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

基本信息

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
项目类别：
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

项目摘要

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导致失明的主要原因，其特征是视网膜神经节进行性丧失细胞（RGC）、视神经凹陷和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、神经胶质激活和增强促炎细胞因子的产生目前，尚无拯救 RGC 的临床治疗方法。因此，需要有效的神经保护策略和药物来挽救 RGC。这种病。我们的实验室已证明 δ-阿片受体持续激活 7 天可提供显着的效果对慢性大鼠青光眼模型的长期（42 天）RGC 神经保护作用。反应支持阿片类药物诱导视网膜和视神经发生表观遗传变化，从而允许 RGC 的观点在通常导致进行性神经丧失的情况下保持其功能完整性。管理研究表明表观遗传变化与阿片类药物诱导的耐受性和长期使用阿片类药物后产生的依赖性有两个主要因素。这些阿片类药物诱导的表观遗传变化：组蛋白乙酰化增加，以及组蛋白乙酰化水平长期升高。我们提供了初步数据，显示蛋白质乙酰化、cAMP 水平和磷酸化。 cAMP 反应元件结合蛋白 (CREB) 在高眼压眼中显着减少。长期使用 δ-阿片类药物会增加组蛋白 H3 乙酰化水平，刺激 cAMP/CREB 信号传导，并最终根据这些初步基准增加神经营养素的表达。数据中，我们得出：“δ-阿片受体的激活会诱导表观遗传变化，从而减弱为了检验这一假设，我们提出了两个具体目标 1) 确定的作用。蛋白质乙酰化在 δ-阿片受体激动剂的神经保护反应中的作用以及 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不会。只会对阿片类药物介导的 RGC 机制的理解产生积极影响神经保护，但还将确定治疗青光眼的新的神经保护策略患者。