Detection and treatment of early glaucoma would be greatly enhanced by the development of a technique to evaluate the risks of glaucoma of an eye based on its architecture, and a more thorough understanding of the mechanisms leading to neural tissue degeneration. Our goal is to identify properties of the eye that predict susceptibility to neural tissue damage before it occurs. Early glaucomatous neural tissue degeneration is often localized to specific regions of the optic nerve head (ONH), and aging and elevated intraocular pressure (IOP) increase the risk for developing glaucoma. Our central hypothesis is that the architecture of the connective tissues of the ONH, and in particular of the lamina cribrosa within, determines the local robustness and sensitivity to IOP, and with this the regional susceptibility to neural tissue damage in early glaucoma. We have developed novel imaging techniques to obtain previously inaccessible micron-scale information of the tissues of the ONH, including detailed maps of collagen fiber alignment and the degree of stretch or relaxation of the fibers, referred to as crimp. With this information we characterize in high detail the architecture of the human lamina cribrosa and surrounding tissues at normal and elevated IOP.
In Aim 1 we test the prediction that there is an association between regional susceptibility to neural tissue damage in early glaucoma and tissue architecture.
In Aim 2 we test the prediction that the regions of known susceptibility to early glaucomatous damage are more sensitive to elevated IOP, in that the collagen fibers in the lamina trabeculae of these regions are the first to stretch and lose all crimp when reaching elevated IOP. We also test the hypotheses that aging is associated with changes in the tissue architecture such that older eyes are less robust than younger eyes.
In Aim 3 we use numerical modeling to determine the functional relationship between age and tissue architecture and sensitivity to IOP, and test the hypotheses that the architectures of the lamina cribrosa and peripapillary sclera are major determinants of the local sensitivity to IOP, and that age- related changes in tissue architecture increase the sensitivity to IOP. This project will result in the most detailed characterization yet of the architecture of the tissues of the ONH, and of their changes with age. We will develop a comprehensive model for understanding the key elements of architecture that determine the local sensitivity to IOP, and identify characteristics of ONH architecture that are associated with the regional susceptibility to neural tissue damage in early glaucoma. This characterization will span multiple scales, from highly detailed micro-architectural features of the collagen fibers, such as fiber crimp, to the larger scale canal size and shape. This project will be an important step towards the ultimate goal of diagnosing eyes at risk of glaucoma based on their anatomy, and will provide a powerful platform for developing strategies and interventions to mitigate the risk and preserve vision, improving health.

Public Health Relevance

Glaucoma is the second leading cause for blindness worldwide. Our goal is to identify properties of the eye that predict susceptibility to neural tisse damage before it occurs. This project will result in the most detailed characterization yet of the architecture of the tissues of the optic nerve head, where neural tissue degeneration, and thus glaucomatous vision loss, is believed to initiate. We will employ this information to identify the characteristics of ONH architecture that are associated with regional susceptibility to neural tissue damage in early glaucoma. This project will be an important step towards the ultimate goal of diagnosing eyes at risk of glaucoma based on their anatomy, and will provide a powerful platform for developing strategies and interventions to mitigate the risk and preserve vision, improving health.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY023966-01
Application #
8610418
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Chin, Hemin R
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$298,000
Indirect Cost
$94,337
Name
University of Pittsburgh
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Voorhees, Andrew P; Ho, Leon C; Jan, Ning-Jiun et al. (2017) Whole-globe biomechanics using high-field MRI. Exp Eye Res 160:85-95
Jan, Ning-Jiun; Gomez, Celeste; Moed, Saundria et al. (2017) Microstructural Crimp of the Lamina Cribrosa and Peripapillary Sclera Collagen Fibers. Invest Ophthalmol Vis Sci 58:3378-3388
Voorhees, Andrew P; Jan, Ning-Jiun; Austin, Morgan E et al. (2017) Lamina Cribrosa Pore Shape and Size as Predictors of Neural Tissue Mechanical Insult. Invest Ophthalmol Vis Sci 58:5336-5346
Pant, Anup D; Kagemann, Larry; Schuman, Joel S et al. (2017) An imaged-based inverse finite element method to determine in-vivo mechanical properties of the human trabecular meshwork. J Model Ophthalmol 1:100-111
Tran, Huong; Jan, Ning-Jiun; Hu, Danielle et al. (2017) Formalin Fixation and Cryosectioning Cause Only Minimal Changes in Shape or Size of Ocular Tissues. Sci Rep 7:12065
Voorhees, A P; Jan, N-J; Sigal, I A (2017) Effects of collagen microstructure and material properties on the deformation of the neural tissues of the lamina cribrosa. Acta Biomater 58:278-290
Wang, Bo; Tran, Huong; Smith, Matthew A et al. (2017) In-vivo effects of intraocular and intracranial pressures on the lamina cribrosa microstructure. PLoS One 12:e0188302
Jan, Ning-Jiun; Lathrop, Kira; Sigal, Ian A (2017) Collagen Architecture of the Posterior Pole: High-Resolution Wide Field of View Visualization and Analysis Using Polarized Light Microscopy. Invest Ophthalmol Vis Sci 58:735-744
Squires, Alexander; Chan, Kevin C; Ho, Leon C et al. (2016) MAPS - a Magic Angle Positioning System for Enhanced Imaging in High-Field Small-Bore MRI. J Med Robot Res 1:
Ho, Leon C; Sigal, Ian A; Jan, Ning-Jiun et al. (2016) Non-invasive MRI Assessments of Tissue Microstructures and Macromolecules in the Eye upon Biomechanical or Biochemical Modulation. Sci Rep 6:32080

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