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进行性丧失。 (RGCs)，挖出的视神经外观，以及视力丧失。青光眼的病因很复杂， 涉及生物力学应激、促炎细胞因子、神经营养因子的剥夺和表观遗传学 改变。目前，还没有临床治疗方法来挽救青光眼患者的视网膜神经节细胞。因此，有效的 需要神经保护策略和药物来拯救视网膜节细胞。表观遗传修饰是一种新兴的 然而，在神经退行性疾病中，它在调节细胞功能方面的作用 青光眼的定义仍然不明确。我们实验室已经证明了δ-阿片受体的持续激活 SNC-121对慢性青光眼大鼠的长期(42天)RGC神经保护作用 模特。这种长期的神经保护反应支持阿片类药物诱导表观遗传学改变的观点 视网膜允许RGC在通常导致进展性疾病的条件下保持其功能完整性 RGCS损失。疼痛管理研究表明，表观遗传变化与阿片类药物诱导有关 长期服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 研究表明，表观遗传调节因子，如I类和IIb类组蛋白脱乙酰酶、DNA甲基转移酶 (Dnmts)活性和表达，以及全基因组DNA甲基化显著增加 高眼压所致的损伤。此外，RNA序列、聚合酶链式反应阵列、免疫组织化学和ATAC序列 数据提供了细胞因子、促凋亡途径、转录因子、神经营养因子和 高眼压损伤和δ阿片类药物治疗对染色质结构有显著影响。我们也 已经表明，CpG岛上许多基因的转录起始点(TS)受到不同程度的影响 δ-阿片类药物。根据我们的初步数据，我们假设δ-阿片受体的激活诱导 高乙酰化和低甲基化可减少青光眼视网膜神经节细胞的死亡“。为了检验这一假设， 我们提出了以下两个具体目标。具体目标1.确定I类和IIb类组蛋白的关键作用 去乙酰酶在高眼压动物RGC死亡中的作用。特定目标2.确定DNA的作用 δ阿片类药物对高眼压动物视网膜节细胞神经保护作用的甲基化。选举的结果是 拟议的研究不仅将对理解潜在的机制产生积极影响 阿片介导的RGC神经保护，但也将确定青光眼治疗的新和创新的靶点。