IOP and Cerebrospinal Fluid Pressure-related Risk Factors for Glaucoma

眼压和脑脊液压力相关的青光眼危险因素

• 批准号: 10696076
• 负责人: J CRAWFORD DOWNS
• 金额: $ 57.99万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696076
• 关键词: Accounting; Acute; Address; Adult; Age; Animal Model; Axon; Bilateral; Biomechanics; Blindness; Brain; Cerebrospinal Fluid Pressure; Clinical Research; Connective Tissue; Coupled; Coupling; Data; Development; Diagnostic; Disease; Disease Progression; Exhibits; Eye; Functional disorder; Future; Glaucoma; Goals; Height; Hour; Human; Implant; Individual; Intracranial Pressure; Knowledge; Macaca mulatta; Measurable; Measurement; Measures; Mechanics; Modeling; Monitor; Morphology; Neural Pathways; Onset of illness; Optic Disk; Optic Nerve; Pathogenesis; Pathway interactions; Patients; Physiologic Intraocular Pressure; Play; Predisposition; Primates; Rattus; Reporting; Retina; Retinal Ganglion Cells; Risk; Risk Factors; Role; Sleep; Stress; Structure; System; Telemetry; Testing; Therapeutic; Thick; Thinness; Tissues; Vision; absorption; aqueous; axon injury; behavior prediction; in vivo; insight; instrument; loss of function; mechanical energy; neural; novel therapeutic intervention; novel therapeutics; pressure; response; retinal nerve fiber layer; translaminar pressure gradient; transmission process; visual information

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.

抽象的 青光眼是全球永久视力丧失的主要原因，但损害的机制尚未完全 理解齿。视网膜神经节细胞（RGC）及其轴突将视觉信息从视网膜传输到 大脑，这些轴突通过视神经头（ONH）的巩膜管从眼睛中传递出来， 被称为lamina cribrosa（LC）的结缔组织结构跨越。优势 证据表明，在青光眼的ONH的层状区域中，RGC轴突受损。之一 尽管“安全” IOP 个体之间的阈值差异很大。尽管有一些证据表明IOP波动有助于 由于缺乏连续的IOP测量，青光眼，先前的研究受到了阻碍。反载体 围绕视神经的脑脊液压力（CSFP）通过LC在LC处部分抵消 thranpaminar压力（TLP = IOP-CSFP）。回顾性临床研究表明，CSFP较高 （和低TLP）受到青光眼和低CSFP（和高型TLP）的保护，增加了青光眼风险 考虑IOP的影响。此外，由于LC承担了大部分压力负载 相对于周围神经组织，LC厚度在其高刚度中起着至关重要的作用 TLP在ONH中的分布通过转换压力梯度（TLPG = TLP/LC厚度），添加了A TLP的形态成分。因此，该项目的目的是检验IOP，TLP和 TLPG波动独立有助于特异性的对青光眼发作和进展的敏感性 在考虑了同伴的差异均值IOP之后，并确认了最近的发现CSFP和IOP是 通过神经通路结合。在这个项目中，我们将执行机械合规性测试以量化LC 在单侧青光眼的动物模型中，体内的变形响应受控急性TLP挑战。 用连续的IOP，CSFP，TLP和TLPG遥测仪器进行仪器。然后，我们将确定关系 在轴突和视觉功能之间的每单位单位差分平均值IOP之间的损失和1）瞬态和 昼夜波动，2）TLP和TLPG（平均和波动）和3）响应急性的LC变形 TLP挑战，在眼睛正常和青光眼发作和进展之后进行测量。影响：如果结果 表明IOP波动，TLP和/或TLPG有助于青光眼的发病机理和进展 意思是IOP，可以开发出新的治疗方法来调节这些因素以治疗青光眼。