Glaucoma is a major blinding disease. The primary risk factor and only current treatment target for all types of glaucoma is elevated intraocular pressure (IOP). We have identified a robust IOP homeostatic mechanism in which sustained pressure deviations are sensed as mechanical stretching/distortion by cells within the juxtacanalicular (JCT) region of the outflow pathway and corrective adjustments are made to the outflow resistance which restore IOP to appropriate levels. This appears to be a key reason that most people do not develop glaucoma. We recently showed that glaucomatous anterior segments cannot execute a normal IOP homeostatic response. Outflow is segmental around the circumference of the eye with regions of high flow (HF) intermediate flow (IF) and low flow (LF). We recently showed that glaucomatous eyes have more LF regions than normal eyes. This proposal is directed at understanding these two phenomena, IOP homeostasis and outflow segmentation, and exploiting this understanding to correct the glaucomatous deficiencies in them. To begin understanding the IOP homeostatic process and outflow segmentation, we evaluated molecular distribution differences between HF and LF regions of human anterior segments that had been perfused at 1x (normal) or 2x (homeostatic response) pressures. We selected a subset of the molecular differences that seemed most relevant to these processes; they were mostly extracellular matrix (ECM) proteins that function in ECM organization and remodeling. We will refine their distributions, evaluate their regional biosynthesis/dynamics rates, use RNAi silencing to knockdown their levels, interfere directly with their binding interactions, and conduct a few select protein overexpression studies. Primary readouts will be outflow segmentation changes and outflow facility changes in perfused human anterior segment organ culture. Next we will obtain the same molecular distribution data for glaucomatous eyes and using the most effective RNAi silencing and binding interaction perturbations from normal and apply them to glaucomatous eyes. The point will be to modify outflow segmentation and IOP homeostatic responsiveness in diseased tissue to restore function.

Public Health Relevance

This proposal is aimed at understanding in detail the robust intraocular pressure (IOP) homeostasis mechanism that we have recently identified, which normally keeps IOP within safe ranges, but does not function in glaucomatous eyes.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY025721-05
Application #
9817434
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Liberman, Ellen S
Project Start
2015-08-01
Project End
2023-07-31
Budget Start
2019-09-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
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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Raghunathan, Vijay Krishna; Benoit, Julia; Kasetti, Ramesh et al. (2018) Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior. Acta Biomater 71:444-459
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Vranka, Janice A; Bradley, John M; Yang, Yong-Feng et al. (2015) Mapping molecular differences and extracellular matrix gene expression in segmental outflow pathways of the human ocular trabecular meshwork. PLoS One 10:e0122483
Vranka, Janice A; Kelley, Mary J; Acott, Ted S et al. (2015) Extracellular matrix in the trabecular meshwork: intraocular pressure regulation and dysregulation in glaucoma. Exp Eye Res 133:112-25