We propose that intraocular pressure (IOP) elevation in primary open angle glaucoma results from increased stiffness of Schlemm's canal (SC) endothelial cells, which impairs pore formation, and consequently obstructs aqueous humor outflow. This hypothesis is mechanistic, testable and when exploited can lead to novel therapies for glaucoma. Data obtained during the first award period of this BRP achieved all set milestones, and strongly supports the central hypothesis. We have shown that SC cells are highly contractile, modifying their contractile stresses and stiffnesses to levels comparable to smooth muscle cells. We have demonstrated that mechanical strain on SC cells potentiates pore formation. We have also discovered a remarkable link between cell stiffness and outflow resistance, specifically that drugs that increase (decrease) SC cell stiffness increase (decrease) resistance. Together, these observations demonstrate that SC cells are highly mechanosensitive and their biomechanical activity is tightly tied to aqueous outflow regulation and survival in a mechanically demanding environment. Moreover, our studies have further demonstrated that glaucomatous SC cells have altered mechanobiology including: (i) elevated cell stiffness, (ii) reduced pore-forming capability, and (iii) enhanced mechanosensitivity to substrate stiffness. This latter finding of ours is particularly relevant to recent findings of othrs, showing elevated stiffness in the trabecular meshwork of glaucomatous eyes. Our renewal application builds upon these milestones and focuses upon mechanism, genetics and translation to therapeutic applications. To test our hypothesis, we have designed five specific aims: First, we will extend a conceptual model we have developed that details the relationship between cell stiffness and outflow resistance. Second, we will look to extend our seminal findings of elevated stiffness of glaucomatous SC cells in vitro to the situation in situ, and will also examine whether the effect is magnified under physiological load. Third, we will determine the role of genetic regulatory processes in the altered biomechanics of glaucomatous SC cells, exploring underlying mechanisms. Fourth, we will introduce high-throughput functional (mechanobiologically based) screening to identify new candidate compounds that decrease SC cell contractile forces. Finally, we will use viral vectors to deliver cell stiffness-altering gene that specifically target the SC (and not TM, or other cell types) and monitor effects on outflow function. Testing of our hypothesis will enable rational development of targeted glaucoma therapies that selectively decrease cell stiffness at the level of Schlemm's canal, consequently reducing IOP.
Current treatments for glaucoma alter the rate of aqueous humor formation or the path of aqueous humor outflow, but do not target the diseased tissue responsible for the elevated intraocular pressure that is characteristic of most cases of glaucoma. These treatments often slow the progression of the disease at the optic nerve head, but frequently do not stop it. This Bioengineering Research Partnership has identified cellular dysfunction in this diseased tissue and plans to develop a targeted pressure-lowering treatment or cure for this debilitating disease.
| Tanna, Angelo P; Johnson, Mark (2018) Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension. Ophthalmology 125:1741-1756 |
| Stack, Trevor; Vahabikashi, Amir; Johnson, Mark et al. (2018) Modulation of Schlemm's canal endothelial cell stiffness via latrunculin loaded block copolymer micelles. J Biomed Mater Res A 106:1771-1779 |
| O'Callaghan, Jeffrey; Crosbie, Darragh E; Cassidy, Paul S et al. (2017) Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma. Hum Mol Genet 26:1230-1246 |
| Klingeborn, Mikael; Dismuke, W Michael; Skiba, Nikolai P et al. (2017) Directional Exosome Proteomes Reflect Polarity-Specific Functions in Retinal Pigmented Epithelium Monolayers. Sci Rep 7:4901 |
| Tam, Lawrence C S; Reina-Torres, Ester; Sherwood, Joseph M et al. (2017) Enhancement of Outflow Facility in the Murine Eye by Targeting Selected Tight-Junctions of Schlemm's Canal Endothelia. Sci Rep 7:40717 |
| Klingeborn, Mikael; Dismuke, W Michael; Bowes Rickman, Catherine et al. (2017) Roles of exosomes in the normal and diseased eye. Prog Retin Eye Res 59:158-177 |
| Li, Guorong; Cui, Gang; Dismuke, W Michael et al. (2017) Differential response and withdrawal profile of glucocorticoid-treated human trabecular meshwork cells. Exp Eye Res 155:38-46 |
| Fini, M Elizabeth; Schwartz, Stephen G; Gao, Xiaoyi et al. (2017) Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine. Prog Retin Eye Res 56:58-83 |
| Johnson, Mark; McLaren, Jay W; Overby, Darryl R (2017) Unconventional aqueous humor outflow: A review. Exp Eye Res 158:94-111 |
| Williams, Andrew M; Stamer, W Daniel; Allingham, R Rand (2016) Increasing the Availability and Quality of Donor Eyes for Research. JAMA Ophthalmol 134:351-2 |
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