Opioid-Induced RGC Neuroprotection via Changes in Protein Acetylation

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逐渐丧失。 细胞(RGCs)，视神经的开挖外观，以及视力丧失。青光眼的病因是 复杂，涉及生物力学和缺血应激，神经营养因子剥夺，胶质细胞激活，以及 促进促炎细胞因子的产生。目前，还没有临床治疗方法来拯救视网膜神经节细胞。 青光眼患者。因此，需要有效的神经保护策略和药物来拯救视网膜节细胞。 这种病。 我们的实验室已经证明，δ阿片受体的持续激活7天提供了显著的 长期(42天)RGC对慢性大鼠青光眼模型的神经保护作用。这种长期的神经保护作用 反应支持阿片类药物导致视网膜和视神经的表观遗传变化的想法，允许视网膜节细胞 在通常会导致进行性神经元丧失的情况下保持其功能的完整性。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和 长期服用阿片类药物后形成的依赖。有两个主要事件负责 这些阿片类药物诱导的表观遗传学改变：组蛋白乙酰化增加，并持续升高 夏令营。我们提供的初步数据显示，蛋白质乙酰化、cAMP水平和磷酸化 高眼压眼cAMP反应元件结合蛋白(CREB)显著降低。 慢性δ阿片给药增加组蛋白-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改变，从而减弱 青光眼损伤“。为了检验这一假设，我们提出了两个具体目标。1)确定 蛋白质乙酰化在δ阿片激动剂的神经保护反应中的作用 δ阿片激动剂神经保护反应中的信号转导。拟议研究的结果将不会 只有对了解阿片介导的RGC的机制才有积极的影响 神经保护，但也将确定治疗青光眼的新的神经保护策略 病人。

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.