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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的爆炸、钝器伤和穿透伤造成的眼部损伤会对眼睛造成严重后果。受伤士兵、退伍军人和社区成员的临床管理及其受伤后的生活质量。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视力模糊视力、畏光、视野缺损、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以及视网膜细胞死亡。分子眼损伤伴随的细胞变化包括电压门控钙的早期失调 (Ca2+) 通道和 AMPA 谷氨酸受体，进而导致细胞内 Ca2+ 流量过多进入神经节细胞。过量的 Ca2+ 对细胞代谢和信号传导产生有害影响，导致细胞死亡。这些发现表明，可以通过阻断神经节细胞存活率来增强神经节细胞的存活率。损伤后 Ca2+ 早期流入神经节细胞。拟议的研究重点是测试两种药理学化合物，一种 L/T 型 Ca2+ 通道拮抗剂洛美利嗪和高选择性 AMPA 谷氨酸受体拮抗剂吡仑帕奈。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、突触的作用视神经损伤后的连接性和视觉功能，以及 2) 维持视觉行为。调查将重点关注众所周知的丛状视网膜神经节细胞（ipRGC）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留其形态特性和行为功能。具体目标 1 将测试吡仑帕奈和洛美利嗪是否能增强视神经损伤后 ipRGC 的存活率并保留其树突形态和突触连接。具体来说，调查将确定这些药物是否 A) 增强神经节细胞存活，B) 保留 ipRGC 形态，以及 C) 保留 ipRGC 突触连接。具体目标 2 将测试吡仑帕奈和洛美利嗪是否恢复 ipRGC 视神经损伤后介导的行为功能。调查将测试由以下因素介导的视觉行为 ipRGC 包括 A) 昼夜节律、B) 瞳孔光反射和 C) 光感知/厌恶。这些新颖的药理学方法将有助于更好地理解基本过程介导细胞内 Ca2+ 通量以及过量 Ca2+ 通量对神经节细胞变性的影响。这些研究将为开发至关重要的治疗方法和诊断工具奠定基础治疗和预防眼部损伤，符合 NEI 预防眼部损伤的健康相关目标视力受损和失明。