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)
Type
Research Project (R01)
Project #
5R01EY011610-18
Application #
8704936
Study Section
(BVS)
Program Officer
Chin, Hemin R
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emanuel Hospital and Health Center
Department
Type
DUNS #
City
Portland
State
OR
Country
United States
Zip Code
97232
He, Lin; Yang, Hongli; Gardiner, Stuart K et al. (2014) Longitudinal detection of optic nerve head changes by spectral domain optical coherence tomography in early experimental glaucoma. Invest Ophthalmol Vis Sci 55:574-86
Yang, Hongli; He, Lin; Gardiner, Stuart K et al. (2014) Age-related differences in longitudinal structural change by spectral-domain optical coherence tomography in early experimental glaucoma. Invest Ophthalmol Vis Sci 55:6409-20
Fortune, Brad; Burgoyne, Claude F; Cull, Grant et al. (2013) Onset and progression of peripapillary retinal nerve fiber layer (RNFL) retardance changes occur earlier than RNFL thickness changes in experimental glaucoma. Invest Ophthalmol Vis Sci 54:5653-61
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Reynaud, Juan; Cull, Grant; Wang, Lin et al. (2012) Automated quantification of optic nerve axons in primate glaucomatous and normal eyes--method and comparison to semi-automated manual quantification. Invest Ophthalmol Vis Sci 53:2951-9
Reis, Alexandre S C; O'Leary, Neil; Yang, Hongli et al. (2012) Influence of clinically invisible, but optical coherence tomography detected, optic disc margin anatomy on neuroretinal rim evaluation. Invest Ophthalmol Vis Sci 53:1852-60
Reis, Alexandre S C; Sharpe, Glen P; Yang, Hongli et al. (2012) Optic disc margin anatomy in patients with glaucoma and normal controls with spectral domain optical coherence tomography. Ophthalmology 119:738-47
Burgoyne, Claude F (2011) A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma. Exp Eye Res 93:120-32

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