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.

青光眼是全球失明的主要原因，其特征是残留神经节细胞的逐渐丧失 （RGC），视神经的发掘外观和视力丧失。青光眼的病因很复杂， 涉及生物力学应力，促炎性细胞因子，神经营养因素的剥夺和表观遗传学 更改。目前，尚无临床治疗可挽救青光眼患者的RGC。因此，有效 需要神经保护策略和药物来营救RGC。表观遗传修饰是一种新兴和 然而，有前途的新型方法调节神经退行性疾病中细胞功能的作用 青光眼的定义较差。我们的实验室表明，δ-阿片类受体的持续激活 SNC-121的7天为慢性大鼠青光眼提供了显着的长期（42天）RGC神经保护作用 模型。这种长期神经保护反应支持了阿片类药物诱导表观遗传变化的观念 视网膜允许RGC在通常导致进步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 慢性阿片类药给药后发展的耐受性和依赖性。我们提供了初步数据 表明表观遗传调节剂，例如I类和IIB组蛋白脱乙酰基酶，DNA甲基转移酶 （DNMT）活性和表达以及基因组宽的DNA甲基化的反应显着增加 眼睛高血压诱导的损伤。此外，RNA SEQ，PCR阵列，免疫组织化学和ATAC SEQ 数据提供了重要的潜在客户，即细胞因子，促凋亡途径，转录因子，神经营养蛋白和 染色质结构受眼高血压损伤和δ阿片类药物治疗的显着影响。我们也是 已经表明，“ CpG”岛中许多基因的转录起始位点（TSS）受到不同的影响 δ-阿片类药物。基于我们的初步数据，我们假设“δ阿片受体的激活会影响 高乙酰化和低甲基化可减轻青光眼中的RGC死亡。” 我们提出以下两个具体目标。具体目标1。确定I类和IIB组蛋白的关键作用 眼部高血压动物RGC死亡中的脱乙酰基酶（HDACS）。具体目标2。确定DNA的作用 眼部高血压动物中δ-阿片类介导的RGC神经保护作用中的甲基化。结果 拟议的研究不仅将对对基本机制的理解产生积极影响 阿片类药物介导的RGC神经保护作用，但还将确定青光眼治疗的新颖和创新靶标。