Understanding cellular mechanisms of axonal injury from elevated intraocular pressure (IOP) is essential for developing glaucoma treatments that will protect the optic nerve. We have determined that an 8- hour exposure to Controlled Elevation of IOP (CEI) in anesthetized rats will reproduce optic nerve injury and gene expression changes within the optic nerve head (ONH) that are characteristic of chronic IOP elevation. Working with this model, and manipulating systemic blood pressure (BP) as well as IOP, we now propose to identify injurious cellular pathways that are activated within the ONH, paying particular attention to IOP-induced biomechanical stress/strain and ischemia/hypoxia Specific Aim 1 will (a) define the development and timing of optic nerve injury to 8 hours'exposure to 50 and 60 mmHg (CEI 50-8 and CEI 60-8) using histologic evidence of axonal degeneration and functional assessment of retinal ganglion cell/inner retina injury with the scotopic threshold response (STR) by electroretinography. We will then (b) use a microarray cluster analysis to determine the chronological cascade of gene expression changes to CEI 60-8, with (c) confirmation by qPCR and comparison to CEI 50-8, which we anticipate will produce fewer ischemia/hypoxia changes and less dynamic changes from biomechanical stress/strain.
Specific Aim 2 will identify specific ischemia/hypoxia gene expression changes by (a) reducing ONH perfusion in eyes with normal IOP and (b) increasing BP to improve perfusion in eyes with elevated IOP, using qPCR confirmation of the appearance of ischemia/hypoxia responses in the former and their reduction and/or elimination in the latter. These will be guided by assessment of retina and ONH perfusion with Doppler-Optical Coherence Tomography, adapted for rat eyes by Dr. Ruikang Wang at the University of Washington.
Specific Aim 3 will demonstrate that inhibition of the Jak2/Stat3 pathway, an initial ONH responder to elevated IOP, can suppress downstream specific ONH gene expression responses and alter axonal injury from acute IOP elevation, identifying a key role for this pathway in axon survival or injury, and a potential futue neuroprotective target.
Specific Aim 4 will demonstrate that elderly animals are more susceptible to IOP-induced axonal injury and that this results from age-related alterations in gene expression responses to IOP elevation. These studies will reveal ONH pathways activated by IOP-induced biomechanical stress/strain and ischemia/hypoxia to produce axonal injury and will lead to neuroprotective treatments "targeted" to specific clinical situations like vasospasm and aging. Successful development of the CEI model in rodents will simplify and accelerate the study of glaucomatous optic nerve damage and testing of potential neuroprotective agents.

Public Health Relevance

This project will identify early cellular responses of the optic nerve head in glaucoma using a model of controlled, elevated intraocular pressure, a major glaucoma risk factor. These insights will lead to new methods of treating glaucoma that can be combined with traditional, pressure-lowering therapies.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (DPVS)
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Chin, Hemin R
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Oregon Health and Science University
Schools of Medicine
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Zhi, Zhongwei; Chao, Jennifer R; Wietecha, Tomasz et al. (2014) Noninvasive imaging of retinal morphology and microvasculature in obese mice using optical coherence tomography and optical microangiography. Invest Ophthalmol Vis Sci 55:1024-30
Tehrani, Shandiz; Johnson, Elaine C; Cepurna, William O et al. (2014) Astrocyte processes label for filamentous actin and reorient early within the optic nerve head in a rat glaucoma model. Invest Ophthalmol Vis Sci 55:6945-52
Johnson, Elaine C; Doser, Thomas A; Cepurna, William O et al. (2011) Cell proliferation and interleukin-6-type cytokine signaling are implicated by gene expression responses in early optic nerve head injury in rat glaucoma. Invest Ophthalmol Vis Sci 52:504-18
Morrison, John C; Cepurna Ying Guo, William O; Johnson, Elaine C (2011) Pathophysiology of human glaucomatous optic nerve damage: insights from rodent models of glaucoma. Exp Eye Res 93:156-64
Guo, Ying; Cepurna, William O; Dyck, Jennifer A et al. (2010) Retinal cell responses to elevated intraocular pressure: a gene array comparison between the whole retina and retinal ganglion cell layer. Invest Ophthalmol Vis Sci 51:3003-18
Morrison, John C; Jia, Lijun; Cepurna, William et al. (2009) Reliability and sensitivity of the TonoLab rebound tonometer in awake Brown Norway rats. Invest Ophthalmol Vis Sci 50:2802-8
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Johnson, Elaine C; Guo, Ying; Cepurna, William O et al. (2009) Neurotrophin roles in retinal ganglion cell survival: lessons from rat glaucoma models. Exp Eye Res 88:808-15
Johnson, Elaine C; Morrison, John C (2009) Friend or foe? Resolving the impact of glial responses in glaucoma. J Glaucoma 18:341-53
Lloyd, Michael; Giegengack, Matthew; Morrison, John C (2008) Surgical reduction of dysesthetic blebs. Arch Ophthalmol 126:1759-64

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