Optic nerve head glymphatics and debris clearance in glaucoma

青光眼中的视神经乳头淋巴管和碎片清除

• 批准号: 10455455
• 负责人: NICHOLAS R MARSH-ARMSTRONG
• 金额: $ 49.7万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-17 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455455
• 关键词: Adult; Affect; Animal Model; Architecture; Area; Astrocytes; Autopsy; Axon; Basic Science; Biological Process; Blood Vessels; Characteristics; Clinical; Data; Development; Diagnosis; Diagnostic; Disease; Drainage procedure; Electron Microscopy; Equilibrium; Flushing; Future; Genes; Genetic; Glaucoma; Goals; Health; Human; Imaging technology; Infiltration; Injury; Intervention; LOC118430 gene; Laboratories; Lead; Maps; Measures; Microglia; Mitochondria; Modeling; Molecular; Monkeys; Mus; Myelin; Myelogenous; Myeloid Cells; Neuraxis; Neurodegenerative Disorders; Optic Disk; Optic Nerve; Optical Coherence Tomography; Pathway interactions; Phagocytes; Phagocytosis; Phagocytosis Inhibition; Phenotype; Physiology; Primates; Process; Refuse Disposal; Resolution; Retinal Ganglion Cells; Rodent; Role; Scanning; Site; Stroke; Structure; Subarachnoid Space; Testing; Therapeutic; Work; axon injury; base; diagnostic strategy; experimental study; glymphatic system; in vivo; macrophage; monocyte; mouse model; neuroprotection; nonhuman primate; novel; novel strategies; optic nerve disorder; perivascular channels; reconstruction; recruit; retinal damage; therapeutic target; tomography; tool; wasting

The long-term goal of the Marsh-Armstrong laboratory is to discover new biological processes that may some day become treatment targets in glaucoma. Our laboratory discovered that astrocytes in the optic nerve head, the site where axon loss likely happens in glaucoma, are intrinsically phagocytic, and recently, that axonal mitochondria are one of the major targets of their phagocytosis. Preliminary studies of one the phagocytic genes expressed by optic nerve astrocytes, which is called Mfge8, have lead to the discovery that during development, injury and disease, but to some extent also normal adult physiology, there is much debris within the optic nerve head that is partially processed by astrocytes but then cleared through glymphatic channels around blood vessels that are contiguous with the subarachnoid space. In this application, we set out to examine these “Glymphatics and Debris Clearance in Glaucoma”, to determine how the glymphatic system works at the optic nerve head and how it is affected in animal models of glaucoma. Many of the experiments will be carried out in mice, to: 1) determine the relationship between debris, glymphatic channels, and myeloid cells, which we propose enter the optic nerve center under conditions where debris is not properly removed, 2) determine how the glymphatics, debris clearance, and myeloid cells are affected in mouse models of glaucoma, and 3) determine what happens when debris builds up due to inhibition of the key phagocytic pathways. Other experiments will be carried out in a non-human primate model of glaucoma to: 1) determine whether glymphatics and debris clearance from the optic nerve are similar in mice and primates, and 2) determine whether they are similarly affected by glaucomatous insults. The primate studies will use some of the same tools used in the mouse studies, to be able to integrate the results coming from both species, but also very high resolution reconstructions of areas within the optic nerve that have low amounts of axon damage, that is, areas representing early stages in glaucomatous damage. Altogether, the proposed studies will rigorously test the idea that efficient debris clearance by astrocytes is critical for maintaining a healthy optic nerve, and that in the absence of efficient debris clearance there is myeloid infiltration and axonal damage. Should the experiments demonstrate that the proposed hypothesis is largely correct, it would represent a significant departure from current views of how glaucomatous axonal loss occurs, and this would have important implications as to how glaucoma should be diagnosed and treated.

马什-阿姆斯特朗实验室的长期目标是发现新的生物过程，这些过程可能会 日成为青光眼的治疗目标。我们的实验室发现视神经乳头中的星形胶质细胞 青光眼中轴突丢失可能发生的部位，本质上是吞噬细胞，最近，该轴突 线粒体是其吞噬作用的主要目标之一。吞噬细胞的初步研究 视神经星形胶质细胞表达的基因（称为 Mfge8）导致发现 发育、损伤和疾病，但在某种程度上也是正常的成人生理机能，里面有很多碎片 视神经乳头部分由星形胶质细胞处理，然后通过类淋巴通道清除 与蛛网膜下腔相邻的血管周围。在这个应用程序中，我们着手 检查这些“青光眼的类淋巴系统和碎片清除”，以确定类淋巴系统如何 作用于视神经乳头以及它在青光眼动物模型中如何受到影响。许多实验 将在小鼠中进行，目的是：1）确定碎片、类淋巴通道和骨髓之间的关系 细胞，我们建议在碎片未正确清除的情况下进入视神经中枢，2） 确定小鼠模型中的类淋巴系统、碎片清除和骨髓细胞如何受到影响 青光眼，以及 3) 确定当由于关键吞噬细胞的抑制而导致碎片堆积时会发生什么 途径。其他实验将在非人类灵长类动物青光眼模型中进行，以：1）确定 小鼠和灵长类动物中视神经的类淋巴系统和碎片清除是否相似，2) 确定他们是否同样受到青光眼损伤的影响。灵长类动物研究将使用一些 与小鼠研究中使用的工具相同，能够整合来自两个物种的结果，但是 还可以对视神经内轴突数量较少的区域进行高分辨率重建 损伤，即代表青光眼损伤早期阶段的区域。总而言之，拟议的研究 将严格测试星形胶质细胞有效清除碎片对于维持健康的视神经至关重要的想法 神经，并且在缺乏有效的碎片清除的情况下，会出现骨髓浸润和轴突损伤。 如果实验证明所提出的假设在很大程度上是正确的，那么它将代表一个 与目前关于青光眼轴突损失如何发生的观点有很大的不同，这将有 对于如何诊断和治疗青光眼具有重要意义。

项目成果

Optic Nerve Head Myelin-Related Protein, GFAP, and Iba1 Alterations in Non-Human Primates With Early to Moderate Experimental Glaucoma.

• DOI: 10.1167/iovs.63.11.9
• 发表时间: 2022-10-03
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Chaudhary P;Stowell C;Reynaud J;Gardiner SK;Yang H;Williams G;Williams I;Marsh-Armstrong N;Burgoyne CF
• 通讯作者: Burgoyne CF