Steroid-induced intraocular pressure (IOP) elevation is a frequent complication of chronic treatment with corticosteroids. If unrecognized, prolonged steroid-induced IOP elevation can lead to glaucomatous optic neuropathy and loss of vision. Steroid-induced IOP elevation is the result of increased aqueous humor outflow resistance. However, the exact pathogenetic mechanism remains unknown. Through work in relevant animal models we have identified tissue plasminogen activator (tPA) as a critical component in this process and shown that tPA expression in the trabecular meshwork (TM) is down-regulated by steroids; that lack of tPA reduces while over-expressed or exogenous tPA increases outflow facility; and that the tPA-induced increase in outflow facility involves upregulation of MMPs. Thus it appears that tPA has a central role in modulating IOP in steroid-induced glaucoma. Critical next steps will be to determine whether tPA modulates IOP in other well defined forms of open angle glaucoma (e.g. myocilin glaucoma); understand how steroids regulate tPA expression; and elucidate the mechanisms by which tPA leads to changes in outflow facility. Our hypotheses are [a] that tPA expression is directly affected by TM stress (such as that induced by steroid or mutant myocilin) and [b] that tPA controls outflow facility by regulating plasmin and MMPs (through both transcriptional control and post-translational mechanisms). To test these hypotheses we propose the following specific aims: 1. Determine the time course of tPA expression and activity changes in human TM cells after steroid treatment, and test the additional hypothesis that the transcriptional changes are glucocorticoid receptor (GR) mediated. 2. Test the Plasmin component of our hypothesis: that tPA affects outflow facility in a plasmin-dependent manner. 3. Test the MMP component of our hypothesis: that tPA affects outflow facility in an MMP-dependent manner. 4. Test the myocilin/TM stress/tPA expression component of our hypothesis: that TM stress caused by mutant myocilin leads to tPA downregulation, that reduction of TM stress (but not IOP reduction) reverses this down- regulation and that tPA can overcome the effects of TM stress on outflow facility. Completion of this project will reveal whether steroids down-regulate tPA through the GR, whether tPA affects outflow facility by activating plasmin, whether tPA enzymatic activity and MMP activation are required to affect outflow facility, whether myocilin-induced TM stress affects tPA activity and whether tPA can reverse myocilin induced IOP elevation. Thus, investigating tPA regulation and downstream effects will deepen our understanding of the development of steroid-induced IOP elevation and more broadly open angle glaucoma and provide insights into outflow facility regulation. In addition because of the pleiotropic roles of tPA, our results will have important implications for the broader field of tissue remodeling.
The current project aims to understand part of the pathogenetic mechanisms that underlie IOP elevation in steroid-induced and more broadly open angle glaucoma. Steroid-induced glaucoma similarly to open angle glaucoma can (and often does) lead to blindness. Because tPA has a central role in modulating IOP in steroid-induced glaucoma, understanding in detail its actions will form the basis for more specific therapies for glaucoma.
| Hu, Yan; Danias, John (2018) Noninvasive Intraocular Pressure Measurement in Animals Models of Glaucoma. Methods Mol Biol 1695:49-61 |
| Rybkin, Ilya; Gerometta, Rosana; Fridman, Gabrielle et al. (2017) Model systems for the study of steroid-induced IOP elevation. Exp Eye Res 158:51-58 |
| Torrejon, Karen Y; Papke, Ellen L; Halman, Justin R et al. (2016) Bioengineered glaucomatous 3D human trabecular meshwork as an in vitro disease model. Biotechnol Bioeng 113:1357-68 |
| Torrejon, Karen Y; Papke, Ellen L; Halman, Justin R et al. (2016) TGF?2-induced outflow alterations in a bioengineered trabecular meshwork are offset by a rho-associated kinase inhibitor. Sci Rep 6:38319 |
