Dissection and manipulation of inflammatory pathways underlying post-traumatic visual outcomes

创伤后视觉结果的炎症途径的剖析和操纵

• 批准号: 9910605
• 负责人: Lucy Pratt Evans
• 金额: $ 3.6万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-09 至 2023-04-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910605
• 关键词: Accidents; Acute; Affect; Blindness; Bone Marrow Transplantation; Brain; Brain Injuries; Cell physiology; Cells; Cellular Structures; Clinical; Cytokine Signaling; Data; Detection; Development; Dissection; Drug Utilization; Electroretinography; Eye; Eye Injuries; Family; Family member; Functional disorder; Genes; Genetic; Goals; Immune; Individual; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-1 alpha; Interleukin-1 beta; Invaded; Knockout Mice; Knowledge; Label; Lead; Leukocytes; Mediating; Military Personnel; Modeling; Molecular; Mus; Neuraxis; Neuronal Injury; Neurons; Optical Coherence Tomography; Optics; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Peripheral; Pharmacology; Photophobia; Recombinants; Reporting; Retina; Retinal Diseases; Retinal Ganglion Cells; Role; Secondary to; Shapes; Signal Transduction; Structure; Supportive care; TBI treatment; Terrorism; Testing; Therapeutic; Therapeutic Intervention; Tissues; Traumatic Brain Injury; Tumor-infiltrating immune cells; Vision; Visual; Visual Fields; Workplace; anakinra; cell motility; clinically relevant; combat; cytokine; improved outcome; in vivo; insight; member; mouse model; neuroinflammation; novel; novel therapeutic intervention; null mutation; optic nerve disorder; preservation; prevent; receptor; repaired; response; retinal damage; targeted agent; targeted treatment; therapeutic candidate; therapy development; tissue injury; vision development; visual processing

Project Summary Blast-mediated traumatic brain injury (bTBI) affects military members and civilians as a direct result of combat, workplace accidents, or intentional terrorist attacks. There are currently no effective pharmacologic therapies for TBI and treatment is limited to supportive care. The retina is a central nervous system (CNS) tissue that is vulnerable to blast exposure. Individuals with blast-mediated TBI often report visual dysfunction, which may manifest months to years after the initial exposure. These problems include light sensitivity, retinopathy, optic neuropathy, dysfunctional optic motility, and visual field loss, although little is known about the molecular changes in both the retina and higher order visual processing centers that lead to visual dysfunction. Following a TBI, secondary signaling cascades occur in the brain, including robust neuroinflammation that exacerbates the initial neuronal insult. Modulating neuroinflammation is a potential therapeutic strategy for treating TBI. The initial inflammatory cascades that occur in the minutes to days following primary tissue injury include interleukin-1 (IL-1) cytokine release. While components of the IL-1 pathway contribute to both CNS repair and secondary injury, overwhelming evidence indicates IL-1 worsens neuronal injury overall after a brain injury. Among members of the IL-1 family, IL-1α and IL-1β increase rapidly after TBI in the brain. The exact role of these cytokines in shaping the neuronal response to TBI is yet unclear, and it is unknown whether modulation of these pathways might prevent neuronal deficits. Furthermore, the role of ocular inflammation and the relative contribution of each IL-1 molecule following TBI has not been systematically explored. My long-term goal is to identify mechanisms of neuroinflammation that contribute to secondary ocular injury and develop novel, targeted therapies. The overall objective of this proposal is to evaluate the role of IL-1 pathway molecules in the retina following blast-mediated TBI. My central hypothesis is that blockade of specific IL-1 pathway molecules following TBI will reduce secondary retinal injury and will be achievable with available anti-IL-1 pathway agents. Understanding the role of individual IL-1 pathway molecules and cellular effectors in the eye following TBI represents a critical knowledge gap. My study may also reveal novel therapeutic approaches that utilize drugs already approved for clinical use. To test my hypothesis, I propose the following Specific Aims: 1) Determine the specific IL-1 pathway molecules that contribute to bTBI pathogenesis in the retina using genetic mouse models and pharmacologic blockade and 2) Determine the role of peripheral cellular effectors contributing to retinal inflammation in bTBI.

项目摘要 爆炸介导的创伤性脑损伤（bTBI）影响军事人员和平民作为战斗的直接结果， 工作场所事故或故意恐怖袭击。目前还没有有效的药物治疗 并且治疗仅限于支持性护理。视网膜是中枢神经系统（CNS）组织， 易受爆炸影响爆炸介导的TBI患者经常报告视觉功能障碍， 在初次接触后数月到数年内就会出现这些问题包括光敏感性，视网膜病变， 神经病变，功能障碍性视运动和视野丧失，尽管对分子机制知之甚少。 视网膜和高级视觉处理中心的变化导致视觉功能障碍。 在TBI之后，在大脑中发生次级信号级联，包括强烈的神经炎症， 加剧了最初的神经元损伤。调节神经炎症是一种潜在的治疗策略， 治疗TBI。在原发性组织损伤后数分钟至数天内发生的初始炎症级联反应 包括白细胞介素-1（IL-1）细胞因子释放。虽然IL-1通路的组分有助于CNS和 修复和继发性损伤，压倒性的证据表明，IL-1的神经元损伤后，整体脑 损伤在IL-1家族成员中，IL-1α和IL-1β在脑TBI后迅速增加。的确切 这些细胞因子在形成对TBI的神经元反应中的作用尚不清楚， 这些通路的调节可以防止神经元缺陷。此外，眼部炎症和 TBI后各IL-1分子的相对作用还没有被系统地研究。 我的长期目标是确定导致继发性眼损伤的神经炎症机制 并开发新的靶向疗法。本提案的总体目标是评估IL-1的作用 在视网膜中的爆炸介导的TBI后的信号通路分子。我的主要假设是， TBI后的IL-1通路分子将减少继发性视网膜损伤，并且将通过可用的 抗IL-1通路药物。了解单个IL-1通路分子和细胞效应物在 眼睛跟随TBI代表了关键的知识差距。我的研究也可能揭示新的治疗方法 使用已经批准用于临床的药物的方法。为了验证我的假设，我提出以下建议 具体目的：1）确定在脑梗死患者中有助于bTBI发病机制的特异性IL-1途径分子。 使用遗传小鼠模型和药理学阻断的视网膜和2）确定外周的作用， bTBI中导致视网膜炎症的细胞效应物。