Myopia is the most common of all ocular problems, affecting 25 percent of the US adult population. The most common structural abnormality associated with myopia is excessive lengthening of the posterior segment of the ocular globe (axial myopia). Generally, myopia increases just before and during puberty and then stabilizes. If axial elongation fails to stabilize, an individual has an increased risk for a number of severe ocular diseases including glaucoma, retinal detachment and blindness. While it is clear that changes in the shape of the sclera produce myopia, the basis for this shape change is largely unknown. The sclera is a connective tissue, consisting of interwoven collagen fibrils in close association with proteoglycans, that provides the structural framework that defines the shape and therefore the axial length of the eye. Recent studies have shown that the scleral extracellular matrix undergoes significant changes during growth and aging and is dramatically influenced by the visual environment. We hypothesize that changes in extracellular matrix synthesis and/or turnover in the sclera contribute to age related changes in scleral structure and can significantly alter the rate of vitreous chamber elongation during the process of visually guided ocular growth. The overall objective of this application is to identify and characterize mechanisms involved in the regulation of scleral extracellular matrix synthesis, assembly, and turnover and how these mechanisms relate to scleral changes associated with growth, aging and the development of myopia. Experiments outlined in the current application combine whole animal, cellular and molecular approaches to determine whether: 1) changes in proteoglycan synthesis and accumulation observed in the sclera are regulated by alterations in the actions of growth factors, 2) the rate of vitreous chamber elongation in the primate eye is controlled by scleral extracellular matrix changes, 3) the choroid synthesizes and releases proteins which regulate scleral proteoglycan synthesis, 4) scleral extracellular matrix remodeling is stimulated by localized mechanical stresses placed upon the ocular globe, and 5) the lumican core protein is present in the sclera and is involved in cellular and extracellular matrix interactions within the scleral matrix. Results obtained from these studies will provide insights into the mechanisms which regulate scleral extracellular matrix remodeling and the control of ocular growth. Ultimately, this information may be applied to strategies to reverse or prevent the scleral extracellular matrix changes associated with myopia development.
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