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.

项目总结 视网膜神经节细胞(RGC)及其视神经轴突变性致盲 通过对眼压(IOP)的敏感性进行投射。尽管做出了努力，许多患者仍继续失明 控制眼压。因此，未得到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 长期目标是在神经元修复、保护和恢复的基础上确定新的治疗靶点。在……里面 在之前的资助周期中，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。我们发现了两种新的适应性重塑形式 增强和保存RGC信号和缓慢的进展。单侧眼压升高，代谢重新分布 眼压升高将代谢产物从非应激性视神经转移到视网膜和神经 通过星形细胞网络。缝隙连接蛋白Cx43(Cx43)的条件性敲除 这一网络，并防止重新分配。最后，对于暴露在高眼压下的单个RGC，增强 兴奋性放大光反应，即使树突的复杂性减少，通过重组 无髓鞘轴突节段的电压门控钠通道(NAV)。这两种现象都发生得很早，而且 是暂时的，它们的保护作用也是暂时的。我们此次竞争性更新的目标是在这些基础上再接再厉 识别兴奋性增强和代谢重新分配如何与机械相关的重要结果 轴突和树突的变性，以及是否可以加强它们以延长RGC的生存时间。作为推论， 我们将测试这两种适应的暂时性是否源于新陈代谢和氧化应激。 到星形胶质细胞网络，如果外源性资源的增加减少了这种压力并扩大了视力 功能。这一假设得到了新的初步数据的支持，这些数据显示了一种饮食代谢物(丙酮酸) 增加视神经中的星形胶质细胞糖原，并增强神经兴奋，以应对高眼压， 提示这两种形式的适应性重塑可能是有联系的。在我们的诱导性青光眼模型中，我们将 利用结合电生理、细胞和活体成像的跨学科方法，以及 转基因工具。目标1将确定适应性重构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之间的相互依赖关系 兴奋性和通过星形胶质细胞网络的代谢重新分配是否从视网膜到空间映射 完整的RGC轴突和树突功能区段。最后，目标3将测试是否能促进新陈代谢 资源可减少星形胶质细胞应激，延长适应性重塑，并减缓小鼠和非 人类青光眼的灵长类动物模型。我们的创新战略将以前一批赠款的成果为基础 阐明两个新的、本质上是代偿的适应过程如何利用代谢资源促进 青光眼患者的RGC存活率。通过将结果转化为我们的非人类灵长类动物模型，我们将测试治疗 靶向增强兴奋性和代谢再分配作为临床干预的价值。