VRC: Reduction of Vision Loss with Early Interventions After Optic Nerve Injury

VRC：视神经损伤后早期干预可减少视力丧失

• 批准号: 10597946
• 负责人: NICHOLAS C. BRECHA
• 金额: $ 20.12万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597946
• 关键词: Acute; Americas; Anti-Inflammatory Agents; Apoptosis; Axon; Behavior; Behavioral; Blast Injuries; Blindness; Blunt Trauma; Blurred vision; Calcium; Cell Death; Cell Survival; Cell model; Cell physiology; Cellular Morphology; Cellular Structures; Chronic; Circadian Rhythms; Clinical; Clinical Management; Communities; Dendrites; Department of Defense; Development; Disease; Early Intervention; Emergency Care; Excitatory Amino Acid Antagonists; Eye Injuries; Eye diseases; Foundations; Generalized Epilepsy; Glaucoma; Glutamate Receptor; Goals; Health; Health Care Costs; Homeostasis; Hospitals; Injectable; Injury; Intervention; Investigation; Japan; Knowledge; Mediating; Metabolism; Migraine; Modeling; Molecular; Morphology; Nerve Degeneration; Neurologic; Neuronal Injury; Optic Nerve; Optic Nerve Injuries; Oral; Perception; Permeability; Pharmaceutical Preparations; Pharmacology; Photophobia; Photosensitivity; Prevention; Process; Property; Protocols documentation; Pupil light reflex; Quality of life; Recovery; Reporting; Retina; Retinal Degeneration; Retinal Ganglion Cells; Role; Savings; Scotoma; Signal Transduction; Synapses; Testing; Traumatic Brain Injury; Veterans; Vision; Visual; Visual impairment; antagonist; blast trauma; combat; diagnostic tool; drug action; drug preservation; drug testing; ganglion cell; member; military service; novel; novel therapeutic intervention; optic nerve disorder; preservation; prevent; response to injury; retinal ganglion cell degeneration; service member; therapeutic development; treatment strategy; visual dysfunction; visual processing; voltage; wounded soldier

Abstract Ocular injury due to blast, blunt-force trauma and penetrating injuries have dramatic consequences on the clinical management of injured soldiers, Veterans and community members, and their quality of life after injury. Visual dysfunctions caused by traumatic brain injury, combat ocular trauma and glaucoma include blurred vision, photophobia, visual field defects, loss of acuity and blindness. These clinical signs are often due to ocular injury that leads to retinal ganglion cell and optic nerve degeneration, and retinal cell death. Molecular and cellular changes concomitant with ocular injury include the early dysregulation of voltage-gated calcium (Ca2+) channels and AMPA glutamate receptors, which in turn contributes to excessive intracellular Ca2+ flux into ganglion cells. Excessive Ca2+ has deleterious effects on cellular metabolism and signaling leading to cell death. These findings suggest the enhancement of ganglion cell survival can be increased by blocking the early influx of Ca2+ into ganglion cells after injury. Proposed investigations are focused on testing two pharmacological compounds, a L/T-type Ca2+ channel antagonist, lomerizine and a highly selective AMPA glutamate receptor antagonist, perampanel. We will test the action of these drugs on 1) short- and long-term ganglion cell survival, dendritic morphology, synaptic connectivity and visual function after optic nerve injury, and 2) maintaining visual behaviors. Investigations will focus on the well understood interplexiform retinal ganglion cell (ipRGCs) as a model ganglion cell model and test if these drugs preserve their morphological properties and behavioral functions following optic nerve injury. Specific Aim 1 will test if perampanel and lomerizine enhance ipRGC survival after optic nerve injury and preserve their dendritic morphology and synaptic connectivity. Specifically, investigations will determine if these drugs A) enhance ganglion cell survival, B) preserve ipRGC morphology and C) preserve ipRGC synaptic connectivity. Specific Aim 2 will test if perampanel and lomerizine restore ipRGC mediated behavioral function after optic nerve injury. Investigations will test visual behaviors mediated by ipRGCs including A) circadian rhythms, B) pupillary light reflex and C) light perception/aversion. These novel pharmacological approaches will lead to better understanding of fundamental processes mediating intracellular Ca2+ flux and the impact of excessive Ca2+ flux on ganglion cell degeneration. These studies will set the stage for the development of therapeutic approaches and diagnostic tools essential for the treatment and prevention of ocular damage, consistent with the health-related goals of the NEI to prevent impaired vision and blindness.

摘要 由于爆炸、钝力创伤和穿透伤造成的眼损伤对眼神经系统有显著的影响， 受伤士兵，退伍军人和社区成员的临床管理，以及他们受伤后的生活质量。 由创伤性脑损伤、战斗性眼外伤和青光眼引起的视觉功能障碍包括模糊 视力、恐惧症、视野缺陷、敏锐度丧失和失明。这些临床症状通常是由于 导致视网膜神经节细胞和视神经变性以及视网膜细胞死亡的眼损伤。分子 与眼损伤同时发生的细胞变化包括早期电压门控钙离子失调 (Ca2+）通道和AMPA谷氨酸受体，这反过来又导致细胞内Ca 2+通量过多 神经节细胞过量的Ca 2+对细胞代谢和信号传导具有有害影响，导致细胞凋亡。 死亡这些发现表明，通过阻断神经节细胞的生长， 损伤后早期Ca ~（2+）内流到神经节细胞。 建议的研究集中在测试两种药理学化合物，L/T型钙通道 拮抗剂洛美利嗪和高选择性AMPA谷氨酸受体拮抗剂perampanel。我们将测试 这些药物对1）短期和长期神经节细胞存活、树突形态、突触 视神经损伤后的连接和视觉功能; 2）维持视觉行为。调查将 集中于作为模型神经节细胞模型的已充分理解的网间视网膜神经节细胞（ipRGC）， 测试这些药物在视神经损伤后是否保持其形态学特性和行为功能。 具体目标1将测试perampanel和洛美利嗪是否能增强视神经损伤后ipRGC的存活率 并保持它们的树突形态和突触连接。具体而言，调查将 确定这些药物是否A）增强神经节细胞存活，B）保持ipRGC形态和C）保持 ipRGC突触连接。Specific Aim 2将检测perampanel和洛美利嗪是否能恢复ipRGC 介导的视神经损伤后的行为功能。调查将测试视觉行为， ipRGC包括A）昼夜节律，B）瞳孔光反射和C）光感知/厌恶。 这些新的药理学方法将导致更好地了解基本过程 介导细胞内Ca 2+流以及过量Ca 2+流对神经节细胞变性的影响。这些 研究将为发展治疗方法和诊断工具奠定基础， 治疗和预防眼损伤，与NEI的健康相关目标一致，以防止 视力受损和失明。