Opioid-Induced RGC Neuroprotection via Changes in Protein Acetylation

阿片类药物通过蛋白质乙酰化的变化诱导 RGC 神经保护

• 批准号: 9383249
• 负责人: Shahid Husain
• 金额: $ 37.38万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383249
• 关键词: Acetylation; Acute; Agonist; Appearance; Astrocytes; Attenuated; Benchmarking; Biological Preservation; Biomechanics; Blindness; CREB1 gene; Cessation of life; Chronic; Clinical Treatment; Complex; Cyclic AMP; Cyclic AMP-Responsive DNA-Binding Protein; Data; Dependence; Development; Disease; Epigenetic Process; Etiology; Event; Exhibits; Eye; Glaucoma; Goals; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Homeostasis; Human; Hypoxia; Individual; Inflammatory; Injury; Ischemia; Laboratories; Lead; Link; Maintenance; Mediating; Modeling; Modification; Mus; Nerve Degeneration; Nerve Tissue; Neuraxis; Neuronal Injury; Ocular Hypertension; Opioid; Opioid Receptor; Optic Nerve; Outcome; Pain management; Pathway interactions; Patients; Pharmacology; Phosphorylation; Physiologic Intraocular Pressure; Primary Open Angle Glaucoma; Process; Production; Protein Acetylation; Publishing; Rattus; Rattus norvegicus; Receptor Activation; Retina; Retinal; Retinal Ganglion Cells; Risk Factors; Rodent Model; Role; Signal Pathway; Signal Transduction Pathway; Signaling Protein; Stress; Testing; Translating; Visual Fields; Visual impairment; Work; base; cytokine; deprivation; effective therapy; enzyme activity; epigenetic regulation; glial activation; histone acetyltransferase; inhibitor/antagonist; insight; neuron loss; neuroprotection; neurotrophic factor; novel; novel therapeutics; optic nerve disorder; preconditioning; protein activation; response; transcription factor; treatment strategy

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.

青光眼是世界范围内致盲的主要原因，其特点是视网膜神经节的逐渐丧失