Translamina Cribrosa Pressure Gradient Model of Normal Tension Glaucoma

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Neurodegenerative diseases, including glaucoma, substantially alter quality of life of our affected Veterans. Glaucoma remains a leading cause of irreversible blindness. Currently affecting over 60 million individuals worldwide, this insidious age-dependent optic neuropathy is characterized by a gradual loss of retinal ganglion cell (RGC) neurons and is projected to impact nearly 112 million people within 20 years. The global prevalence of glaucoma for population aged 40-80 years is an alarming 3.5%. An elevated prevalence among our aging Veteran population is no exception. Implications for the US health care system are equally daunting, with an estimated 7.3 million Americans expected to be debilitated by primary open angle glaucoma (POAG), the most common form of glaucoma, within 30 years. Despite being an extraordinarily significant socioeconomic burden, the treatment of US Veterans with glaucoma remains limited and palliative. Several multicenter studies have identified elevated intraocular pressure (IOP) as a primary risk factor for the onset and progression of POAG. While the pathophysiology leading to elevated IOP in affected patients remains poorly understood, several new therapeutic strategies that address this concern appear promising. Of significance, however, is the fact that up to one-third of POAG patients exhibit IOP levels within the normal range. While many laboratories, including our own, have focused on the development and advancement of novel therapeutic strategies for the management of IOP, a critical review of the literature reveals a paucity of experimental studies addressing the mechanistic cause of normal-tension glaucoma. The development of targeted therapeutic strategies directed at the cause of normal tension glaucoma is critical for the advanced management of these affected Veterans. In this BLR&D Merit Review validation pilot project, we propose to advance our current on-going BLR&D-funded studies by determining the effect of pressure gradient differentials across the lamina cribrosa on optic nerve head and retinal morphometrics and on RGC neuronal function using guinea pigs as a novel anatomically- relevant animal model of human optic neuropathic disorders. The design of this validation study will closely follow that detailed in Ostrin and Wildsoet (2016) and Yang et al. (2014) using a lumbar-peritoneal CSF shunt to modulate CSF pressure. Hypothesis: Chronic reduction of cerebrospinal fluid pressure in guinea pigs will elicit quantifiable changes in optic nerve head morphometry and alter RGC neuronal function. The hypothesis of this study will be tested with the following two Specific Aims. Specific Aim 1 will determine, in vivo, time-dependent effects of cerebrospinal fluid pressure reduction on RGC neuronal function in guinea pigs as quantified by pattern electroretinography. Specific Aim 2 will determine the time-dependent effects of cerebrospinal fluid pressure reduction on optic nerve head and retinal morphometrics in guinea pigs as quantified by histological, immunohistochemical, and electron micrographic analyses. The goal of this study is to (i) validate in accordance with the RFA BX-20-042 and (ii) extend the findings of Ostrin and Wildsoet (2016) and Yang et al. (2014) on the applicability of guinea pigs as a relevant clinically useful model of human optic neuropathic disorders. Novel findings produced by this study will determine the role pressure gradient differential across the lamina cribrosa play in the development of human optic neuropathies.