Glaucoma causes progressive damage and death of retinal ganglion cells (RGCs) resulting in blindness. The prevalence of the disease will rise to a projected 3 million Americans by 2020. Our long-term goal is to prevent RGC death in the early stages of glaucoma. The objective of this study is to identify dysfunctioning RGCs and the window of opportunity for their recovery. Our central hypothesis is that RGCs undergo a stage of reversible dysfunction before dying, and that RGC dysfunction is due to impaired tolerance to intraocular pressure (IOP). Our study will include at least 500 subjects at increased risk of having or developing glaucoma and at least 100 normal controls.
Our specific aims are 1) to identify dysfunctional RGCs and evaluate their lifespan, thereby extending the longitudinal study initiated in 2004, 2) to characterize the tolerance of RGC function to both IOP increase and metabolic challenge, and 3) to validate measurements of RGC dysfunction as biomarkers to predict severity of future functional and structural loss. We will use the Pattern Electroretinogram (PERG) and Optical Coherence Tomography (OCT) as non-invasive surrogate measures of RGC function and RGC axon number, respectively. PERG losses result from both reduced activity of viable RGCs and lack of activity of dead RGCs. OCT losses result from lack of axons of dead RGCs. The central hypothesis is supported by our previous results showing that in early glaucoma PERG deficits are relatively larger than OCT deficits, and may be improved by IOP-lowering treatment. Preliminary data show that PERG deficits may be temporarily induced by either IOP elevation obtained with change in body position or by prolonged exposure to metabolically challenging visual stimuli. The rationale is that this innovative approach will provide a set of functional biomarkers to detect susceptibility of RGCs and predict their fate. This outcome will have high significance on identifying individuals at high-risk of developing glaucoma damage and determining the necessity of treatment. Our research team includes experts in glaucoma, visual electrophysiology, retinal imaging, biophysics, and biostatistics. Our clinical setting has a uniquely large population of glaucoma patients and older subjects at increased risk of glaucoma due to African-American and Hispanic ethnicity. The electrical activity of retinal ganglion cells non-invasively measured by pattern electroretinogram over time may be altered in subjects suspected of having glaucoma, or may become temporarily altered in response to a non-invasive stress occurring when the eye pressure is increased by lying on a bed, or the retinal metabolism is accelerated by staring at a contrasted image. These functional biomarkers have great relevance for clinical management of the disease in order to predict future severity of progression, determine the necessity of pressure-lowering treatment, make prevention a cost-effective measure, and limit the impact of side effects and deterioration of quality of life.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014957-08
Application #
8197370
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2003-07-01
Project End
2013-03-30
Budget Start
2011-12-01
Budget End
2013-03-30
Support Year
8
Fiscal Year
2012
Total Cost
$363,528
Indirect Cost
$125,928
Name
University of Miami School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Panarelli, Joseph F; Banitt, Michael R; Sidoti, Paul A et al. (2015) Clinical impact of 8 prospective, randomized, multicenter glaucoma trials. J Glaucoma 24:64-8
Porciatti, Vittorio (2015) Electrophysiological assessment of retinal ganglion cell function. Exp Eye Res 141:164-70
Panarelli, Joseph F; Banitt, Michael R; Sidoti, Paul A (2014) Transscleral diode laser cyclophotocoagulation after baerveldt glaucoma implant surgery. J Glaucoma 23:405-9
Porciatti, Vittorio; Bosse, Brandon; Parekh, Prashant K et al. (2014) Adaptation of the steady-state PERG in early glaucoma. J Glaucoma 23:494-500
Özdamar, Özcan; Toft-Nielsen, Jonathon; Bohórquez, Jorge et al. (2014) Relationship between transient and steady-state pattern electroretinograms: theoretical and experimental assessment. Invest Ophthalmol Vis Sci 55:8560-70
Guy, John; Feuer, William J; Porciatti, Vittorio et al. (2014) Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci 55:841-8
Lam, Byron L; Feuer, William J; Schiffman, Joyce C et al. (2014) Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy : preparation for gene therapy clinical trial. JAMA Ophthalmol 132:428-36
Ventura, Lori M; Golubev, Iuri; Lee, William et al. (2013) Head-down posture induces PERG alterations in early glaucoma. J Glaucoma 22:255-64
Banitt, Michael (2013) The choroid in glaucoma. Curr Opin Ophthalmol 24:125-9
Ventura, Lori M; Golubev, Iuri; Feuer, William J et al. (2013) Pattern electroretinogram progression in glaucoma suspects. J Glaucoma 22:219-25

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