The goal of this project is to understand the """"""""emmetropization"""""""" mechanism that uses visual signals to match the axial length of juvenile eyes to their optical power. Normally this mechanism produces eyes with little refractive error. However, a significant proportion of the population develops refractive errors, particularly myopia, in which the eye is too long for its own optical power. In high myopia, the axial elongation (which is not corrected by optical treatments, including refractive surgery) is a risk factor for glaucoma and retinal detachment, making myopia the 7th leading cause of blindness in the U.S. The emmetropization mechanism has at least three key components: 1) the retina, which detects the amount of defocus, 2) a signaling cascade from the retina, through the choroid to the sclera (the fibrous outer coat of the eye), and 3) fibroblasts in the sclera which respond to retinal signals by regulating the axial length. Our hypothesis is that remodeling of the scleral extracellular matrix controls scleral extensibility, axial elongation and refractive state. In the previous project period, a pattern of changes in mRNA levels was found for specific proteins in tree shrew sclera during the development of myopia induced with monocular form deprivation (MD) and during recovery from induced myopia. In the proposed project period we will expand on this discovery.
Specific Aim I will examine whether myopia induced with a minus-power lens produces the same pattern of changes in scleral mRNA levels (with a different time-course) as when form deprivation is used.
Specific Aim 2 will examine the role played by specific proteins in regulating scleral remodeling. We will measure changes in mRNA and protein levels of a membrane-bound matrix metalloproteinase (MTIMMP), of MMP-3 and mRNA levels of proteoglycan core proteins (biglycan, aggrecan, lumican and fibromodulin) during the development of minus-lens induced myopia and recovery.
Specific Aim 3 will examine the potential role of all-trans-retinoic acid (at-RA) in the signaling cascade to the sclera. We will measure changes in specific mRNAs and changes in scleral extensibility (creep rate) induced in organ culture by physiological levels of at-RA. These experiments will expand our understanding of the visual regulation of axial length and refractive state by describing the molecular events that occur in the sclera of eyes developing myopia. Understanding the mechanisms regulating scleral remodeling may point the way toward targets for drug intervention to one-day control myopia progression.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY005922-17
Application #
6477931
Study Section
Visual Sciences B Study Section (VISB)
Program Officer
Oberdorfer, Michael
Project Start
1986-04-01
Project End
2007-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
17
Fiscal Year
2002
Total Cost
$350,646
Indirect Cost
Name
University of Alabama Birmingham
Department
Physiology
Type
Schools of Optometry/Ophthalmol
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
He, Li; Frost, Michael R; Siegwart Jr, John T et al. (2018) Altered gene expression in tree shrew retina and retinal pigment epithelium produced by short periods of minus-lens wear. Exp Eye Res 168:77-88
Gawne, Timothy J; Siegwart Jr, John T; Ward, Alexander H et al. (2017) The wavelength composition and temporal modulation of ambient lighting strongly affect refractive development in young tree shrews. Exp Eye Res 155:75-84
Ward, Alexander H; Siegwart, John T; Frost, Michael R et al. (2017) Intravitreally-administered dopamine D2-like (and D4), but not D1-like, receptor agonists reduce form-deprivation myopia in tree shrews. Vis Neurosci 34:E003
Norton, Thomas T (2016) What Do Animal Studies Tell Us about the Mechanism of Myopia-Protection by Light? Optom Vis Sci 93:1049-51
Ward, Alexander H; Siegwart Jr, John T; Frost, Michael R et al. (2016) The effect of intravitreal injection of vehicle solutions on form deprivation myopia in tree shrews. Exp Eye Res 145:289-296
Grytz, Rafael; Siegwart Jr, John T (2015) Changing material properties of the tree shrew sclera during minus lens compensation and recovery. Invest Ophthalmol Vis Sci 56:2065-78
Guo, Lin; Frost, Michael R; Siegwart Jr, John T et al. (2014) Scleral gene expression during recovery from myopia compared with expression during myopia development in tree shrew. Mol Vis 20:1643-59
He, Li; Frost, Michael R; Siegwart Jr, John T et al. (2014) Gene expression signatures in tree shrew choroid during lens-induced myopia and recovery. Exp Eye Res 123:56-71
He, Li; Frost, Michael R; Siegwart Jr, John T et al. (2014) Gene expression signatures in tree shrew choroid in response to three myopiagenic conditions. Vision Res 102:52-63
Norton, Thomas T; Siegwart Jr, John T (2013) Light levels, refractive development, and myopia--a speculative review. Exp Eye Res 114:48-57

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