Glaucoma is a major cause of blindness in the world, and currently affects 2.2 million United States citizens. While conventional treatments to lower intraocular pressure (IOP) can stabilize vision in many patients, others continue to lose vision in spite of apparently good pressure control. This suggests that unique changes may occur in glaucoma that leave remaining optic nerve fibers increasingly susceptible to IOP. Identifying and understanding such changes will lead to potent new methods of preventing vision loss in glaucoma, particularly if applied to retinal cells before they are committed to cell death. This proposal concentrates on the hypothesis that both elevated IOP and aging impair the ability of retinal ganglion cells (RGC) to support the organization of the axonal cytoskeleton and axonal transport, functions critical to their survival. This will be tested by performing gene array analysis on inner retinal tissue from a rat model (8 months old) of elevated IOP to determine the range of gene responses common to these biological responses. These findings will be confirmed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry will be used to localize protein products to the specific cells of this layer. Identification of gene changes specifically to RGC will be done using laser capture microdissection of RGC labeled by fluorescent tracers and qRT-PCR. Reversibility of these gene changes will then be tested in eyes in which pressure is lowered by cyclodialysis following an initial period of IOP elevation. These will be evaluated in the inner retina by gene array analysis and in RGC specifically with qRT-PCR. Finally, qRT-PCR will be used in tissue from aged animals (28 months old) to evaluate RGC gene responses to elevated IOP and their ability to recover following pressure normalization by cyclodialysis. ? Relevance to public health: These experiments will provide information on cellular mechanisms of retinal damage and visual loss in glaucoma, a disease expected to increase in the United States by 50% in the next 15 years due to rapid aging of our population. This knowledge will lead to effective new therapies that can be added to conventional pressure-lowering treatment to protect vision in patients at greatest risk of progression, such as the elderly and those with advanced disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY010145-11
Application #
7097811
Study Section
Special Emphasis Panel (ZRG1-BDCN-H (91))
Program Officer
Liberman, Ellen S
Project Start
1993-04-01
Project End
2010-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
11
Fiscal Year
2006
Total Cost
$366,638
Indirect Cost
Name
Oregon Health and Science University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Tehrani, Shandiz; Delf, R Katherine; Cepurna, William O et al. (2018) In Vivo Small Molecule Delivery to the Optic Nerve in a Rodent Model. Sci Rep 8:4453
Jiang, Xiaoyun; Johnson, Elaine; Cepurna, William et al. (2018) The effect of age on the response of retinal capillary filling to changes in intraocular pressure measured by optical coherence tomography angiography. Microvasc Res 115:12-19
Morrison, John C; Johnson, Elaine C; Cepurna, William O (2018) Hypertonic Saline Injection Model of Experimental Glaucoma in Rats. Methods Mol Biol 1695:11-21
Lozano, Diana C; Choi, Dongseok; Jayaram, Hari et al. (2018) Utilizing RNA-Seq to Identify Differentially Expressed Genes in Glaucoma Model Tissues, Such as the Rodent Optic Nerve Head. Methods Mol Biol 1695:299-310
Teotia, Pooja; Chopra, Divyan A; Dravid, Shashank Manohar et al. (2017) Generation of Functional Human Retinal Ganglion Cells with Target Specificity from Pluripotent Stem Cells by Chemically Defined Recapitulation of Developmental Mechanism. Stem Cells 35:572-585
Jayaram, Hari; Phillips, Jay I; Lozano, Diana C et al. (2017) Comparison of MicroRNA Expression in Aqueous Humor of Normal and Primary Open-Angle Glaucoma Patients Using PCR Arrays: A Pilot Study. Invest Ophthalmol Vis Sci 58:2884-2890
Tan, Ou; Liu, Liang; Zhang, Xinbo et al. (2016) Glaucoma Increases Retinal Surface Contour Variability as Measured by Optical Coherence Tomography. Invest Ophthalmol Vis Sci 57:OCT438-43
Tehrani, Shandiz; Davis, Lauren; Cepurna, William O et al. (2016) Astrocyte Structural and Molecular Response to Elevated Intraocular Pressure Occurs Rapidly and Precedes Axonal Tubulin Rearrangement within the Optic Nerve Head in a Rat Model. PLoS One 11:e0167364
Morrison, John C; Cepurna, William O; Tehrani, Shandiz et al. (2016) A Period of Controlled Elevation of IOP (CEI) Produces the Specific Gene Expression Responses and Focal Injury Pattern of Experimental Rat Glaucoma. Invest Ophthalmol Vis Sci 57:6700-6711

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