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

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）及其轴突的变性而致盲 通过对眼内压（IOP）的敏感性进行预测。许多患者继续失去视力，尽管努力 控制IOP。因此，未满足的临床需求是直接解决RGC变性的治疗。我们 长期目标是确定基于神经元修复、保护和恢复的新的治疗靶点。在 在上一个资助周期中，我们利用转基因小鼠品系来辨别RGC树突状细胞之间的相互作用， 修剪、轴突变性和星形胶质细胞胶质。我们发现了两种新的适应性重塑形式， 增强和保护RGC信号传导并减缓进展。单侧眼压升高，代谢再分布 将代谢物从未受压的视神经转移到视网膜和受到IOP升高挑战的神经 通过星形胶质细胞网络。条件性敲除差距连接蛋白连接蛋白43（Cx43）解偶联 这个网络，防止再分配。最后，对于暴露于升高的IOP的个体RGC， 兴奋性放大光反应，即使树突的复杂性减少，通过重组 电压门控钠通道（NaV）在无髓鞘轴突段。这两种现象都发生在早期， 是短暂的，它们的保护作用也是如此。我们在这次竞争性更新中的目标是建立在这些基础上， 重要的结果，以了解如何增强兴奋性和代谢再分配机制， 轴突和树突变性以及它们是否可以增强以延长RGC存活。作为推论， 我们将测试这两种形式的适应的短暂性是否来自代谢和氧化应激 如果外源性地增加资源可以减少这种压力， 功能这一假设得到了新的初步数据的支持，这些数据显示， 增加视神经中的星形胶质细胞糖原并增强对IOP升高的反应的神经兴奋， 这表明这两种形式的适应性重塑可能是相关的。在我们的诱导型青光眼模型中，我们将 利用结合电生理学、细胞和体内成像的跨学科方法， 转基因工具目的1将确定适应性重塑对轴突病变和树突状细胞的依赖性。 修剪目标2将描述代谢再分配和增强的 兴奋性以及是否通过星形胶质细胞网络的代谢再分布将视网膜定位映射到空间 完整的RGC轴突和树突功能。最后，Aim 3将测试是否促进代谢 资源减少星形胶质细胞压力，延长适应性重塑，并减缓小鼠和非 青光眼的人类灵长类动物模型。根据上一个赠款期的成果，我们的创新战略将 阐明两个新的，内在补偿适应过程如何利用代谢资源，以促进 青光眼中的RGC存活率。通过将结果转化到我们的非人类灵长类动物模型中，我们将测试治疗效果。 靶向增强兴奋性和代谢再分布作为临床干预的价值。