Mechanisms of Epigenetic Plasticity in Neuropathic Pain

神经病理性疼痛的表观遗传可塑性机制

• 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
• 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

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。 与慢性疼痛有关的网络。神经病理性疼痛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的持续性变化 水平对于慢性疼痛的发展是必不可少的。α2δ-1(由CacNA2d1基因编码)是一种 临床验证的神经病理性疼痛靶点，并介导加巴喷丁的治疗作用。 创伤性神经损伤和某些癌症化疗药物引起背根α-2、δ-1上调 神经节和脊髓，通过直接相互作用增加对脊髓背角神经元的伤害性输入 与NMDA受体结合。然而，我们对神经损伤如何引发和维持兴奋几乎一无所知。 α-2δ-1的表达水平。组蛋白尾部赖氨酸残基的乙酰化受多种因素的动态调节 组蛋白脱乙酰酶(HDAC)。然而，负责上调α2δ的特定HDAC亚型- 1等神经可塑性相关基因在神经病理性疼痛中的作用尚未得到严格的研究或鉴定。至 为了解决这一关键知识差距，我们将具体确定I类HDAC亚型在控制中的作用 组蛋白乙酰化和α-2、δ-1等突触可塑性相关基因靶点的表达 神经病理性疼痛模型。在我们初步数据的基础上，我们建议检验总体假设 神经损伤和化疗减少了HDAC2的占有率，从而通过CK2- DRG中Cacna 2d1和其他神经可塑性相关基因启动子的介导的磷酸化 而HDAC2通过抑制Cacna 2d1转录和α2δ-1-1来结构性地抑制慢性疼痛。 依赖于脊髓水平的NMDA受体激活。我们将应用几个创新和充满活力的 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 在分子、细胞和行为水平上研究神经可塑性。我们的项目将产生根本性的新 关于神经病理性疼痛的表观遗传学基础的信息。我们项目的发现有望取得进展 我们对表观遗传可塑性的分子机制的认识并指导开发新的策略 治疗神经病理性疼痛。