The primary goal of this project is to identify clinical targets that predict eye-specific optic nerve head (ONH) behavior (depth of cupping) and retinal ganglion cell (RGC) axon susceptibility within the monkey unilateral experimental glaucoma model so as to translate this knowledge to human patients in future research. We test three hypotheses regarding the relationships between eye-specific behavior, ONH connective tissue remodeling and RGC axon susceptibility. First, that stiff eyes are more susceptible to a shallow form of cupping and RGC axon loss than compliant eyes at similar levels of IOP insult. Second, that the behavior and susceptibility of individual eyes can be predicted from the results of in viv spectral domain optical coherence tomography (SDOCT) ONH compliance testing, post-mortem 3D reconstruction of the ONH connective tissues and stress/strain outputs of engineering finite element (FE) models. Third, that ONH connective tissue remodeling contributes not only to the depth of cupping but to RGC axon susceptibility by being both more robust and more protective of axons in compliant and/or young ONHs.
Aim 1 is to characterize age-related differences in ONH behavior and susceptibility among young, adult and old monkey eyes followed from early to severe experimental glaucoma.
Aim 2 is to identify those components of normal SDOCT ONH compliance testing and post mortem ONH 3D reconstructions and FE models that best predict eye-specific differences in ONH behavior/susceptibility.
Aim 3 is to test predictions regarding the fundamental anatomical nature of ONH connective tissue remodeling and its relationships with RGC axon susceptibility and age in early monkey experimental glaucoma. The methodology includes: longitudinal 870 and 1050 nm SDOCT ONH dataset acquisition;their visualization, delineation and quantification within custom Multiview software;3D episcopic fluorescent ONH reconstruction;automated 100% optic nerve axon counts;and characterization of the relationships between ONH connective tissue remodeling, axonal myelination and astrocyte phagocytosis by immunohistochemistry, in situ hybridization and, serial block-face scanning electron microscopy. Expected outcomes include: identification of clinical targets that predict the regional pattern and magnitude of eye connective tissue deformation and axon loss in glaucoma;improved clinical imaging tools necessary for predicting human eye-specific IOP and ONH progression targets;support for the conclusion that laminar remodeling is a deformation-driven phenomenon and therefore occurs in the most compliant eyes and/or in those eyes with the highest IOP at all ages;and support for the conclusion that where remodeling occurs, the mechanisms of axonal insult and/or preservation include age-related differences in astrocyte and microglial remodeling and phagocytosis of newly engulfed myelin. These findings will set the stage for studying effective neuroprotective interventions in future proposals.

Public Health Relevance

The goal of this project is to identify clinical targets that predict eye-specific optic nerve head (ONH) behavior (depth of cupping and remodeling) and retinal ganglion cell (RGC) axon susceptibility within the monkey unilateral experimental glaucoma model so as to translate this knowledge to human patients in future research. To do so we will first test the hypothesis that the behavior and susceptibility of individual eyes to glaucomatous damage can be predicted from the results of in vivo spectral domain optical coherence tomography (SDOCT) ONH compliance testing, post-mortem 3D reconstruction of the ONH connective tissues and stress/strain outputs of engineering finite element (FE) models. We will then test the hypothesis that ONH connective tissue deformation and remodeling are linked to RGC axon susceptibility in an age-related manner by being both more robust and more protective of axons in compliant and/or young ONHs.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY011610-16
Application #
8383401
Study Section
Special Emphasis Panel (BVS)
Program Officer
Chin, Hemin R
Project Start
1998-08-01
Project End
2016-06-30
Budget Start
2012-08-01
Budget End
2013-06-30
Support Year
16
Fiscal Year
2012
Total Cost
$783,403
Indirect Cost
$290,776
Name
Emanuel Hospital and Health Center
Department
Type
DUNS #
050973098
City
Portland
State
OR
Country
United States
Zip Code
97232
Stowell, Cheri; Burgoyne, Claude F; Tamm, Ernst R et al. (2017) Biomechanical aspects of axonal damage in glaucoma: A brief review. Exp Eye Res 157:13-19
Wilsey, Laura; Gowrisankaran, Sowjanya; Cull, Grant et al. (2017) Comparing three different modes of electroretinography in experimental glaucoma: diagnostic performance and correlation to structure. Doc Ophthalmol 134:111-128
Yang, Hongli; Reynaud, Juan; Lockwood, Howard et al. (2017) The connective tissue phenotype of glaucomatous cupping in the monkey eye - Clinical and research implications. Prog Retin Eye Res 59:1-52
Wilsey, Laura J; Reynaud, Juan; Cull, Grant et al. (2016) Macular Structure and Function in Nonhuman Primate Experimental Glaucoma. Invest Ophthalmol Vis Sci 57:1892-900
Ing, Eliesa; Ivers, Kevin M; Yang, Hongli et al. (2016) Cupping in the Monkey Optic Nerve Transection Model Consists of Prelaminar Tissue Thinning in the Absence of Posterior Laminar Deformation. Invest Ophthalmol Vis Sci 57:2914–2927
Fortune, Brad; Hardin, Christy; Reynaud, Juan et al. (2016) Comparing Optic Nerve Head Rim Width, Rim Area, and Peripapillary Retinal Nerve Fiber Layer Thickness to Axon Count in Experimental Glaucoma. Invest Ophthalmol Vis Sci 57:OCT404-12
Fortune, Brad; Reynaud, Juan; Hardin, Christy et al. (2016) Experimental Glaucoma Causes Optic Nerve Head Neural Rim Tissue Compression: A Potentially Important Mechanism of Axon Injury. Invest Ophthalmol Vis Sci 57:4403-11
Ivers, Kevin M; Yang, Hongli; Gardiner, Stuart K et al. (2016) In Vivo Detection of Laminar and Peripapillary Scleral Hypercompliance in Early Monkey Experimental Glaucoma. Invest Ophthalmol Vis Sci 57:OCT388-403
Reynaud, Juan; Lockwood, Howard; Gardiner, Stuart K et al. (2016) Lamina Cribrosa Microarchitecture in Monkey Early Experimental Glaucoma: Global Change. Invest Ophthalmol Vis Sci 57:3451-69
Fortune, Brad; Cull, Grant; Reynaud, Juan et al. (2015) Relating Retinal Ganglion Cell Function and Retinal Nerve Fiber Layer (RNFL) Retardance to Progressive Loss of RNFL Thickness and Optic Nerve Axons in Experimental Glaucoma. Invest Ophthalmol Vis Sci 56:3936-44

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