Mechanotransduction in corneal disorders

项目总结

PROJECT SUMMARY We have determined that transcriptional co-activators and mechanotransducers, YAP/TAZ, influence corneal epithelial contact guidance, myofibroblast transformation, and that TAZ (encoded by WWTR1 in humans and Wwtr1 in mice) is crucial for a healthy corneal endothelium. Corneal disease is a leading cause of blindness worldwide; corneal transplantation is often required to restore vision particularly for the common condition, Fuchs endothelial corneal dystrophy (FECD). Hallmarks of FECD include premature corneal endothelial cell (CEC) degeneration and the formation of excrescences of extracellular matrix (ECM), termed guttae, on Descemet’s membrane (DM). Biophysical cues intrinsic to ECMs are widely recognized as ubiquitous and potent modulators of myriad cell behaviors, including their response to stress. Despite this, there remains a major knowledge gap in regard to the mechanical properties of DM in health and disease and the associated mechanotransduction events in CECs. Furthermore, a large body of evidence points to oxidative stress playing a major role in FECD. Together, we hypothesize that TAZ plays a critical role in the onset and progression of FECD via changes in cell signaling, matrix remodeling, and cellular stress responses. Exciting preliminary data document that TAZ knockout (Wwtr1-/-) mice have reduced CEC density, increased cellular polymegathism, and an abnormal DM with guttae in comparison to wildtype (WT) littermates. Furthermore, CEC injury to TAZ deficient mice results in bullous keratopathy and diminished CEC regeneration similar to what is observed in severe, chronic FECD. These data suggest that TAZ deficient mice may represent an important late-onset model for FECD to define the role of mechanotransduction in its etiopathogenesis and to test new therapies to delay disease onset and/or progression. In this proposal, we utilize this model to test the efficacy of netarsudil, a rho-kinase and norepinephrine transport inhibitor, recently approved for glaucoma in the US. Preliminary data suggests that netarsudil increases CEC regeneration in TAZ deficient mice. The literature supports the use of rho-kinase inhibitors in CEC regeneration but netarsudil has never been studied in this context to our knowledge. The central goals of this proposal are to 1) determine the role of TAZ in CEC regeneration and 2) investigate the efficacy of netarsudil for CEC regeneration using murine models more predictive of human FECD.