Mechanisms of Adaptive Remodeling and Their Therapeutic Potential in Glaucoma

适应性重塑机制及其在青光眼中的治疗潜力

• 批准号: 10583190
• 负责人: David J. Calkins
• 金额: $ 45.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-02 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583190
• 关键词: Acceleration; Address; Apoptotic; Astrocytes; Axon; BAX gene; Bioenergetics; Blindness; Brain; Cell Survival; Cellular Stress; Clinical; Connexin 43; Connexins; Coupling; Data; Dendrites; Dependence; Dietary Supplementation; Disease; Electrophysiology (science); Exposure to; Glaucoma; Glycogen; Goals; Grant; Individual; Insulin-Like Growth Factor I; Intervention; Knock-out; Light; Link; Maps; Measures; Metabolic; Metabolic stress; Metabolism; Microspheres; Modeling; Mouse Strains; Mus; National Eye Institute; Nature; Nerve; Nerve Degeneration; Neurons; Optic Disk; Optic Nerve; Optics; Outcome; Oxidative Stress; Patients; Pattern; Persons; Physiologic Intraocular Pressure; Physiological; Process; Publishing; Pyruvate; Resources; Retina; Retinal Ganglion Cells; Rodent; Saimiri; Signal Transduction; Sodium Channel; Stress; Supplementation; Testing; Therapeutic; Transgenes; Transgenic Mice; Transgenic Organisms; Translating; Vision; Wallerian Degeneration; Work; age related; axonal degeneration; axonopathy; cell type; conditional knockout; dietary; improved; in vivo imaging; innovation; neurotransmission; new therapeutic target; nonhuman primate; novel; preservation; pressure; prevent; protective effect; public health relevance; repaired; response; restoration; retinal ganglion cell degeneration; retinotopic; stress reduction; therapeutic evaluation; tool; voltage; Acceleration; Address; Apoptotic; Astrocytes; Axon; BAX gene; Bioenergetics; Blindness; Brain; Cell Survival; Cellular Stress; Clinical; Connexin 43; Connexins; Coupling; Data; Dendrites; Dependence; Dietary Supplementation; Disease; Electrophysiology (science); Exposure to; Glaucoma; Glycogen; Goals; Grant; Individual; Insulin-Like Growth Factor I; Intervention; Knock-out; Light; Link; Maps; Measures; Metabolic; Metabolic stress; Metabolism; Microspheres; Modeling; Mouse Strains; Mus; National Eye Institute; Nature; Nerve; Nerve Degeneration; Neurons; Optic Disk; Optic Nerve; Optics; Outcome; Oxidative Stress; Patients; Pattern; Persons; Physiologic Intraocular Pressure; Physiological; Process; Publishing; Pyruvate; Resources; Retina; Retinal Ganglion Cells; Rodent; Saimiri; Signal Transduction; Sodium Channel; Stress; Supplementation; Testing; Therapeutic; Transgenes; Transgenic Mice; Transgenic Organisms; Translating; Vision; Wallerian Degeneration; Work; age related; axonal degeneration; axonopathy; cell type; conditional knockout; dietary; improved; in vivo imaging; innovation; neurotransmission; new therapeutic target; nonhuman primate; novel; preservation; pressure; prevent; protective effect; public health relevance; repaired; response; restoration; retinal ganglion cell degeneration; retinotopic; stress reduction; therapeutic evaluation; tool; voltage

PROJECT SUMMARY Glaucoma blinds through degeneration of retinal ganglion cells (RGCs) and their axons in the optic projection through sensitivity to intraocular pressure (IOP). Many patients continue to lose vision despite efforts to manage IOP. Thus, an unmet clinical need is a treatment that addresses RGC degeneration directly. Our long-term goal is to identify new therapeutic targets based on neuronal repair, protection, and restoration. In the previous grant cycle, we leveraged transgenic mouse strains to discern interplay between RGC dendritic pruning, axon degeneration, and astrocyte glia. We discovered two novel forms of adaptive remodeling that boost and preserve RGC signaling and slow progression. With unilateral IOP elevation, metabolic redistribution transfers metabolites from the unstressed optic nerve to the retina and nerve challenged by IOP elevation through astrocyte networks. Conditional knock-out of the gap junction protein connexin 43 (Cx43) uncouples this network and prevents redistribution. Finally, for individual RGCs exposed to elevated IOP, enhanced excitability amplifies the light response, even as dendritic complexity diminishes, through reorganization of voltage-gated sodium channels (NaV) in the unmyelinated axon segment. Both phenomena occur early and are transient, as are their protective effects. Our objective in this competitive renewal is to build upon these important results to discern how enhanced excitability and metabolic redistribution mechanistically relate to axonal and dendritic degeneration and whether they can be enhanced to extend RGC survival. As a corollary, we will test whether the transient nature of both forms of adaptation arises from metabolic and oxidative stress to the astrocyte network and if boosting resources exogenously reduces this stress and extends visual function. This hypothesis is supported by new preliminary data showing a dietary metabolite (pyruvate) increases astrocyte glycogen in the optic nerve and enhances nerve excitation in response to elevated IOP, suggesting that the two forms of adaptive remodeling may be linked. In our inducible glaucoma models, we will utilize a cross-disciplinary approach that combines electrophysiological, cellular and in vivo imaging, and transgenic tools. Aim 1 will determine the dependence of adaptive remodeling on axonopathy and dendritic pruning. Aim 2 will characterize the interdependence between metabolic redistribution and enhanced excitability and whether metabolic redistribution through astrocyte networks maps retinotopically to spatial sectors of intact RGC axon and dendritic function. Finally, Aim 3 will test whether boosting metabolic resources reduces astrocyte stress, extends adaptive remodeling, and slows progression in mouse and non- human primate models of glaucoma. Building from results in the prior grant period, our innovative strategy will elucidate how two novel, intrinsically compensatory adaptive processes utilize metabolic resources to promote RGC survival in glaucoma. By translating results to our non-human primate model, we will test the therapeutic value of targeting enhanced excitability and metabolic redistribution as clinical interventions.

项目摘要 青光眼通过视网膜神经节细胞（RGC）及其轴突的变性而在视线 通过对眼内压（IOP）的敏感性投影。尽管努力，许多患者仍继续失去视力 管理IOP。因此，未满足的临床需求是一种直接解决RGC变性的治疗方法。我们的 长期目标是根据神经元修复，保护和恢复确定新的治疗靶标。在 上一个赠款周期，我们利用转基因小鼠应变来辨别RGC树突状的相互作用 修剪，轴突变性和星形胶质细胞神经胶质。我们发现了两种新型的自适应改造形式 提升并保留RGC信号传导和缓慢的进展。单侧IOP高程，代谢再分配 从无重大的视神经转移到视网膜，并受到IOP高程挑战的神经 通过星形胶质细胞网络。间隙连接蛋白连接素43（CX43）的条件敲除 该网络并防止重新分布。最后，对于暴露于IOP升高的单个RGC，增强了 兴奋性会放大光反应，即使树突复杂性通过重新组织而降低 不髓鞘轴突段中的电压门控钠通道（NAV）。这两种现象都早于 是短暂的，它们的保护作用也是如此。我们在这种竞争更新中的目标是建立在这些基础上 重要的结果，以辨别增强的兴奋性和代谢重新分布如何机械上有关 轴突和树突变性以及是否可以增强它们以延长RGC的存活。作为推论， 我们将测试两种适应形式的瞬时性质是否来自代谢和氧化应激 到星形胶质细胞网络，如果增加资源会外源减轻这种压力并扩展视觉 功能。该假设得到了新的初步数据的支持，显示了饮食代谢物（丙酮酸） 增加视神经中的星形胶质细胞糖原，并响应于IOP升高，增强神经激发 提示可以连接两种形式的自适应重塑。在我们诱导的青光眼模型中，我们将 利用一种结合电生理，细胞和体内成像的跨学科方法，以及 转基因工具。 AIM 1将确定适应性重塑对轴突病和树突状的依赖性 修剪。 AIM 2将表征代谢再分配与增强之间的相互依赖性 兴奋性以及通过星形胶质细胞网络的代谢重新分布是否在视网膜上映射到空间 完整的RGC轴突和树突函数的扇区。最后，AIM 3将测试是否增强代谢 资源减少星形胶质细胞应力，扩展自适应重塑，并减慢小鼠和非 - 青光眼的人类灵长类动物模型。在上一批赠款期间的结果中建立，我们的创新策略将 阐明两个新颖的内在补偿性自适应过程如何利用代谢资源来促进 青光眼中的RGC存活。通过将结果转换为我们的非人类灵长类动物模型，我们将测试治疗性 靶向增强兴奋性和代谢再分配作为临床干预措施的价值。