from acute to chronic neuropathic pain following nerve injury, in many respects, results from a maladaptive plasticity of the nervous system, i.e. it is a disease of the nervous system. The plasticity is manifest at molecular, structural, biochemical and physiological levels, all leading to a condition in which there is ongoing, intense spontaneous pain, pain in response to normally innocuous stimuli (allodynia) and exaggerated pain in response to normally painful stimuli (hyperalgesia). The initiation and maintenance of neuropathic pain involves remodeling of injured nerve circuits, changes in synaptic strength as the pain message is processed through the spinal cord and brain as and perturbations in signaling processes, at all levels of the "pain" pathway. Many of these changes, however, are the product and/or the cause of long lasting alterations in gene expression. As the most stable modulation of gene expression programs is under epigenetic regulatory control, here we will perform studies to test the hypothesis that nerve injury induces significant alterations to the neuronal epigenome, and most importantly that some of these changes contribute to the generation and persistence of the neuropathic pain condition. In other words, we will dissect the epigenetic landscape of chronic neuropathic pain. Our initial studies will focus on changes that occur in the spinal cord following nerve injury, in standard rodent models of neuropathic pain. Our objective is to obtain a better understanding of the molecular underpinnings of this maladaptive process, which is a critical first step to identifying new targets for therapeutic intervention.