Primary open angle glaucoma (POAG) represents a serious and growing health problem accounting for ~12% of global blindness. Studies have identified age, ancestral group (racial background), and intra- ocular pressure (IOP) as significant risk factors for the development and progression of POAG. Our long- range goal is to understand the relationship between these established risk factors and the responsive loss of retinal ganglia cells that characterizes this disease. Current wisdom proposes that the biomechanical properties of the optic nerve head (ONH) and lamina cribrosa (LC) play a critical role in defining the pathology of POAG. In preliminary studies, we have identified that regions of the LC susceptible to glaucomatous change (inferior, superior) contain less collagen and show more pressure-induced deformation (more compliant) than other regions of the LC (nasal and temporal). Building on these findings, the objective of this proposal is to define the 3 dimensional biomechanical properties of the ONH by microscopically reconstructing the structural components and biomechanical properties across the LC at a micron scale and relate these properties to POAG risk factors. Based on our preliminary studies we propose the following testable hypotheses:1) That there are regional differences in both the structure and pressure-induced deformation of the LC such that regions susceptible to early glaucomatous change have decreased collagen and increased deformation;2) That the regional differences in LC structure and pressure-induced deformation increase with age and vary with ancestral group, such that older individuals and those with ancestries more susceptible to POAG will have greater structural changes and show greater pressure induced deformation;3) That the regional differences in LC structure and pressure-induced deformation are directly related to differences in the 3 dimensional, microscopic elastic modulus such that regions of the LC most susceptible to glaucomatous damage (and related to age and ancestry) will have significant differences in the elastic modulus compared to other regions. To test these hypotheses, we have developed innovative, state of the art technologies to globally assess the three dimensional (3D) structure and biomechanical properties of the human ONH with high resolution. These technologies take advantage of known non-linear optical affects that occur when high intensity photons generated by ultrafast lasers interact with tissue. Using these novel technologies we propose to study ex vivo human eyes from normal individuals and different ancestries at varying ages by the following Specific Aims: 1) Dynamically map in 4 dimensions (time and space) IOP induced changes in collagen fibril and elastic fiber structure in ex vivo human ONH using an artificial pressure chamber and an ultrafast laser;2) Three dimensionally reconstruct the ONH at high resolution (0.9 mm lateral and 2 mm axial) to volumetrically measure the regional changes in structure and relate these to the measured pressure induce deformations in the same eye;3) Measure the regional (superior vs. inferior etc.) biomechanical properties of ex vivo human ONH to relate structure to the biomechanical properties and susceptibility to POAG. We expect that these investigations will provide new, and critically important, information concerning the biomechanical properties of the human ONH and provide a clearer understanding of the risk factors for POAG.

Public Health Relevance

In this proposal, we will clarify the role of collagen and elastic components of the lamina cribrosa (LC) in the pathophysiology of axonal injury that occurs with aging and how it may be accelerated by increased IOP. We fully expect these data to lead to critically important information concerning the biomechanical properties of the human optic nerve head (ONH) and provide a clearer understanding of the risk factors for primary open angle glaucoma (POAG). To achieve our goal, we will use innovative, state of the art technologies based on ultrafast lasers that can produce two photon excited fluorescence for identifying elastin, second harmonic generated signals for identifying collagen and laser induced optical breakdown to probe the microscopic biomechanical properties using Acoustic Radiation Force Elastic Microscopy to globally assess the three dimensional structure and biomechanical properties of the ONH.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY019719-01A1
Application #
7887791
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
Project Start
2010-04-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$369,250
Indirect Cost
Name
University of California Irvine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Jester, James V; Parfitt, Geraint J; Brown, Donald J (2015) Meibomian gland dysfunction: hyperkeratinization or atrophy? BMC Ophthalmol 15 Suppl 1:156
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Winkler, Moritz; Simon, Melinda G; Vu, Timothy et al. (2014) A microfabricated, optically accessible device to study the effects of mechanical cues on collagen fiber organization. Biomed Microdevices 16:255-67
Sigal, Ian A; Grimm, Jonathan L; Jan, Ning-Jiun et al. (2014) Eye-specific IOP-induced displacements and deformations of human lamina cribrosa. Invest Ophthalmol Vis Sci 55:1-15
Parfitt, Geraint J; Xie, Yilu; Geyfman, Mikhail et al. (2013) Absence of ductal hyper-keratinization in mouse age-related meibomian gland dysfunction (ARMGD). Aging (Albany NY) 5:825-34
Winkler, Moritz; Shoa, Golroxan; Xie, Yilu et al. (2013) Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma. Invest Ophthalmol Vis Sci 54:7293-301
Chai, Dongyul; Juhasz, Tibor; Brown, Donald J et al. (2013) Nonlinear optical collagen cross-linking and mechanical stiffening: a possible photodynamic therapeutic approach to treating corneal ectasia. J Biomed Opt 18:038003
Parfitt, Geraint J; Xie, Yilu; Reid, Korey M et al. (2012) A novel immunofluorescent computed tomography (ICT) method to localise and quantify multiple antigens in large tissue volumes at high resolution. PLoS One 7:e53245
Jester, James V; Brown, Donald; Pappa, Aglaia et al. (2012) Myofibroblast differentiation modulates keratocyte crystallin protein expression, concentration, and cellular light scattering. Invest Ophthalmol Vis Sci 53:770-8
Myrna, Kathern E; Mendonsa, Rima; Russell, Paul et al. (2012) Substratum topography modulates corneal fibroblast to myofibroblast transformation. Invest Ophthalmol Vis Sci 53:811-6

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