Opioid-Induced Epigenetic Mechanisms in Glaucoma

阿片类药物诱导的青光眼表观遗传机制

• 批准号: 10563745
• 负责人: Shahid Husain
• 金额: $ 44.31万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563745
• 关键词: ATAC-seq; Acetylation; Acute; Affect; Agonist; Animals; Apoptotic; Appearance; Astrocytes; Attenuated; Binding; Biomechanics; Blindness; Brain-Derived Neurotrophic Factor; CREB1 gene; Cataract; Cell Death; Cell physiology; Characteristics; Chromatin Structure; Chronic; Clinical Treatment; Complex; CpG Islands; DNA Methylation; DNA Modification Methylases; DNMT3B gene; DNMT3a; Data; Decitabine; Dependence; Epigenetic Process; Etiology; Event; Exhibits; Eye; Gene Expression; Genes; Glaucoma; Glial Fibrillary Acidic Protein; Goals; Histone Acetylation; Histone Deacetylase; Histones; Homeostasis; Hypermethylation; Immunohistochemistry; Inflammatory; Injury; Laboratories; Lead; Measures; Mediating; Methylation; Modeling; Modification; Mus; Nerve Degeneration; Neurodegenerative Disorders; Ocular Hypertension; Opioid; Optic Disk; Optic Nerve; Outcome; Pain management; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Physiologic Intraocular Pressure; Physiological; Primary Open Angle Glaucoma; Promoter Regions; Rattus; Rattus norvegicus; Receptor Activation; Regulation; Retina; Retinal Ganglion Cells; Retinoblastoma; Risk Factors; Role; STAT3 gene; Stress; Testing; Therapeutic; Transcription Initiation Site; Visual impairment; Work; cytokine; delta opioid receptor; deprivation; genome-wide; inhibitor; innovation; mRNA Expression; neuroprotection; neurotrophic factor; novel; novel strategies; novel therapeutics; optic nerve disorder; prevent; protein expression; response; transcription factor; transcriptome sequencing

Glaucoma, a leading cause of blindness worldwide, is characterized by progressive loss of retinal ganglion cells (RGCs), an excavated appearance of the optic nerve, and vision loss. The etiology of glaucoma is complex, involving biomechanical stress, pro-inflammatory cytokines, deprivation of neurotrophic factors, and epigenetic changes. Currently, there is no clinical treatment to rescue RGCs in glaucoma patients. Therefore, effective neuroprotective strategies and agents are needed to rescue RGCs. Epigenetic modification is an emerging and promising novel approach to modulate cellular function in neurodegenerative diseases, however, its role in glaucoma remains poorly defined. Our laboratory has demonstrated that sustained activation of δ-opioid receptor by SNC-121 for 7-days offered significant long-term (42-days) RGC neuroprotection in a chronic rat glaucoma model. This long-term neuroprotective response supports the idea that opioids induce epigenetic changes in the retina allowing RGCs to maintain their functional integrity under conditions that normally lead to progressive RGCs loss. Pain management studies have shown that epigenetic changes are associated with opioid-induced tolerance and dependence that develops following chronic opioid-administration. We provided preliminary data showing that epigenetic regulators such as class I and IIb histone deacetylases, DNA methyltransferases (DNMTs) activities and expression, and genome wide DNA methylation were significantly increased in response to ocular hypertension-induced injury. Additionally, RNA Seq, PCR array, immunohistochemistry, and ATAC Seq data provide significant leads that cytokines, pro-apoptotic pathways, transcriptional factors, neurotrophins, and chromatin structure are significantly affected by ocular hypertension injury and δ-opioids treatment. We also have shown that transcription start sites (TSS) of numerous genes in “CpG” Island were differentially affected by δ-opioids. Based on our Preliminary Data, we hypothesize that “Activation of δ-opioid receptors induces hyperacetylation and hypomethylation that attenuates RGCs death in glaucoma”. To test this hypothesis, we propose the following two Specific Aims. Specific Aim 1. Determine the crucial roles of class I and IIb histone deacetylases (HDACs) in RGC death in ocular hypertensive animals. Specific Aim 2. Determine the role of DNA methylation in δ-opioid-mediated RGC neuroprotection in ocular hypertensive animals. The outcome of the proposed studies will not only have a positive impact on the understanding of mechanisms underlying the opioid-mediated RGC neuroprotection, but will also identify novel and innovative targets for glaucoma therapy.

青光眼是世界范围内导致失明的主要原因，其特征是视网膜神经节细胞逐渐丧失 （RGC）、视神经凹陷和视力丧失 青光眼的病因很复杂。 生物力学应激、促炎细胞因子、神经营养因子的剥夺以及涉及表观遗传的 目前，临床上尚无有效的治疗方法来挽救青光眼患者的 RGC。 拯救 RGC 需要神经保护策略和药物，表观遗传修饰是一种新兴的技术。 在神经退行性疾病中调节细胞功能的有前景的新方法，然而，其在 我们的实验室已经证明 δ-阿片受体持续激活，青光眼的定义仍然不明确。 SNC-121 持续 7 天对慢性大鼠青光眼提供显着的长期（42 天）RGC 神经保护 这种长期的神经保护反应支持阿片类药物诱导表观遗传变化的观点。 视网膜允许 RGC 在通常导致进行性进展的条件下保持其功能完整性 疼痛管理研究表明，RGC 损失与阿片类药物引起的表观遗传变化有关。 长期使用阿片类药物后产生的耐受性和依赖性我们提供了初步数据。 显示表观遗传调节因子，例如 I 类和 IIb 类组蛋白脱乙酰酶、DNA 甲基转移酶 (DNMT) 活性和表达以及全基因组 DNA 甲基化响应显着增加 另外，RNA Seq、PCR 阵列、免疫组织化学和 ATAC Seq。 数据提供了重要线索，表明细胞因子、促凋亡途径、转录因子、神经营养因子和 染色质结构受到高眼压损伤和 δ-阿片类药物治疗的显着影响。 已经表明，“CpG”岛中许多基因的转录起始位点（TSS）受到不同程度的影响 根据我们的初步数据，我们认为“δ-阿片受体的激活会诱导 过度乙酰化和低甲基化可减轻青光眼中 RGC 的死亡”。 我们提出以下两个具体目标： 1. 确定 I 类和 IIb 类组蛋白的关键作用。 脱乙酰酶 (HDAC) 在高眼压动物 RGC 死亡中的作用 具体目标 2. 确定 DNA 的作用。 δ-阿片类药物介导的高眼压动物 RGC 神经保护中的甲基化。 拟议的研究不仅会对理解其背后的机制产生积极影响 阿片类药物介导的 RGC 神经保护，但也将确定青光眼治疗的新颖和创新靶点。