Understanding the factors that modify the optic nerve's response to intraocular pressure (IOP) will lead to important advances in glaucoma diagnosis and management. By dictating the physical behavior of laminar beams, the optic nerve head extracellular matrix (ECM) may affect nerve fiber susceptibihty to elevated IOP by allowing beams to either impinge on nerve fibers directly or compress their capabilities and alter nerve fiber nutrition. Since preliminary evidence suggests that elevated IOP changes the optic nerve head ECM, optic nerve susceptibility may change throughout the glaucomatous process. This has important implications for the clinical management of glaucoma patients. This proposal will use light and electron microscopic immunohistochemistry to delineate the presence and distribution of proteoglycans in the normal optic nerve head. Proteoglycans are important constituents of the ECM with diverse effects on cell-matrix interactions and matrix organization that have to date been little studied in this tissue. Because young and old optic nerves appear to respond to elevated IOP differently, the effects of age on proteoglycans will also be studied to gain further insight into the roles these macromolecules play in protecting optic nerve fibers. Immunohistochemistry will also be used to detect the proteoglycan distribution in glaucomatous human optic nerve heads. These results will be compared to experimentally glaucomatous monkey eyes to separate primary changes in glaucoma patients from the effects of elevated IOP. Finally, two clinically relevant forms of IOP elevation, acute high IOP and chronic moderate IOP elevation, will be created in monkey eyes. These eyes will be studied and compared with their fellow control eyes for changes in the synthesis of proteoglycans using in situ hybridization. In addition, they will be studied for changes in metalloproteinase distribution and synthesis using immunohistochemistry and in situ hybridization, respectively. Because the metalloproteinase enzymes are thought to be early initiators of connective tissue remodeling, these experiments provide a highly sensitive assay of elevated IOP as a stimulus for remodeling of the optic nerve head ECM. Studying the effects of acute and chronic elevations of IOP will establish the clinical conditions under which these effects take place.
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