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.

Public Health Relevance

Corneal transplantation is often required to restore vision particularly for the common condition, Fuchs endothelial corneal dystrophy (FECD). This proposal will define a new animal model for FECD and increase our understanding of the mechanisms that contribute to FECD pathology. We will also test a novel therapy, netarsudil, to treat FECD using relevant animal models for this common corneal disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016134-10
Application #
10074565
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mckie, George Ann
Project Start
2006-09-01
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
10
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of California Davis
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Thomasy, Sara M; Raghunathan, Vijay Krishna; Miyagi, Hidetaka et al. (2018) Latrunculin B and substratum stiffness regulate corneal fibroblast to myofibroblast transformation. Exp Eye Res 170:101-107
Miyagi, Hidetaka; Jalilian, Iman; Murphy, Christopher J et al. (2018) Modulation of human corneal stromal cell differentiation by hepatocyte growth factor and substratum compliance. Exp Eye Res 176:235-242
Raghunathan, Vijay Krishna; Thomasy, Sara M; Strøm, Peter et al. (2017) Tissue and cellular biomechanics during corneal wound injury and repair. Acta Biomater 58:291-301
Ali, Maryam; Raghunathan, VijayKrishna; Li, Jennifer Y et al. (2016) Biomechanical relationships between the corneal endothelium and Descemet's membrane. Exp Eye Res 152:57-70
Thomasy, Sara M; Cortes, Dennis E; Hoehn, Alyssa L et al. (2016) In Vivo Imaging of Corneal Endothelial Dystrophy in Boston Terriers: A Spontaneous, Canine Model for Fuchs' Endothelial Corneal Dystrophy. Invest Ophthalmol Vis Sci 57:OCT495-503
Strom, Ann R; Cortés, Dennis E; Rasmussen, Carol A et al. (2016) In vivo evaluation of the cornea and conjunctiva of the normal laboratory beagle using time- and Fourier-domain optical coherence tomography and ultrasound pachymetry. Vet Ophthalmol 19:50-6
Strom, Ann R; Cortés, Dennis E; Thomasy, Sara M et al. (2016) In vivo ocular imaging of the cornea of the normal female laboratory beagle using confocal microscopy. Vet Ophthalmol 19:63-7
Horikawa, Taemi; Thomasy, Sara M; Stanley, Amelia A et al. (2016) Superficial Keratectomy and Conjunctival Advancement Hood Flap (SKCAHF) for the Management of Bullous Keratopathy: Validation in Dogs With Spontaneous Disease. Cornea 35:1295-304
Yáñez-Soto, Bernardo; Leonard, Brian C; Raghunathan, Vijay Krishna et al. (2015) Effect of Stratification on Surface Properties of Corneal Epithelial Cells. Invest Ophthalmol Vis Sci 56:8340-8
Kol, Amir; Arzi, Boaz; Athanasiou, Kyriacos A et al. (2015) Companion animals: Translational scientist's new best friends. Sci Transl Med 7:308ps21

Showing the most recent 10 out of 41 publications