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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010145-16
Application #
8623130
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Chin, Hemin R
Project Start
1993-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
16
Fiscal Year
2014
Total Cost
$612,037
Indirect Cost
$183,949
Name
Oregon Health and Science University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Teotia, Pooja; Chopra, Divyan A; Dravid, Shashank Manohar et al. (2016) Generation of Functional Human Retinal Ganglion Cells with Target Specificity from Pluripotent Stem Cells by Chemically Defined Recapitulation of Developmental Mechanism. Stem Cells :
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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Lu, Wennan; Hu, HuiLing; Sévigny, Jean et al. (2015) Rat, mouse, and primate models of chronic glaucoma show sustained elevation of extracellular ATP and altered purinergic signaling in the posterior eye. Invest Ophthalmol Vis Sci 56:3075-83
Pazos, Marta; Yang, Hongli; Gardiner, Stuart K et al. (2015) Rat optic nerve head anatomy within 3D histomorphometric reconstructions of normal control eyes. Exp Eye Res 139:1-12
Zhi, Zhongwei; Cepurna, William; Johnson, Elaine et al. (2015) Evaluation of the effect of elevated intraocular pressure and reduced ocular perfusion pressure on retinal capillary bed filling and total retinal blood flow in rats by OMAG/OCT. Microvasc Res 101:86-95
Parameswaran, Sowmya; Dravid, Shashank Manohar; Teotia, Pooja et al. (2015) Continuous non-cell autonomous reprogramming to generate retinal ganglion cells for glaucomatous neuropathy. Stem Cells 33:1743-58
Johnson, Elaine C; Cepurna, William O; Choi, Dongseok et al. (2015) Radiation pretreatment does not protect the rat optic nerve from elevated intraocular pressure-induced injury. Invest Ophthalmol Vis Sci 56:412-9

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