Interleukin-6 and Retinal Ganglion Cell Degeneration in Glaucoma

项目摘要 视网膜神经节细胞（RGC）变性是全世界数百万人视力丧失的原因。RGC 退化遵循生理功能障碍和结构性萎缩的顺序范例， 到中枢神经系统的神经退化这个神经元死亡程序开始于功能性 与神经元通过轴突与其他神经元保持连接的能力相关的缺陷。该第一 功能缺陷定义了治疗干预的最有希望的窗口。由于其与 在这一神经元死亡程序的几个步骤中，白细胞介素-6（IL-6）具有显著的干预潜力， 神经退行性疾病不幸的是，报告的结果含糊不清， 作用机制阻碍了IL-6作为治疗靶点的发展。IL-1的促生存结局 RGC中的6信号传导最常被描述用于发展中的RGC或其细胞具有灾难性损伤的那些。 轴突相反，对于RGC轴突保留的疾病模型， 相对完整，退化更类似于细胞解体。我们的目标在拟议的奖励 阶段是系统地和机械地建立IL-6结果不明确的背景基础， RGC神经变性和描绘IL-6信号通路介导他们。我们的初步数据 表明IL-6直接影响RGC轴突的发育和功能。此外，平衡 IL-6信号通路之间的变化相对于损伤和发育状态。我们将测试中央 假设RGC中IL-6信号传导的机制和结果直接依赖于 它们轴突的结构和功能状态。在RGC发育模型（目标1）中，RGC变性伴 完整的轴突（目标2）和RGC变性与结构性轴突损伤（目标3），我们将：1）定义功能性 IL-6信号转导在RGC中的结果，2）描绘IL-6经典和.反传信号 这些结果的途径和3）确定下游目标的信号。在诱导型、条件性IL-6 受体敲除小鼠，我们将进行药理学治疗以诱导：天然IL-6信号传导，整体IL-6信号传导， 6信号传导缺陷、单独的IL-6反式信号传导和单独的IL-6经典信号传导。通过测量整体视觉 RGC的许多结构和功能结果以及下游信号传导的诱导 我们将测试以下工作假设：1）IL-6促进RGC发育和轴突形成 通过经典的信号传导介导的细胞存活和分化途径，2）IL-6有助于 通过反式信号转导介导的炎症诱导成熟RGC及其完整轴突的变性 3）IL-6通过经典的信号通路促进具有结构性轴突损伤的成熟RGC中的轴突修复 信号传导介导的细胞存活和分化途径的诱导类似于 发展成功完成拟议的工作将提供开发IL-6所需的知识 作为治疗靶点，抑制RGC变性和促进RGC 再生

Project Summary Retinal ganglion cell (RGC) degeneration is the cause of vision loss for millions of individuals worldwide. RGC degeneration follows a sequential paradigm of physiological dysfunction and structural atrophy that is common to neurodegeneration across the central nervous system. This neuronal death program begins with functional deficits associated with a neuron's ability to maintain connections with other neurons via their axons. This first functional deficit defines the most promising window for therapeutic intervention. Due to its association with several steps in this neuronal death program, interleukin-6 (IL-6) has significant interventional potential across neurodegenerative disorders. Unfortunately, ambiguities in reported outcomes and lack of clarity regarding mechanisms of action have impeded development of IL-6 as a therapeutic target. Pro-survival outcomes of IL- 6 signaling in RGCs are most often described for developing RGCs or those with catastrophic injury of their axons. In contrast, detrimental outcomes are often described for disease models where RGC axons remain relatively intact and degeneration is more akin to cell disintegration. Our goal during the proposed award period is to systematically and mechanistically establish the contextual basis for IL-6 outcome ambiguities in RGC neurodegeneration and delineate the IL-6 signaling pathways that mediate them. Our preliminary data indicate that IL-6 directly impacts the development and function of RGC axons. Furthermore, the balance between IL-6 signaling pathways shifts with respect to insult and developmental state. We will test the central hypothesis that the mechanisms and outcomes of IL-6 signaling in RGCs are directly dependent upon the structural and functional state of their axons. In models of RGC development (Aim 1), RGC degeneration with intact axons (Aim 2) and RGC degeneration with structural axon injury (Aim 3), we will: 1) define the functional outcomes of IL-6 signaling in RGCs, 2) Delineate the relative contributions of IL-6 classical and. trans-signaling pathways to those outcomes and 3) Identify downstream targets of signaling. In inducible, conditional IL-6 receptor knockout mice, we will perform pharmacological treatments to induce: native IL-6 signaling, global IL- 6 signaling deficiency, IL-6 trans-signaling alone and IL-6 classical signaling alone. By measuring overall visual function, numerous structural and functional outcomes for RGCs and induction of downstream signaling pathways, we will test the working hypotheses that: 1) IL-6 promotes RGC development and axon formation via classical signaling-mediated induction of cell survival and differentiation pathways, 2) IL-6 contributes to degeneration of mature RGCs and their intact axons via trans-signaling-mediated induction of inflammatory signaling pathways and 3) IL-6 promotes axon repair in mature RGCs with structural axon injury via classical signaling-mediated induction of cell survival and differentiation pathways similar to those in development. Successful completion of the proposed work will provide the knowledge required to develop IL-6 as a target for therapeutics directed at both inhibition of RGC degeneration and promotion of RGC regeneration.