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， 日成为青光眼的治疗靶点。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，最近，轴突 线粒体是它们吞噬的主要目标之一。一种吞噬细胞的初步研究 被称为Mfge8的视神经星形胶质细胞表达的基因导致了在 发育、损伤和疾病，但在某种程度上也是正常的成人生理，里面有很多碎片 由星形胶质细胞部分加工，然后通过淋巴通道清除的视神经头 环绕着与蛛网膜下腔相邻的血管。在此应用程序中，我们开始 检查这些“青光眼中的淋巴管和碎片清除”，以确定淋巴系统是如何 作用于视神经头，以及在青光眼动物模型中它是如何受到影响的。许多实验 将在小鼠身上进行，以：1)确定碎片、淋巴通道和髓系之间的关系 细胞，我们建议在碎片未被适当清除的情况下进入视神经中心，2) 确定淋巴系统、碎片清除和髓系细胞是如何在小鼠模型中受到影响的 青光眼，以及3)确定由于关键吞噬细胞抑制而导致碎片堆积时会发生什么 小路。其他实验将在非人类灵长类青光眼模型中进行，以确定：1) 小鼠和灵长类动物的视神经淋巴和碎片清除情况是否相似，以及2) 确定他们是否同样受到青光眼侮辱的影响。灵长类研究将使用一些 在老鼠研究中使用的相同工具，能够整合来自两个物种的结果，但 对视神经内轴突数量较少的区域也进行非常高分辨率的重建 损害，即代表青光眼损害早期阶段的区域。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维持健康视神经至关重要的观点 在缺乏有效的碎片清除的情况下，会出现髓鞘渗透和轴突损伤。 如果实验证明所提出的假设在很大程度上是正确的，它将代表一种 与目前关于青光眼轴突丢失发生的观点有很大不同，这将是 对于青光眼应该如何诊断和治疗具有重要的意义。

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.