The sclera, a connective tissue consisting of proteoglycans and collagen, provides the structural integrity that defines the shape and focal length of the eye. Therefore, alterations in the synthesis, degradation and net accumulation of these extracellular matrix components are likely to lead to significant changes in eye shape and severely affect vision. High myopia is a common condition characterized by excessive lengthening of the eye, primarily due to elongation of the vitreous chamber. Generally, myopia develops before puberty, and then stabilizes. If axial elongation fails to stabilize, an individual has an increased risk of retinal detachment, glaucoma, and blindness. This proposal examines the hypothesis that myopia is a connective tissue disorder in which the scleral extracellular matrix components are inappropriately remodeled. The objective of this proposal is to characterize the biochemical events which lead to scleral elongation and to identify regulatory mechanisms that govern these events. The well established model of myopia in chicks (form deprivation myopia) will be used to determine whether: 1) proteoglycan accumulation within the chick sclera is directly responsible for normal and myopic scleral growth, 2) changes in the fibrous sclera of form-deprived chick eyes parallel changes observed in myopic mammalian sclera 3) regional extracellular matrix turnover is mediated by the regulation of the 72 kDa gelatinase (MMP-2) and its associated inhibitors (TIMP-1 and TIMP-2) in the normal and form-deprived sclera, and 4) changes in the visual environment trigger the differential expression of genes within the eye which regulate scleral growth. Additionally, we propose to characterize the extracellular matrix of the human sclera from donors ranging in age from fetal - 90 years, in order to identify structural and biochemical differences which would predispose children to the development of myopia. Together, this information will serve as a basis for understanding the mechanisms by which myopia develops in chicks as well as in humans. Ultimately, this information may lead to the development of an anti-myopia therapy in children which would slow the progression of myopia by altering scleral metabolism and growth.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009391-07
Application #
2331653
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1992-01-01
Project End
2000-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of North Dakota
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
Harper, Angelica R; Le, Anh T; Mather, Timothy et al. (2018) Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes. Bioorg Med Chem 26:5766-5779
Harper, Angelica R; Wang, Xiang; Moiseyev, Gennadiy et al. (2016) Postnatal Chick Choroids Exhibit Increased Retinaldehyde Dehydrogenase Activity During Recovery From Form Deprivation Induced Myopia. Invest Ophthalmol Vis Sci 57:4886-4897
Summers, Jody A; Harper, Angelica R; Feasley, Christa L et al. (2016) Identification of Apolipoprotein A-I as a Retinoic Acid-binding Protein in the Eye. J Biol Chem 291:18991-9005
Harper, Angelica R; Wiechmann, Allan F; Moiseyev, Gennadiy et al. (2015) Identification of active retinaldehyde dehydrogenase isoforms in the postnatal human eye. PLoS One 10:e0122008
Harper, Angelica R; Summers, Jody A (2015) The dynamic sclera: extracellular matrix remodeling in normal ocular growth and myopia development. Exp Eye Res 133:100-11
Summers, Jody A (2013) The choroid as a sclera growth regulator. Exp Eye Res 114:120-7
Rada, Jody A Summers; Hollaway, Lindsey R; Lam, Wengtse et al. (2012) Identification of RALDH2 as a visually regulated retinoic acid synthesizing enzyme in the chick choroid. Invest Ophthalmol Vis Sci 53:1649-62
Summers Rada, Jody A; Hollaway, Lindsey R (2011) Regulation of the biphasic decline in scleral proteoglycan synthesis during the recovery from induced myopia. Exp Eye Res 92:394-400
Rada, Jody A Summers; Wiechmann, Allan F; Hollaway, Lindsey R et al. (2010) Increased hyaluronan synthase-2 mRNA expression and hyaluronan accumulation with choroidal thickening: response during recovery from induced myopia. Invest Ophthalmol Vis Sci 51:6172-9
Wiechmann, Allan F; Hollaway, Lindsey R; Rada, Jody A Summers (2009) Melatonin receptor expression in Xenopus laevis surface corneal epithelium: diurnal rhythm of lateral membrane localization. Mol Vis 15:2384-403

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