Opioid-Induced RGC Neuroprotection via Changes in Protein Acetylation

青光眼是世界范围内致盲的主要原因，其特征在于视网膜神经节的进行性丧失 视网膜神经节细胞（RGC），视神经的挖掘外观和视力丧失。青光眼的病因是 复杂，涉及生物力学和缺血性应激，神经营养因子剥夺，神经胶质活化， 促进促炎细胞因子的产生。目前，没有临床治疗来挽救RGC， 青光眼患者。因此，需要有效的神经保护策略和药物来拯救RGC， 这种疾病。 本实验室已证实δ-阿片受体持续激活7天， 慢性大鼠青光眼模型中的长期（42天）RGC神经保护作用。这种长期的神经保护 反应支持阿片类药物诱导视网膜和视神经的表观遗传变化， 以在通常导致进行性神经元丧失的条件下保持其功能完整性。疼痛 管理研究表明，表观遗传变化与阿片类药物诱导的耐受性有关， 长期服用阿片类药物后产生的依赖性。两个主要事件导致了 这些阿片类药物诱导的表观遗传变化：组蛋白乙酰化增加， 营我们提供的初步数据表明，蛋白质乙酰化，cAMP水平，磷酸化， cAMP反应元件结合蛋白（CREB）在高眼压眼中显著降低。 慢性δ-阿片类药物给药增加组蛋白-H3乙酰化水平，刺激cAMP/CREB 信号，并最终增加神经营养因子的表达。根据这些基准初步 数据，我们假设：“δ-阿片受体的激活诱导表观遗传变化， 昏迷性损伤”。为了验证这一假设，我们提出了两个具体目标。1)确定的角色 蛋白乙酰化在δ-阿片激动剂的神经保护反应中的作用; 2）确定CREB的作用 δ-阿片受体激动剂的神经保护反应中的信号传导。拟议研究的结果将不会 仅对理解阿片类药物介导的RGC的机制产生积极影响 神经保护，但也将确定新的和新颖的神经保护策略治疗青光眼 患者

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 and ischemic stress, neurotrophic factor deprivation, glial activation, and enhanced production of pro-inflammatory cytokines. Currently, there is no clinical treatment to rescue RGCs in glaucoma patients. Therefore, effective neuroprotective strategies and agents are needed to rescue RGCs in this disease. Our laboratory has demonstrated that sustained activation of δ-opioid receptor 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 and optic nerve allowing RGCs to maintain their functional integrity under conditions that normally lead to progressive neuronal loss. Pain management studies have shown that epigenetic changes are associated with opioid-induced tolerance and dependence that develops following chronic opioid-administration. Two central events are responsible for these opioid-induced epigenetic changes: an increase in histone acetylation, and prolonged elevation in cAMP. We provided preliminary data showing that protein acetylation, levels of cAMP, and phosphorylation of cAMP response element binding protein (CREB) are significantly reduced in ocular-hypertensive eyes. Chronic δ-opioid administration increases the level of histone-H3 acetylation, stimulates cAMP/CREB signaling, and eventually increases the expression of neurotrophins. Based on these benchmark preliminary data, we hypothesize that: "Activation of δ-opioid receptors induces epigenetic changes that attenuate glaucomatous injury”. To test this hypothesis, we propose two Specific Aims. 1) Determine the roles of protein acetylation in the neuroprotective response to δ-opioid agonist and 2) Determine the role of CREB signaling in the neuroprotective response to δ-opioid agonist. 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 new and novel neuroprotective strategies for the treatment of glaucoma patients.