Mechanisms of Traumatic Retinal Injury: Targeting the Arginase Pathway

外伤性视网膜损伤的机制：针对精氨酸酶途径

• 批准号: 9031913
• 负责人: Ruth B Caldwell
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031913
• 关键词: 3-nitrotyrosine; Acute; Arginine; Attenuated; Axon; Biochemical; Biological Markers; Blindness; Blood Vessels; Cells; Complex; Data; Development; Early Intervention; Edema; Enzymes; Eye; Eye Injuries; Freedom; Functional disorder; Glaucoma; Goals; Health; Inflammation; Injury; Ischemia; Knowledge; Lead; Macrophage Activation; Mediating; Mediator of activation protein; Metabolic Pathway; Metabolism; Microglia; Mission; Mitochondria; Modeling; Molecular; Nerve Crush; Neurons; Nitric Oxide Synthase; Optic Nerve; Optic Nerve Injuries; Ornithine; Outcome; Oxidants; Oxidative Stress; Pathway interactions; Permeability; Peroxonitrite; Personal Satisfaction; Polyamines; Prevention; Production; Research; Retina; Retinal; Retinal Ganglion Cells; Risk; Safety; Secondary to; Signal Transduction; Structure; Study models; Superoxides; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Trauma; Traumatic injury; Treatment Efficacy; Validation; Vascular Diseases; Vasodilation; Veterans; Vision; Visual; Wild Type Mouse; Work; arginase; base; combat; effective therapy; functional outcomes; improved; in vivo; in vivo imaging; inhibitor/antagonist; injured; innovation; knock-down; mouse model; neurovascular; neurovascular injury; new therapeutic target; novel; novel strategies; novel therapeutics; operation; oxidation; polyamine oxidase; preclinical study; prevent; protective effect; public health relevance; repaired; research study; retinal neuron; treatment effect; vascular inflammation

 DESCRIPTION (provided by applicant): The long term goal of this research is to delineate the molecular mechanisms that lead to trauma-induced retinal neuronal and vascular injury and identify novel strategies to prevent or reverse the damage and preserve vision. The lack of understanding of the detailed molecular mechanisms by which ocular trauma damages the retinal neurons and vascular cells represents a critical knowledge gap in developing effective therapies. Therefore, the goal of this research is to define these mechanisms and identify innovative approaches to prevent such damage, improve functional outcomes and reduce the risk of blindness to veterans returning from the battlefield. Preliminary data suggest that ischemia or trauma-induced activation of the mitochondrial, ureahydrolase enzyme arginase 2 causes microglia/macrophage activation, inflammation and neurovascular degeneration by increasing oxidative stress. Overactive arginase can increase oxidative stress by 1) decreasing the L-arginine supply needed by nitric oxide synthase (NOS) to produce NO, thereby causing NOS to become uncoupled and produce superoxide that reacts with NO to form the toxic oxidant peroxynitrite and/or 2) causing excessive activation of the ornithine-polyamine pathway, thereby leading to polyamine oxidation and production of toxic oxidants. The global hypothesis of this project is that excessive activation of arginase 2 causes microglia/macrophage activation and neurovascular damage by inducing NOS uncoupling and/or excessive activation of the polyamine metabolic pathway. The proposed experiments will test and develop this working model by studies in a mouse model of traumatic optic nerve injury. Two specific aims are proposed. Aim 1 is to test the hypothesis that traumatic retinal injury is mediated by arginase-induced uncoupling of NOS and/or altered polyamine metabolism. These studies will determine the effects of arginase knockdown on microglia/macrophage activation, neurovascular degeneration and vascular function following optic nerve injury. The protective effects of arginase deletion on microglia/macrophage activation, inflammation and neurovascular damage will be examined in relation to NOS function, polyamine metabolism and their activity in producing ROS. Vasorelaxation and permeability barrier function will be determined by in vivo imaging. Arginase 2 deletion should limit microglia/macrophage activation and mitigate the neurovascular damage/dysfunction by normalizing NOS function, reducing polyamine oxidation and limiting oxidative stress and inflammation. Aim 2 is to perform preclinical studies for prevention and treatment of traumatic neurovascular injury. These studies we will determine and compare the treatment efficacy and safety of inhibiting arginase signaling and/or polyamine metabolism in limiting or preventing microglia/macrophage activation, inflammation and retinal neurovascular injury in the model of traumatic injury as explained for Aim 1. The beneficial effects of the treatments in preserving retinal structure and neuronal function will also be assessed using in vivo imaging and electroretingraphic recording. The expected outcomes include validation of the arginase/polyamine pathway as a novel target for therapeutic intervention to attenuate oxidative stress, inflammation and neurovascular degeneration and promote healthy repair following traumatic retinal injury. The impact of this work will be to provide a new understanding of the complex interactions between arginase, NOS and polyamine metabolism-associated inflammation and injury that will serve as a basis for development of novel therapeutic agents to treat traumatic retinal injury. Successful completion of this project is highly relevant to the mission of VA and to the health and well-being of veterans.

 描述（由申请人提供）： 这项研究的长期目标是描述导致创伤引起的视网膜神经元和血管损伤的分子机制，并确定预防或逆转损伤并保护视力的新策略。创伤损害视网膜神经元和血管细胞是开发有效疗法的关键知识差距。 确定这些机制并确定创新方法来预防此类损伤，改善功能结果并降低从战场返回的退伍军人失明的风险。初步数据表明，缺血或创伤引起的线粒体、尿素水解酶精氨酸酶 2 的激活会导致小胶质细胞/。过度活跃的精氨酸酶会通过增加氧化应激来激活巨噬细胞、炎症和神经血管变性，从而增加氧化应激：1) 减少硝酸所需的 L-精氨酸供应。氧化物合酶（NOS）产生NO，从而导致NOS解偶联并产生超氧化物，该超氧化物与NO反应形成有毒氧化剂过亚硝酸盐和/或2）导致鸟氨酸-多胺途径过度激活，从而导致多胺氧化和产生该项目的总体假设是精氨酸酶 2 的过度激活通过诱导 NOS 导致小胶质细胞/巨噬细胞激活和神经血管损伤。所提出的实验将通过对创伤性视神经损伤的小鼠模型进行研究来测试和开发该工作模型，目的 1 是检验创伤性视网膜的假设。损伤是由精氨酸酶诱导的 NOS 解偶联和/或改变的多胺代谢介导的。这些研究将确定精氨酸酶敲低对小胶质细胞/巨噬细胞活化、神经血管变性和血管功能的影响。视神经损伤后精氨酸酶缺失对小胶质细胞/巨噬细胞活化、炎症和神经血管损伤的保护作用将通过体内确定与NOS功能、多胺代谢及其产生血管舒张和渗透性屏障功能的活性相关。精氨酸酶 2 缺失应限制小胶质细胞/巨噬细胞的激活，并通过使 NOS 功能正常化、减少多胺氧化和限制氧化应激来减轻神经血管损伤/功能障碍。目标 2 是进行预防和治疗创伤性神经血管损伤的临床前研究，我们将确定和比较抑制精氨酸酶信号传导和/或多胺代谢在限制或预防小胶质细胞/巨噬细胞激活、炎症和炎症方面的治疗效果和安全性。正如目标 1 所解释的，创伤性损伤模型中的视网膜神经血管损伤。还将使用体内成像和视网膜电图记录来评估治疗在保留视网膜结构和神经元功能方面的有益效果。预期结果包括验证精氨酸酶/多胺途径作为治疗干预的新靶点，以减轻氧化应激、炎症和神经血管变性并促进创伤性视网膜损伤后的健康修复。这项工作的影响将是提供对视网膜损伤的新认识。精氨酸酶、NOS 和多胺代谢相关炎症和损伤之间复杂的相互作用，将作为开发治疗创伤性视网膜损伤的新型治疗药物的基础，该项目的成功完成与任务高度相关。退伍军人管理局以及退伍军人的健康和福祉。