Interleukin-6 and Retinal Ganglion Cell Degeneration in Glaucoma

白细胞介素 6 和青光眼视网膜神经节细胞变性

• 批准号: 10015270
• 负责人: REBECCA M SAPPINGTON
• 金额: $ 41.39万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015270
• 关键词: Appearance; Atrophic; Award; Axon; Blindness; Cell Culture Techniques; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Cellular Structures; Custom; Data; Development; Disease; Disease model; Equilibrium; Etiology; Exhibits; Functional disorder; Glaucoma; Goals; In Vitro; Individual; Inflammatory; Injury; Interleukin 6 Receptor; Interleukin-6; Intervention; Knockout Mice; Knowledge; Measures; Mediating; Microspheres; Modeling; Mus; Natural regeneration; Nerve Crush; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Ocular Hypertension; Optic Nerve; Optic Nerve Injuries; Outcome; Pathway interactions; Pharmacological Treatment; Pharmacology; Physiologic Intraocular Pressure; Physiological; Plant Roots; Preparation; Process; Publishing; Recombinant Proteins; Reporting; Retinal Ganglion Cells; Retinal Vein Occlusion; Secondary to; Series; Signal Pathway; Signal Transduction; Steroid therapy; Structure; Synapses; Testing; Therapeutic Intervention; Transgenic Organisms; Vision; Work; axon injury; base; cell injury; cell regeneration; cytokine; functional outcomes; improved; in vitro Model; in vivo Model; interleukin-6 receptor alpha; neuron loss; prevent; programs; regenerative; repaired; retinal ganglion cell degeneration; survival outcome; targeted treatment; therapeutic target

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.

项目摘要 视网膜神经节细胞(RGC)变性是全球数百万人失明的原因。研资局 退行性疾病遵循一种常见的生理功能障碍和结构性萎缩的顺序范例 到整个中枢神经系统的神经退化。这个神经元死亡程序从功能性开始 与神经元通过轴突与其他神经元保持联系的能力有关的缺陷。这是第一次 功能缺陷为治疗干预提供了最有希望的窗口。由于它与 在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，报告结果的模棱两可和不清楚 作用机制阻碍了IL-6作为治疗靶点的发展。IL-2对生存的促进作用 视网膜节细胞中的信号最常被描述为发展中的视网膜节细胞或具有灾难性损伤的视网膜节细胞。 轴突。相反，通常在RGC轴突残留的疾病模型中描述有害的结果。 相对完整和退化更类似于细胞解体。我们在提议颁奖期间的目标 期间是系统和机械地建立IL-6结果模棱两可的背景基础 RGC神经退行性变，并描绘了介导它们的IL-6信号通路。我们的初步数据 提示IL-6直接影响RGC轴突的发育和功能。此外，天平 IL-6信号通路随着损伤和发育状态的不同而变化。我们将测试中央 假设视网膜节细胞中IL-6信号的机制和结果直接依赖于 轴突的结构和功能状态。在RGC发育模型(目标1)中，RGC退行性变与 完整轴突(目标2)和RGC变性伴结构性轴突损伤(目标3)，我们将：1)定义功能性 IL-6信号在视网膜节细胞中的转归，2)描述了IL-6经典信号和IL-6信号在RGC中的作用。转信令 通向这些结果的途径，以及3)确定信号的下游目标。诱导性、条件性IL-6 受体敲除小鼠，我们将进行药物治疗以诱导：天然IL-6信号，全球IL-6- 6信号缺陷、单独IL-6反式信号转导和单独IL-6经典信号转导。通过测量整体视觉 RGC的功能、众多结构和功能结果以及下游信号的诱导 ，我们将检验工作假说：1)IL-6促进RGC发育和轴突形成 通过经典的信号介导的诱导细胞存活和分化途径，2)IL-6有助于 反式信号转导炎症诱导成熟视网膜节细胞及其完整轴突的退变 信号转导途径和3)IL-6促进视网膜神经节细胞结构轴突损伤的轴突修复 信号介导的诱导细胞存活和分化的途径类似于 发展。拟议工作的成功完成将提供开发IL-6所需的知识 作为抑制RGC退变和促进RGC的治疗靶点 再生。