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，钝性创伤和穿透伤害引起的眼部损伤对受伤的士兵，退伍军人和社区成员的临床管理及其受伤后的生活质量。由脑外伤引起的视觉功能障碍，战斗眼创伤和青光眼包括模糊视力，恐惧症，视野缺陷，敏锐度和失明的丧失。这些临床体征通常是由于眼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。分子与眼部损伤同时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，进而有助于细胞内Ca2+通量过多进入神经节细胞。过多的Ca2+对细胞代谢和信号传导具有有害影响死亡。这些发现表明，可以通过阻止神经节细胞存活的增强损伤后，早期将Ca2+涌入神经节细胞。建议的研究重点是测试两种药理学化合物，即L/T型Ca2+通道拮抗剂，Lomerizine和高度选择性的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通性和视觉功能，以及2）保持视觉行为。调查会专注于良好理解的链型式视网膜神经节细胞（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和行为功能。特定的目标1将测试Perampanel和Lomerizine是否在视神经损伤后增强IPRGC生存并保留其树突形态和突触连通性。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形态并c）保留 IPRGC突触连接。特定的目标2将测试Perampanel和Lomerizine Restore IPRGC是否还原视神经损伤后介导的行为功能。调查将测试由 IPRGC在内，包括a）昼夜节律，b）瞳孔光反射和c）光感知/厌恶。这些新型的药理学方法将使人们更好地了解基本过程介导细胞内Ca2+通量以及过度Ca2+通量对神经节细胞变性的影响。这些研究将为开发治疗方法和诊断工具的开发奠定阶段治疗和预防眼损伤，与NEI的健康相关目标一致视力和失明受损。