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 冲击伤、钝器伤和穿透伤造成的眼部损伤对 受伤士兵、退伍军人和社区成员的临床处理以及他们受伤后的生活质量。 创伤性脑损伤、战斗眼外伤和青光眼引起的视觉功能障碍包括模糊 视力、畏光、视野缺陷、视力丧失和失明。这些临床症状通常是由于 眼部损伤，导致视网膜神经节细胞和视神经变性，视网膜细胞死亡。分子 伴随着眼部损伤的细胞变化包括早期电压门控钙的失调 (Ca~(2+))通道和AMPA谷氨酸受体，进而导致细胞内过量的钙流量 转化成神经节细胞。过量的钙离子对细胞新陈代谢和导致细胞死亡的信号转导产生有害影响 死亡。这些发现表明，通过阻断神经节细胞存活可以增加神经节细胞的存活。 损伤后早期钙离子内流至神经节细胞。 拟议的研究重点是测试两种药理化合物，一种L/T型钙通道 拮抗剂洛美利嗪和高选择性AMPA谷氨酸受体拮抗剂帕拉帕林。我们将测试 这些药物对神经节细胞的短期和长期存活、树突状细胞形态、突触 视神经损伤后的连通性和视觉功能，以及2)维持视觉行为。调查将会 重点介绍了众所周知的网状视网膜神经节细胞(IpRGCs)作为模型神经节细胞模型和 测试这些药物在视神经损伤后是否保持其形态特征和行为功能。 特定目标1将测试帕拉帕坦和洛美利嗪是否能提高视神经损伤后ipRGC的存活率 并保持其树突形态和突触连通性。具体地说，调查将 确定这些药物是否A)增强神经节细胞的存活，B)保护ipRGC的形态和C)保存 IpRGC突触连接。特定目标2将测试perampanel和洛美利嗪是否能恢复ipRGC 调节视神经损伤后的行为功能。调查将测试由 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对基本过程的更好理解 调节细胞内钙离子流量及过量钙离子流量对神经节细胞退行性变的影响。这些 研究将为开发治疗方法和诊断工具奠定基础 治疗和预防眼损伤，符合NEI预防保健相关目标 视力受损和失明。