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过渡到慢性神经性疼痛，在许多方面，是神经系统适应性不良的结果，即它是一种神经系统疾病。这种可塑性在分子、结构、生化和生理水平上都表现出来，所有这些都导致持续的、强烈的自发疼痛、对正常无害刺激的疼痛（异常性疼痛）和对正常疼痛刺激的过度疼痛（痛觉过敏）。神经性疼痛的发生和维持涉及损伤神经回路的重塑，疼痛信息通过脊髓和大脑处理时突触强度的变化，以及“疼痛”通路各级信号过程的扰动。然而，许多这些变化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下进行的，因此我们将进行研究来验证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，这些改变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性疼痛的表观遗传景观。我们最初的研究将集中在标准的神经性疼痛啮齿动物模型中，神经损伤后脊髓发生的变化。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的第一步。

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. PUBLIC HEALTH RELEVANCE: Nerve injury-induced chronic neuropathic pain is a maladaptive neuronal process, of unknown etiology, that affects the quality of life of millions of Americans. Here, we propose experiments that will reveal the epigenetic and genetic contributors to this condition, with the objective of obtaining a better understanding of the molecular underpinnings of neuropathic pain, but also of identifying novel targets for effective therapeutic interventions.