EXTRACELLULAR MATRIX COMPOSITION OF THE OPTIC NERVE HEAD

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.