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.

神经性疼痛表观可塑性的机制 我们项目的主要目的是确定创伤性神经损伤如何影响表观遗传调节 涉及慢性疼痛的网络。神经性疼痛仍然是一个主要的临床问题和治疗挑战。 脊髓的原发性神经元中基因表达的持续变化和突触可塑性 水平对于慢性疼痛的发展至关重要。 α2δ-1（由cacna2d1基因编码）是A 通过临床验证的神经性疼痛靶标，并介导gabapentinoids的治疗作用。 创伤性神经损伤和某些癌症化学治疗药物在背根中引起α2Δ1上调 神经节和脊髓，通过直接相互作用来增强对脊柱背角神经元的伤害感受性输入 与NMDA接收器。然而，我们几乎一无所知 α2δ-1的表达水平。组蛋白尾巴中赖氨酸残留物的乙酰化受到各种不同的调节 组蛋白脱乙酰基酶（HDACS）。但是，负责α2Δ-上调的特定HDAC亚型 1和神经性疼痛中的其他神经塑性相关基因尚未被严格研究或鉴定。到 解决此关键知识差距，我们将特别确定I类HDAC子类型在控制中的作用 在两种突触可塑性中实施的α2δ-1和其他基因靶标的组蛋白乙酰化和表达 神经性疼痛模型。根据我们的初步数据，我们建议测试总体假设 通过CK2-- 在CACNA2D1的启动子和DRG中的其他神经可塑性相关基因上介导的磷酸化 HDAC2通过反映CACNA2D1转录和α2Δ-1–组成构成判断慢性疼痛 脊髓水平的依赖性NMDA受体激活。我们将采用一些创新和有力的 方法，包括无偏基因组的表观遗传学分析，转基因小鼠和突触记录 研究分子，细胞和行为水平的神经可塑性。我们的项目将产生基本的新 有关神经性疼痛的表观遗传基础的信息。预计我们项目的发现将进步 我们对表观遗传可塑性的分子机制的了解，并指导新策略的发展 用于治疗神经性疼痛。