Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model

项目摘要 开角型青光眼是世界范围内视力损害和失明的主要原因。然而，自然 由于被诊断患有青光眼的受试者 治疗，改变其自然轨迹。一种确定纵向轨迹的通用方法 青光眼是汇集跨患者队列的横截面数据。这种方法主要受 个体间的差异，并且不能捕获所有的个体眼睛行为。或者，啮齿动物模型 但是由于与人类视觉系统的广泛结构差异， 这些对人类的研究有限。非人灵长类动物（NHP）的研究具有极大的价值，因为它们的高 与人眼和视觉通路相似。对这些动物的昏迷性损伤的诱导 通常通过眼内压的增加来进行，这不能完全捕获眼内压。 多因素昏迷过程。因此，期望具有天然存在的NHP模型， 青光眼作为青光眼的自发性发展表明存在疾病倾向， 这是确定昏迷过程的核心，而不存在现有研究中存在的混杂因素。 问题研究 我们确定了一组表现出自然发生的青光眼的恒河猴。我们建议 调查这一队列，以回答有关青光眼的基本问题，特别关注纵向 在其他任何环境中无法解决的变化。我们将使用一个跨越广泛范围的队列， 年龄和昏迷损伤严重程度的关系，沿着健康动物，以检验我们的总体假设 视神经和视网膜结构（包括视网膜脉管系统）以及眼内和 颅内压影响青光眼未来进展的速度。我们将确定自然率 健康和疑似青光眼NHP眼结构进展沿着功能进展 (Aim#1）。我们将建立不同地点的结构变化的空间关系， 全身和眼部协变量的影响。在目标2中，我们将建立宏观和微观结构 筛板的变化-视神经内的多孔结构，轴突通过筛板进行 它们进入大脑的方式-健康和疑似青光眼的眼睛及其与视神经的联系， 视网膜结构和功能改变。在目标3中，我们将确定血管分布快速下降的眼睛是否 与视网膜和视神经结构和功能的快速变化相关。 利用这一独特的队列，我们的多学科研究团队将获得关键的知识，了解 疾病的过程。这将改善临床诊断和监测，并将作为参考， 潜在的治疗方法。这项研究为未来的遗传学、蛋白质组学、微生物组学和 生物力学研究，以充分表征青光眼的中心特征。

Project Summary Open angle glaucoma is a leading cause of visual impairment and blindness worldwide. Yet, the natural longitudinal trajectory of the disease is not fully characterized because subjects diagnosed with glaucoma are treated, altering its natural trajectory. A common approach for determining the longitudinal trajectory of glaucoma is pooling cross-sectional data across a cohort of patients. This approach is mostly affected by the inter-individual variation and does not capture all of the individual eye behavior. Alternatively, rodent models are used but due to the extensive structural differences from human visual system the transability value of these studies to humans is limited. Research in non-human primates (NHP) is of utmost value due to their high similarity with the human eye and visual pathway. Induction of glaucomatous damage to these animals is typically performed through initiation of an increase in intraocular pressure, which does not fully capture the multi-factorial glaucomatous process. It is therefore desirable to have a NHP model with naturally occurring glaucoma as the spontaneous development of glaucoma indicates the presence of the disease predisposition, which is at the core of identifying the glaucomatous process without the confounders present in existing studies. We identified a cohort of rhesus macaques that exhibit naturally occurring glaucoma. We propose to investigate this cohort to answer fundamental questions about glaucoma, specifically focusing on longitudinal changes that cannot be otherwise addressed in any other setting. We will use a cohort spanning a wide range of ages and glaucomatous damage severity, along with healthy animals, to test our overarching hypothesis that optic nerve and retinal structure (including retinal vasculature) as well as intraocular and intracranial pressure affect the future rate of glaucoma progression. We will determine the natural rate of structural progression in healthy and suspected glaucoma NHP eyes along with functional progression (Aim#1). We will establish the spatial relationship of structural changes in the different locations and examine the effect of systemic and ocular co-variable. In Aim#2 we will establish the macro- and micro-structural changes in the lamina cribrosa – a porous structure within the optic nerve through which the axons undergo on their way to the brain – of healthy and suspected glaucoma eyes and their association with optic nerve and retinal structure and function changes. In Aim#3 we will determine if eyes with fast decline in vascularity are associated with fast change in the retina and optic nerve structure and function. Using this unique cohort, our multi-disciplinary research team will gain knowledge critical to understanding the disease process. This will improve clinical diagnosis and monitoring, and will be utilized as a reference for potential treatment. The study sets the stage for future examination of genetic, proteomic, microbiome, and biomechanics studies to fully characterize central features of glaucoma.