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

项目摘要 冲击波介导的创伤性脑损伤(BTBI)作为战斗的直接结果影响到军人和平民， 工作场所事故或蓄意恐怖袭击。目前还没有有效的药物疗法。 对于脑外伤，治疗仅限于支持性护理。视网膜是一种中枢神经系统(CNS)组织， 容易受到冲击波的影响。BLAST介导的颅脑损伤患者经常报告视觉功能障碍，这可能 在初次接触后几个月到几年内明显出现。这些问题包括光敏感、视网膜病变、光学 神经病变、视功能障碍和视野丧失，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会导致视觉功能障碍。 脑外伤后，大脑中会发生二级信号级联反应，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 治疗颅脑损伤。在原发组织损伤后的几分钟到几天内发生的最初的炎症级联 包括白介素1(IL-1)细胞因子释放。而IL-1途径的组成部分对这两个中枢神经系统都有贡献 修复和继发性损伤，压倒性证据表明IL-1在脑损伤后全面加重神经元损伤 受伤。在IL-1家族成员中，脑创伤后IL-1α和IL-1β迅速升高。完全相同的 这些细胞因子在塑造脑外伤后神经元反应中的作用尚不清楚，也不清楚是否 对这些通路的调节可能会防止神经元缺失。此外，眼部炎症和炎症的作用 各IL-1分子在颅脑损伤后的相对贡献尚未得到系统的研究。 我的长期目标是确定导致继发性眼部损伤的神经炎症机制。 并开发新的、有针对性的疗法。这项提案的总体目标是评估IL-1的作用 原始细胞介导的脑外伤后视网膜中的通路分子。我的中心假设是封锁特定的 颅脑损伤后的IL-1途径分子将减少继发性视网膜损伤，并将在有效的 抗IL-1途径药物。了解单个IL-1途径分子和细胞效应物在 关注TBI的眼睛代表着一条关键的知识鸿沟。我的研究也可能揭示出新的治疗方法 使用已被批准用于临床的药物的方法。为了验证我的假设，我提出了以下建议 具体目的：1)确定参与bTBI发病机制的IL-1途径的特异性分子。 利用遗传小鼠模型和药物阻断视网膜和2)确定外周的作用 细胞效应器在bTBI视网膜炎症中的作用。

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.