IOP and Cerebrospinal Fluid Pressure-related Risk Factors for Glaucoma

摘要 青光眼是全世界永久性视力丧失的主要原因，但其损害机制尚不完全。 明白了。视网膜神经节细胞(RGC)及其轴突将视觉信息从视网膜传递到 大脑，这些轴突通过巩膜管在视神经头(ONH)流出眼睛，这是 被称为筛板(LC)的有窗口的结缔组织结构所跨越。优势 大量证据表明，青光眼患者视网膜区的RGC轴突受损。其中之一 最一致的青光眼危险因素是高眼压(IOP)，尽管安全的眼压 门槛在不同的人之间差别很大。虽然有一些证据表明眼压波动会导致 对于青光眼，以前的研究由于缺乏连续的眼压测量而受到阻碍。球后 视神经周围的脑脊液压力(CSFP)通过 跨层压(TLP=IOP-CSFP)。回顾性临床研究表明，较高的CSFP (和低TLP)对青光眼有保护作用，而低CSFP(和高TLP)会增加青光眼风险， 考虑了眼压的影响。此外，由于LC承担了ONH中的大部分压力负荷 由于其相对于周围神经组织的高硬度，LC厚度在 通过跨层压力梯度(TLPG=TLP/LC厚度)在ONH中的TLP分布，增加了 TLP的形态成分。因此，该项目的目标是测试IOP、TLP和 TLPG波动对青光眼发生和进展的独立易感性 在考虑了同眼的不同平均眼压后，并证实了最近的发现，CSFP和IOP是 通过神经通路耦合。在这个项目中，我们将进行机械符合性测试来量化LC 单侧青光眼动物模型受控急性TLP刺激后体内的变形 配备连续眼压、CSFP、TLP和TLPG遥测仪器。然后我们将确定这些关系 对侧眼单位差异平均眼压的轴突和视功能损失之间的关系以及1)暂时性和 昼夜眼压波动，2)TLP和TLPG(平均值和波动值)和3)LC对急性变化的响应 TLP挑战，在眼睛正常时和青光眼发生和发展后测量。影响：如果结果 显示眼压波动、TLP和/或TLPG在青光眼的发生和发展中起重要作用 也就是说，可以开发新的治疗方法来调节这些因素来治疗青光眼。

ABSTRACT Glaucoma is a leading cause of permanent vision loss worldwide, but the mechanisms of damage are not fully understood. The retinal ganglion cells (RGC) and their axons transmit visual information from the retina to the brain, and these axons pass out of the eye through the scleral canal at the optic nerve head (ONH), which is spanned by a fenestrated connective tissue structure known as the lamina cribrosa (LC). The preponderance of evidence suggests that the RGC axons are damaged in the laminar region of the ONH in glaucoma. One of the most consistent glaucoma risk factors is elevated intraocular pressure (IOP), although the “safe” IOP threshold varies widely among individuals. While there is some evidence that IOP fluctuations contribute to glaucoma, prior studies have been hampered by the absence of continuous IOP measurement. Retrobulbar cerebrospinal fluid pressure (CSFP) surrounding the optic nerve partially counteracts IOP at the LC through the translaminar pressure (TLP=IOP-CSFP). Retrospective clinical studies have suggested that higher CSFP (and low TLP) is protective for glaucoma and low CSFP (and high TLP) increases glaucoma risk, after accounting for the effects of IOP. In addition, since the LC bears the bulk of the pressure load in the ONH due to its high stiffness relative to the surrounding neural tissues, LC thickness plays a critical role in the distribution of TLP in the ONH via the translaminar pressure gradient (TLPG = TLP/LC thickness), adding a morphological component to TLP. Hence, the goal of this project is to test the hypotheses that IOP, TLP, and TLPG fluctuations independently contribute to eye-specific susceptibility to glaucoma onset and progression after accounting for differential mean IOP in fellow eyes, and confirm the recent finding that CSFP and IOP are coupled via neural pathways. In this project, we will perform mechanical compliance testing to quantify LC deformations in vivo in response to controlled acute TLP challenge, in an animal model of unilateral glaucoma instrumented with continuous IOP, CSFP, TLP, and TLPG telemetry. We will then determine the relationships between axonal and visual function loss per unit of differential mean IOP in fellow eyes and 1) transient and diurnal IOP fluctuation, 2) TLP and TLPG (mean and fluctuation) and 3) LC deformations in response to acute TLP challenge, measured while the eye is normal and after glaucoma onset and progression. Impact: If results show that IOP fluctuations, TLP and/or TLPG contribute to glaucoma pathogenesis and progression in addition to mean IOP, new therapeutic approaches could be developed to modulate these factors to treat glaucoma.