Epigenetic Mechanisms of Neuropathic Pain

描述(申请人提供)：这个项目的目标是研究慢性疼痛的表观遗传学基础，特别强调了解在从急性疼痛到慢性神经性疼痛的转变过程中活跃的表观遗传学机制。慢性疼痛会导致数百万美国人长期受苦，生活质量下降。神经性疼痛仍然是一个主要的临床问题和治疗挑战，因为现有的止痛药往往无效，并可能导致严重的副作用。此外，初级感觉神经元基因表达持续改变的机制以及它们在从急性疼痛到慢性疼痛的转变中的作用仍然知之甚少。神经病理性疼痛的特征之一是背根神经节(DRG)神经元中某些电压激活的K+(Kv)和钙激活的K+通道的表达和功能持续降低。下调Kv1.4、Kv4.2或大电导钙激活的K+(BK)通道可以增加DRG神经元的兴奋性，从而导致异常伤害性输入和慢性疼痛的持续性增加。一种可能性是，这些基因受到表观遗传变化的下调。尽管在理解表观遗传学在调控发育生物学和癌症相关基因中的作用方面取得了重大进展，但人们对表观遗传学变化在慢性疼痛发展中的重要性知之甚少。在这个合作的多学科项目中，在神经可塑性和神经病理性疼痛方面拥有专业知识的神经科学家潘慧琳博士和表观遗传学专家Jean-Pierre Issa博士将合作并确定神经病理性疼痛中DRG的表观遗传学变化。我们将检验表观遗传机制有助于初级感觉神经元神经可塑性的总体假设，初级感觉神经元参与慢性神经病理性疼痛的诱导、发展和维持。本应用的具体目标是(1)确定神经病理性疼痛发生过程中DRG中Kv1.4、Kv4.2和BK基因的DNA甲基化和组蛋白修饰的变化；(2)确定神经病理性疼痛发生过程中DRG中DNA甲基化和组蛋白修饰的全基因组模式；以及(3)确定表观遗传调节在慢性神经病理性疼痛发生中的作用以及DRG中K+通道基因的相关沉默。由于表观遗传机制在神经病理性疼痛的基因表达和发展调控中的关键作用以前还没有被认识到，我们使用表观遗传学方法来回答这些问题可能会改变我们对表观基因组如何定义和促进慢性疼痛发展的知识。我们期待这一提议的新发现将为表观遗传控制慢性疼痛的发展提供新的见解，并极大地提高我们对调控慢性疼痛神经可塑性的分子通路的理解。此外，我们的项目可能提供新的信息，可能导致新的表观遗传治疗药物的开发，以预防和治疗慢性神经病理性疼痛。

DESCRIPTION (provided by applicant): The goal of this project is to study the epigenetic basis of chronic pain, with a specific emphasis on understanding the epigenetic mechanisms active during the transition from acute pain to chronic neuropathic pain. Chronic pain leads to prolonged suffering and a reduced quality of life for millions of Americans. Neuropathic pain remains a major clinical problem and therapeutic challenge because existing analgesics are often ineffective and can cause serious side effects. In addition, the mechanisms involved in the sustained alterations in gene expression found in primary sensory neurons and their role in the transition from acute to chronic pain are still poorly understood. One of the characteristic changes in neuropathic pain is the persistent reduction in the expression and function of certain voltage-activated K+ (Kv) and Ca2+-activated K+ channels in dorsal root ganglion (DRG) neurons. Down regulation of Kv1.4, Kv4.2, or large-conductance Ca2+-activated K+ (BK) channels can increase the excitability of DRG neurons, which causes a persistent increase in abnormal nociceptive input and chronic pain. One possibility is that these genes are down regulated by epigenetic changes. Despite the significant advances being made in understanding the role of epigenetics in regulating genes involved in developmental biology and cancer, little is known about the importance of epigenetic changes in the development of chronic pain. In this collaborative and multi-disciplinary project, Dr. Hui-Lin Pan, a neuroscientist with expertise in neural plasticity and neuropathic pain, and Dr. Jean-Pierre Issa, an expert in epigenetics, will collaborate and identify epigenetic changes in the DRG in neuropathic pain. We will test the overall hypothesis that epigenetic mechanisms contribute to the neuroplasticity in primary sensory neurons that is involved in the induction, development, and maintenance of chronic neuropathic pain. The specific aims of this application are to (1) identify changes in DNA methylation and histone modifications of Kv1.4, Kv4.2, and BK genes in the DRG during neuropathic pain development; (2) identify genome-wide patterns of DNA methylation and histone modifications in the DRG during neuropathic pain development; and (3) determine the effects of epigenetic modulation on the development of chronic neuropathic pain and the associated silencing of K+ channel genes in the DRG. Because the critical role of epigenetic mechanisms in the regulation of gene expression and development of neuropathic pain has not been recognized previously, our use of epigenetic approaches to answer these questions could transform our knowledge of how the epigenome defines and contributes to chronic pain development. We expect that new findings from this proposal will provide novel insight into the epigenetic control of chronic pain development and greatly improve our understanding of the molecular pathways that regulate neuroplasticity in chronic pain. In addition, our project may provide novel information, which could lead to the development of new epigenetic therapeutic agents to prevent and treat chronic neuropathic pain.