Elevated intraocular pressure (IOP) has long been assumed to play a causative role in glaucomatous damage to the optic nerve head (ONH). There is compelling evidence to suggest that the elderly and individuals of African descent are at much greater risk for the onset and progression of glaucomatous damage at elevated levels of IOP. In this proposal, we test the hypothesis that age- and race-related differences in ONH biomechanics may contribute to this difference in risk. Using high-resolution, fluorescent, three-dimensional (3D) reconstructions of the ONH, and principles of biomechanical engineering, we will study the mechanical effects of elevated IOP in glaucoma. However, the relationship between advancing age, African ancestry, and the mechanical effects of elevated IOP is still unclear. How do age- and race-related differences in ONH structure and biomechanics increase its susceptibility to IOP? Is the robustness of the ONH connective tissues the key to understanding individual susceptibility to glaucoma? What role does the structural stiffness of the lamina cribrosa and peripapillary sclera play in the increased risk for glaucomatous progression in the elderly and in individuals of African descent? To answer these questions, we will use novel methods to elucidate the relationship between age, race, and the IOP-induced deformation of ONH connective tissues. By "ONH biomechanics" we mean the interactions between IOP and connective tissue structural stiffness (the combination of tissue architecture and material properties) in the ONH and peripapillary sclera. The immediate goals of this project are to characterize age- and race-related differences in ONH biomechanics and elucidate their effects on ONH susceptibility. Our long-term goal is to develop clinical diagnostics and interventions designed to manage each important biomechanical risk factor in the development and progression of glaucoma. To accomplish our immediate goals, we will build digital three-dimensional reconstructions of human ONH tissues from donors of African and European descent, quantify the ONH connective tissue architecture within each reconstruction, and build computational finite element models of the ONH connective tissues to estimate their biomechanical response to normal and elevated levels of IOP.

Public Health Relevance

Elevated intraocular pressure (IOP) has long been assumed to play a causative role in glaucomatous damage to the optic nerve head (ONH), and the elderly and individuals of African descent have higher risk of development and progression of the disease. We propose to measure the age- and race-related differences in ONH structure and IOP-induced biomechanical response. Then, we will use these data to create computational biomechanical models of the age- and race-related mechanical effects of elevated IOP on the ONH to elucidate the link between age, African ancestry and glaucomatous susceptibility.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY018926-05
Application #
8440150
Study Section
Special Emphasis Panel (BVS)
Program Officer
Chin, Hemin R
Project Start
2008-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$382,679
Indirect Cost
$114,034
Name
University of Alabama Birmingham
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Johnstone, John; Fazio, Massimo; Rojananuangnit, Kulawan et al. (2014) Variation of the axial location of Bruch's membrane opening with age, choroidal thickness, and race. Invest Ophthalmol Vis Sci 55:2004-9
Fazio, Massimo A; Grytz, Rafael; Morris, Jeffrey S et al. (2014) Age-related changes in human peripapillary scleral strain. Biomech Model Mechanobiol 13:551-63
Fazio, Massimo A; Grytz, Rafael; Morris, Jeffrey S et al. (2014) Human scleral structural stiffness increases more rapidly with age in donors of African descent compared to donors of European descent. Invest Ophthalmol Vis Sci 55:7189-98
Grytz, Rafael; Fazio, Massimo A; Girard, Michael J A et al. (2014) Material properties of the posterior human sclera. J Mech Behav Biomed Mater 29:602-17
Grytz, Rafael; Downs, J Crawford (2013) A forward incremental prestressing method with application to inverse parameter estimations and eye-specific simulations of posterior scleral shells. Comput Methods Biomech Biomed Engin 16:768-80
Grytz, Rafael; Sigal, Ian A; Ruberti, Jeffrey W et al. (2012) Lamina Cribrosa Thickening in Early Glaucoma Predicted by a Microstructure Motivated Growth and Remodeling Approach. Mech Mater 44:99-109
Crawford Downs, J; Roberts, Michael D; Sigal, Ian A (2011) Glaucomatous cupping of the lamina cribrosa: a review of the evidence for active progressive remodeling as a mechanism. Exp Eye Res 93:133-40
Sigal, Ian A; Yang, Hongli; Roberts, Michael D et al. (2011) IOP-induced lamina cribrosa deformation and scleral canal expansion: independent or related? Invest Ophthalmol Vis Sci 52:9023-32
Sigal, Ian A; Yang, Hongli; Roberts, Michael D et al. (2011) IOP-induced lamina cribrosa displacement and scleral canal expansion: an analysis of factor interactions using parameterized eye-specific models. Invest Ophthalmol Vis Sci 52:1896-907
Sigal, Ian A; Yang, Hongli; Roberts, Michael D et al. (2010) Morphing methods to parameterize specimen-specific finite element model geometries. J Biomech 43:254-62

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