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.
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