Functional failure of the trabecular meshwork (TM) conventional outflow pathway causes elevation in intraocular pressure (IOP), thus increasing the risk for developing primary open angle glaucoma (POAG) an age-related disease second leading cause of irreversible blindness. The homeostatic mechanisms responsible for IOP regulation and those associated with its alteration in glaucoma remain yet poorly understood. Because of elevation in IOP and other forces, cells in the trabecular meshwork (TM) are constantly subjected to mechanical strain. In order to preserve cellular function and regain homeostasis, cells must sense and adapt to these morphological changes. We and others have already shown that mechanical stress can trigger a broad range of responses in TM cells; however, very little is known about the strategies that TM cells use to respond to this stress, so they can adapt and survive. Autophagy, a lysosomal degradation pathway, has emerged as an important cellular homeostatic mechanism promoting cell survival and adaptation to a number of cytotoxic stresses. Our laboratory has reported the activation of autophagy in TM cells in response to static biaxial strain and high pressure. Moreover, our newest data also suggest the activation of chaperon-assisted selective autophagy, a recently identified tension- induced autophagy essential for mechanotransduction, in TM cells under cyclic mechanical stress. We hypothesize that autophagy is part of an integrated response triggered in TM cells in response to strain, exerting a dual role in repair and mechanotransduction. We further hypothesize that dysregulation of this response contributes to the increased ECM deposition and stiffness reported in the glaucomatous outflow pathway. We propose that activation of autophagy can, therefore, represent a novel therapeutic approach for the treatment of ocular hypertension and glaucoma. To test this hypothesis, we will (1) characterize the induction of autophagy in TM cells in response to mechanical stress and high pressure and determine its contribution to the stretch-induced response in TM cells; (2) assess a role of autophagy in modulating the TGF?-mediated pro-fibrotic response to mechanical injury, and (3) evaluate the ability of pharmacological activators of autophagy to decrease ECM deposition and restore outflow pathway function. We anticipate that completion of this project will definitively contribute to a further understanding of the role of autophagy in outflow pathway tissue physiology and pathophysiology. Most importantly, our studies have the potential of identifying a novel therapeutic target for the treatment of ocular hypertension and glaucoma.
Cells in the trabecular meshwork are constantly subjected to mechanical forces and deformations resulting from changes in intraocular pressure and eye movement. It is expected trabecular meshwork cells to possess adaptive mechanisms, which allow them to cope to this stress and prevent further injury. The objective of this grant proposal is to investigate whether autophagy, a cellular mechanism responsible for the degradation of waste material, forms part of this protective mechanism aimed at modulating a stretch-induced healing response. That being the case, pharmacological activation of this cellular pathway might constitute a novel therapeutic strategy for glaucoma.
|Hirt, Joshua; Porter, Kris; Dixon, Angela et al. (2018) Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model. Cell Death Discov 4:14|