Primary open-angle glaucoma (POAG) is the second leading cause of blindness in the United States and is commonly associated with elevation of intraocular pressure (IOP) resulting from increased resistance to aqueous humor (AH) outflow through the trabecular meshwork (TM) and Schlemm's canal (SC). Although IOP is considered to be a primary risk factor for open angle glaucoma, the etiological mechanisms responsible for increased resistance to AH outflow are largely unknown. The long-range goal of this application is to identify specific etiological mechanisms underlying increased resistance to AH outflow through the TM and SC, and leverage this knowledge to develop novel and targeted therapies for lowering IOP in glaucoma patients. We recently developed an animal model that exhibits a sustained increase in IOP in response to expression of a constitutively active Rho GTPase (RhoAV14) in the AH outflow pathway. Based on the highly significant and promising preliminary observations derived from this model, we propose a novel hypothesis that ocular hypertension induced by aberrant Rho/Rho kinase signaling activity in the trabecular outflow pathway is mechanistically linked to an enhanced endothelial to mesenchymal transition of TM and SC cells into matrix producing myofibroblast-like cells, the activation of which results in extracellular matrix (ECM) deposition and changes in juxtacanalicular connective tissue (JCT) architecture, leading to increased resistance to AH outflow. This central hypothesis is supported by our findings of scarring of the JCT, ECM accumulation and expression of myofibroblast-specific markers in the trabecular pathway of RhoAV14-induced ocular hypertensive rat eyes and in human POAG donor eyes. We propose to investigate this novel hypothesis under three specific aims: 1. Establish the role of Rho/Rho kinase signaling in driving the endothelial to mesenchymal transition (EndMT) of TM and SC cells into matrix-producing myofibroblast-like cells, upon exposure to mechanical strain and physiologically relevant factors (TGF-, autotaxin/LPA axis, connective tissue growth factor) associated with glaucoma; 2. Verify the mechanistic link between ocular hypertension in the RhoAV14 rat model, increased EndMT of TM and SC cells into myofibroblast-like cells, structural alterations within AH outflow pathway tissues, and increased resistance to AH outflow, and 3. Evaluate the validity of the prediction that the efficacy of Rho kinase inhibitors to increase AH outflow in ocular hypertensive glaucomatous eyes is linked partly to suppression of ECM deposition and fibrogenic effects of activated myofibroblasts in AH outflow pathway, using the RhoAV14 ocular hypertensive rat as a model system. Exploration of these studies is expected to identify the specific etiological mechanisms involved in increased resistance to AH outflow in glaucoma subjects and enhance our mechanistic understanding of how certain physiological factors and Rho kinase inhibitors influence AH outflow and IOP in glaucoma patients.
Primary open-angle glaucoma is the second leading cause of blindness in the United States and is commonly associated with elevated intraocular pressure (IOP) due to diminished aqueous humor drainage. Developing effective therapies for increased IOP in glaucoma patients requires identification of the specific etiological mechanisms that underlie resistance to aqueous humor (AH) outflow. In this application we propose to investigate the novel hypothesis that an aberrant endothelial to mesenchymal transition (EndMT) of trabecular meshwork and Schlemm's canal cells into matrix producing activated myofibroblast-like cells represents a critical causative mechanism accounting for impaired AH outflow in glaucoma patients. It is anticipated that completion of this research will provide significant insights into our understanding of both physiological and pathological regulation of aqueous humor outflow resistance in normal and ocular hypertensive glaucoma eyes, respectively, and have a direct impact on development of novel strategies for glaucoma treatment.
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