Post-natal refractive development of the eye matches optical power with axial length to focus the visual image onto the photoreceptors. When successful, the eye reaches emmetropia or zero refractive error. However, ~25% of the US population develops myopia while only 10% develop hyperopia. The prevalence of myopia has reached near epidemic proportions in Asian countries. Progressive myopes and high myopes have increased risk of retinal detachment and blindness. While ~$3.9 billion dollars was spent in 2001 on refractive corrections for distance vision (not including the cost of nearly 1 million refractive surgeries performed), no treatments exist to prevent or arrest the progression of myopia. The mechanisms driving refractive development have been localized to the retina, but the retinal pathways and biochemical signaling remain unknown. Based on the assumption that contrast sensitivity and spatial frequency are characteristics of the visual image that drive this response, we hypothesize that the main retinal pathways involved are the ON and OFF pathways. These pathways are proposed to stimulate unique biochemical signals that suppress default excessive eye growth. Thus, normal refractive development relies on constant biochemical feedback derived from retinal pathways activated by normal visual images. We further hypothesize that abnormalities in the visual environment, retinal pathways, or specific biochemical signals will result in down-regulation of the biochemical signaling which then allows for excess eye growth and myopia. In order to test this hypothesis, (Aim 1) the refractive development of specific mouse models with ON or OFF pathway defects will be tested under normal and form deprived visual conditions. In addition, the possibility that ON or OFF pathways originating from rod or cone photoreceptors may control refractive development will be tested by using mice with only functional rods or cones. Refractive development will be assessed by measurements of refractive error and ocular dimensions. The biochemical signals associated with the ON and OFF pathway will be investigated in Aim 2. We hypothesize that dopamine is a putative ON pathway signal. Thus, dopamine synthesis and release will be examined during refractive development in the ON/OFF pathway mutants as well as determining the consequence of the absence of dopamine on refractive development in a retina-specific dopamine deficient mouse. An OFF pathway biochemical signal will be identified using gene profiling in a mouse model with only functional OFF pathways. Candidate genes will then be tested in OFF pathway mutant mice. These experiments are designed to determine the retinal mechanisms of refractive development, thus identifying novel targets for pharmacological or behavioral interventions that could prevent or retard the development of myopia.

Public Health Relevance

Uncorrected refractive errors represent the leading cause of blindness in the world and are the focus of the World Health Organization Vision 2020 program. In the US, ~25% of the population has myopia and an estimated $3.9 billion is spent annually for refractive correction of distance vision;not including the cost of renewed prescriptions or the nearly 1 million refractive surgeries that are performed annually. The proposed research will reveal new insights into the retinal mechanisms that control refractive development, thus identifying novel targets for new interventions that would prevent or retard refractive errors.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016435-05
Application #
8403027
Study Section
Central Visual Processing Study Section (CVP)
Program Officer
Wiggs, Cheri
Project Start
2009-01-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$291,403
Indirect Cost
$65,684
Name
Emory University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Metlapally, Ravikanth; Park, Han Na; Chakraborty, Ranjay et al. (2016) Genome-Wide Scleral Micro- and Messenger-RNA Regulation During Myopia Development in the Mouse. Invest Ophthalmol Vis Sci 57:6089-6097
Bergen, Michael A; Park, Han Na; Chakraborty, Ranjay et al. (2016) Altered Refractive Development in Mice With Reduced Levels of Retinal Dopamine. Invest Ophthalmol Vis Sci 57:4412-4419
Stone, Richard A; Cohen, Yuval; McGlinn, Alice M et al. (2016) Development of Experimental Myopia in Chicks in a Natural Environment. Invest Ophthalmol Vis Sci 57:4779-89
Deming, Janise D; Pak, Joseph S; Shin, Jung-A et al. (2015) Arrestin 1 and Cone Arrestin 4 Have Unique Roles in Visual Function in an All-Cone Mouse Retina. Invest Ophthalmol Vis Sci 56:7618-28
Prunty, Megan C; Aung, Moe H; Hanif, Adam M et al. (2015) In Vivo Imaging of Retinal Oxidative Stress Using a Reactive Oxygen Species-Activated Fluorescent Probe. Invest Ophthalmol Vis Sci 56:5862-70
Deming, Janise D; Pak, Joseph S; Brown, Bruce M et al. (2015) Visual Cone Arrestin 4 Contributes to Visual Function and Cone Health. Invest Ophthalmol Vis Sci 56:5407-16
Chakraborty, Ranjay; Park, Han Na; Hanif, Adam M et al. (2015) ON pathway mutations increase susceptibility to form-deprivation myopia. Exp Eye Res 137:79-83
Chakraborty, Ranjay; Pardue, Machelle T (2015) Molecular and Biochemical Aspects of the Retina on Refraction. Prog Mol Biol Transl Sci 134:249-67
Park, Han na; Jabbar, Seema B; Tan, Christopher C et al. (2014) Visually-driven ocular growth in mice requires functional rod photoreceptors. Invest Ophthalmol Vis Sci 55:6272-9
Wright, Charles B; Chrenek, Micah A; Feng, Wei et al. (2014) The Rpe65 rd12 allele exerts a semidominant negative effect on vision in mice. Invest Ophthalmol Vis Sci 55:2500-15

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