Optic nerve head glymphatics and debris clearance in glaucoma

马什-阿姆斯特朗实验室的长期目标是发现新的生物过程， 天成为治疗青光眼的目标。我们的实验室发现视神经头中的星形胶质细胞， 青光眼中可能发生轴突丢失的部位本质上是吞噬细胞的，最近，轴突 线粒体是其吞噬作用的主要目标之一。一种吞噬细胞 由视神经星形胶质细胞表达的基因，称为Mfge 8，已经导致发现， 发育、损伤和疾病，但在某种程度上也是正常的成人生理，有很多碎片内 视神经头部分由星形胶质细胞处理，然后通过胶质淋巴通道清除 在与蛛网膜下腔相连的血管周围。在本申请中，我们着手 检查这些“青光眼的淋巴系统和碎片清除”，以确定胶质淋巴系统如何 作用于视神经乳头，以及它在青光眼动物模型中是如何受到影响的。许多实验 将在小鼠中进行，以：1）确定碎片、胶质淋巴通道和骨髓间充质干细胞之间的关系。 细胞，我们建议进入视神经中枢的条件下，碎片没有得到适当的清除，2） 确定胶质细胞，碎片清除和骨髓细胞在小鼠模型中是如何受到影响的。 青光眼，以及3）确定当碎片由于抑制关键吞噬细胞而积聚时会发生什么 途径。其他实验将在青光眼的非人灵长类动物模型中进行，以：1）确定 在小鼠和灵长类动物中，来自视神经的glymphatics和碎片清除是否相似，以及2） 确定他们是否受到类似的昏迷性侮辱。灵长类动物的研究将使用一些 在小鼠研究中使用的相同工具，能够整合来自两个物种的结果， 视神经内轴突数量少的区域的高分辨率重建 损伤，即代表昏迷损伤早期阶段的区域。总体而言，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光学系统至关重要的想法 在缺乏有效碎片清除的情况下，存在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， 这与目前关于昏迷性轴突丢失如何发生的观点有很大的不同， 这对青光眼的诊断和治疗具有重要意义。

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.