Glaucoma, a leading cause of blindness worldwide, damages the Retinal Nerve Fiber Layer (RNFL), which consists of retinal ganglion cell axons. Early diagnosis and treatment can prevent irreversible visual loss. Current optical methods used in clinical diagnosis of glaucoma are often limited to assessing RNFL thickness, which is insensitive to detect early glaucomatous damage. Critical barriers to effective early detection of glaucoma include 1) incomplete understanding of the relationship between RNFL optical properties and its underlying structures and 2) lack of knowledge of changes in the relationship in glaucoma. The goal of this proposal is to identify the relationship between RNFL optical properties and its underlying structures. F-actin, microtubules (MTs) and neurofilaments (NFs), the major cytoskeleton of axons, are the possible candidates for RNFL optical properties. In this project, we will 1) determine the role of F-actin in RNFL reflectance, 2) provide quantitative relationships between RNFL reflectance, birefringence and MTs and 3) test if change of RNFL reflectance speckle, an optical interference pattern, can differentiate between normal and glaucomatous retinas. Our central hypothesis is that ultrastructure change in early glaucoma manifests itself as changes in RNFL optical properties. We will test this hypothesis by determining the relationships among RNFL optical properties, axonal cytoskeleton and glaucomatous damage. Our long term goal is to provide sensitive assessment methods for early diagnosis of glaucoma and prevent irreversible visual loss.
Aim 1 : Hypothesis: axonal F-actin contributes to RNFL reflectance. We will determine F-actin's contribution to RNFL reflectance by depolymerizing F-actin with depolymerizing agents. Significance: Understanding the role of F-actin in RNFL reflectance enables us to assess the capability of RNFL reflectance measurement to detect F-actin alteration, an early sign of glaucoma damage.
Aim 2 : Hypothesis: change of RNFL reflectance and birefringence can provide a quantitative estimate of MT change in glaucoma. We will determine the relationships between RNFL reflectance, birefringence and MT density by measuring these properties and MT density of the same nerve fiber bundles. Significance: The obtained relationship will provide a direct estimate of MT change in glaucoma.
Aim 3 : Hypothesis: temporal change of RNFL reflectance speckle can differentiate between normal and glaucomatous retinas. Our recent study demonstrated that temporal change of RNFL speckle is associated with axonal dynamic activity. We will take a series of RNFL reflectance images and quantify RNFL speckle in normal and glaucomatous retinas. Significance: Because glaucomatous damage impairs axonal transport, this study is expected to demonstrate that change of RNFL speckle can detect change of axonal dynamic activity, a novel idea for detecting physiologic activity of axons with non-invasive optical methods. The knowledge gained can be used to design sensitive methods able to detect early glaucomatous damage.

Public Health Relevance

Glaucoma, a leading cause of blindness worldwide, damages the Retinal Nerve Fiber Layer (RNFL). Early diagnosis and treatment can prevent irreversible visual loss. The outcome of this study will provide a comprehensive understanding of the relationships among the optical properties of RNFL, their underlying structures and changes of these properties/structures in the context of glaucoma. The knowledge gained will lead to the design of non-invasive optical methods that can sensitively detect early glaucomatous damage, methods that will open a therapeutic window, during which damage can be prevented.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY019084-05A1
Application #
8684603
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Chin, Hemin R
Project Start
2008-09-30
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$335,384
Indirect Cost
$110,384
Name
University of Miami School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Huang, Xiang-Run; Knighton, Robert W; Zhou, Ye et al. (2013) Reflectance speckle of retinal nerve fiber layer reveals axonal activity. Invest Ophthalmol Vis Sci 54:2616-23
Zhang, Xiangyang; Hu, Jianming; Knighton, Robert W et al. (2011) Dual-band spectral-domain optical coherence tomography for in vivo imaging the spectral contrasts of the retinal nerve fiber layer. Opt Express 19:19653-9
Huang, Xiangrun; Kong, Wei; Zhou, Ye et al. (2011) Distortion of axonal cytoskeleton: an early sign of glaucomatous damage. Invest Ophthalmol Vis Sci 52:2879-88
Huang, Xiang-Run; Zhou, Ye; Kong, Wei et al. (2011) Reflectance decreases before thickness changes in the retinal nerve fiber layer in glaucomatous retinas. Invest Ophthalmol Vis Sci 52:6737-42
Huang, Xiang-Run; Knighton, Robert W (2009) Altered F-actin distribution in retinal nerve fiber layer of a rat model of glaucoma. Exp Eye Res 88:1107-14