Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model

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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.