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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32EY014515-01A1
Application #
6693600
Study Section
Special Emphasis Panel (ZRG1-F03A (20))
Program Officer
Liberman, Ellen S
Project Start
2003-09-30
Project End
2005-09-29
Budget Start
2003-09-30
Budget End
2004-09-29
Support Year
1
Fiscal Year
2003
Total Cost
$51,904
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Howell, Gareth R; Libby, Richard T; Jakobs, Tatjana C et al. (2007) Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol 179:1523-37
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