Vision loss in glaucoma results from retinal ganglion cell (RGC) death that is typically induced by harmfully high intraocular pressure (IOP). While RGCs are believed to die via apoptosis, the specific pathways that kill RGCs subjected to high IOP in glaucoma are not defined. Similarly, whether high IOP results in initial damage to the neuronal soma, axon or both is unknown. Determining the location of the initial insult(s) to RGCs is important as distinct degeneration pathways may be induced depending upon the site of initial insult. Studies of RGC death in a progressive high IOP glaucoma that resembles the human disease are urgently needed. DBA/2J mice develop elevated IOP and glaucoma with age. DBA/2J mice are a unique and tractable model for dissecting pathways of pressure induced RGC death. I will use DBA/2J mice to determine: 1. Whether Bax induced apoptotic pathways are necessary for RGC degeneration in glaucoma. My initial studies suggest that Bax is essential for the degeneration of RGC somas but does not affect degeneration of RGC axons. 2. Whether the Wld protein, which potently protects axons from degeneration caused by acute experimental paradigms, can protect RGC axons in glaucoma. 3. Whether candidate proteolytic molecules-caspases and calpains-that contribute to somal and axonal degeneration in acute experimental paradigms are activated in RGC somas, axons or both in glaucoma. These experiments will provide insight into pathways responsible for pressure induced RGC degeneration. Additionally these experiments will provide insight into the location of neuronal insults in glaucoma.
