Mechanisms of Epigenetic Plasticity in Neuropathic Pain

神经病理性疼痛的表观遗传可塑性机制

基本信息

批准号：
10678116
负责人：
Shao-Rui Chen
金额：
$ 45.77万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678116
关键词：
Ablation Acetylation Address Afferent Neurons Analgesics Behavioral Binding CNR1 gene Chromatin Structure Chronic Clinical DNA Methylation Data Development Dissociation Down-Regulation Epigenetic Process G9a histone methyltransferase Gene Expression Gene Targeting Genes Genetic Genetic Transcription Goals HDAC2 gene Histone Acetylation Histone Deacetylase Histones Hypersensitivity Individual Knock-out Knowledge Lysine Malignant Neoplasms Mediating Molecular Mus N-Methyl-D-Aspartate Receptors NMDA receptor antagonist Nerve Pain Neuronal Plasticity Neurons Neuropathy Nociception Opioid Paclitaxel Pain Peripheral Nerves Pharmaceutical Preparations Phenotype Phosphorylation Play Posterior Horn Cells Potassium Channel Protein Inhibition Receptor Activation Receptor Gene Regulation Repression Role Small Interfering RNA Spinal Spinal Cord Spinal Ganglia Surgical Injuries Synapses Synaptic plasticity Tail Testing Therapeutic Therapeutic Effect Transgenic Mice Traumatic Nerve Injury Traumatic injury Up-Regulation Vertebral column antinociception casein kinase II chemotherapy chromatin modification chronic pain dorsal horn epigenetic silencing genome-wide injured innovation insight knock-down nerve injury novel therapeutics pain chronification pain model painful neuropathy promoter restraint transcriptomics

项目摘要

Mechanisms of Epigenetic Plasticity in Neuropathic Pain The major objective of our project is to determine how traumatic nerve injury impacts epigenetic regulatory networks involved in chronic pain. Neuropathic pain remains a major clinical problem and therapeutic challenge. Both sustained changes in gene expression in primary afferent neurons and synaptic plasticity at the spinal cord level are essential for to the development of chronic pain. α2δ-1 (encoded by the Cacna2d1 gene) is a clinically validated neuropathic pain target and mediates the therapeutic actions of gabapentinoids. Traumatic nerve injury and certain cancer chemotherapeutic drugs cause α2δ-1 upregulation in the dorsal root ganglion and spinal cord, which augments nociceptive input to spinal dorsal horn neurons by directly interacting with NMDA receptors. Yet we know almost nothing about how nerve injury initiates and sustains the high expression level of α2δ-1. Acetylation of lysine residues in histone tails is dynamically regulated by various histone deacetylases (HDACs). However, the specific HDAC subtypes responsible for the upregulation of α2δ- 1 and other neuroplasticity-related genes in neuropathic pain have not been rigorously studied or identified. To address this key knowledge gap, we will specifically determine the role of class I HDAC subtypes in the control of histone acetylation and expression of α2δ-1 and other gene targets implicated in synaptic plasticity in two neuropathic pain models. On the basis of our preliminary data, we propose to test the overall hypothesis that nerve injury and chemotherapy diminish HDAC2 occupancy to induce histone hyperacetylation, via CK2- mediated phosphorylation, at the promoters of Cacna2d1 and other neuroplasticity-related genes in the DRG and that HDAC2 constitutively restrains chronic pain by repressing Cacna2d1 transcription and α2δ-1– dependent NMDA receptor activation at the spinal cord level. We will apply several innovative and vigorous approaches, including unbiased genome-wide epigenetic analyses, transgenic mice, and synaptic recordings to study neuroplasticity at molecular, cellular, and behavioral levels. Our project will generate fundamental new information about the epigenetic basis of neuropathic pain. Findings from our project are expected to advance our knowledge of molecular mechanisms of epigenetic plasticity and to guide the development of new strategies for treating neuropathic pain.

神经病理性疼痛的表观遗传可塑性机制我们项目的主要目标是确定创伤性神经损伤如何影响表观遗传调控与慢性疼痛有关的神经网络仍然是一个主要的临床问题和治疗挑战。初级传入神经元基因表达和脊髓突触可塑性均持续变化 α2δ-1（由 Cacna2d1 基因编码）对于慢性疼痛的发展至关重要。经临床验证的神经性疼痛靶向并介导加巴喷丁类药物的治疗作用。创伤性神经损伤和某些癌症化疗药物导致背根 α2δ-1 上调神经节和脊髓，通过直接相互作用增强脊髓背角神经元的伤害性输入然而，我们对神经损伤如何引发和维持高水平几乎一无所知。组蛋白尾部赖氨酸残基的乙酰化表达水平受到多种因素的动态调节。然而，特定的 HDAC 亚型负责 α2δ- 的上调。 1 和神经病理性疼痛中的其他神经可塑性相关基因尚未经过严格研究或鉴定。为了解决这个关键的知识差距，我们将具体确定 I 类 HDAC 亚型在控制中的作用组蛋白乙酰化以及 α2δ-1 和其他与突触可塑性有关的基因靶标的表达根据我们的初步数据，我们建议检验以下总体假设：神经损伤和化疗会减少 HDAC2 的占用，从而通过 CK2- 诱导组蛋白过度乙酰化介导的磷酸化，位于 DRG 中 Cacna2d1 和其他神经可塑性相关基因的启动子处 HDAC2 通过抑制 Cacna2d1 转录和 α2δ-1 来组成性抑制慢性疼痛我们将应用几种创新且有力的脊髓水平的 NMDA 受体激活。方法，包括无偏见的全基因组表观遗传分析、转基因小鼠和突触记录我们的项目将在分子、细胞和行为水平上研究神经可塑性。有关神经性疼痛的表观遗传基础的信息预计将取得进展。我们对表观遗传可塑性分子机制的了解并指导新策略的开发用于治疗神经性疼痛。