The cornea focuses light on the retina, providing more than two thirds the refractive power of the eye. To perform this function, it must be completely transparent, and it must have a precise shape, achieved during embryonic development. The adult cornea appears to have multiple mechanisms for leaving a good thing well enough alone, a group of phenomena we defined in the current project period as """"""""corneal constancy"""""""". When damage to the cornea is extensive enough, corneal constancy can be overcome, and a repair response ensues. The quality of repair in the cornea exists on a spectrum, with the process at one end being almost completely regenerative while at the opposite end is fibrotic repair. In the cornea, fibrosis creates opacity, and the contraction of fibrotic repair tissue alters corneal shape. These effects impinge undesirably on the capacity to refract light on the retina. The long-term goal of this project is to improve our understanding of corneal stasis, the repair response, and the mechanisms that confer regenerative character. Over the past decade, this research group and others have developed a model for fibrotic progression as a two step process that begins when keratocytes are """"""""activated"""""""", assuming a """"""""fibroblast"""""""" phenotype, which can progress to the """"""""myofibroblast"""""""" phenotype associated with fibrotic repair. Insight has also been acquired into some of the molecular mechanisms determining activation and progression. Moreover, this lab group has identified important differences between corneal repair and repair in vascularized tissues. In the new project period, the group proposes to follow up on some of these key findings with the goal of clinical application. The two aims address the following: 1) keratocyte activation and the mechanisms for loss of the corneal crystalline transketolase, important for cell transparency;2) transition to fibrosis and the mechanism whereby the corneal epithelial basement membrane determines release of the fibrotic regulator TGF-beta2. At the present time, corneal refractive correction revolves around the increasing refinement of surgical technique to limit the quantity of the wound repair response. However, it could be argued that surgical outcomes might also be improved by controlling the quality of repair. The group will focus on questions that promise to provide new insight into molecular targets for pharmacologic intervention.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009828-17
Application #
8120712
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
Project Start
1993-12-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
17
Fiscal Year
2011
Total Cost
$384,912
Indirect Cost
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Fini, M Elizabeth; Schwartz, Stephen G; Gao, Xiaoyi et al. (2017) Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine. Prog Retin Eye Res 56:58-83
Gordon, Gabriel M; LaGier, Adriana J; Ponchel, Corinne et al. (2016) A cell-based screening assay to identify pharmaceutical compounds that enhance the regenerative quality of corneal repair. Wound Repair Regen 24:89-99
Itakura, Tatsuo; Peters, Donna M; Fini, M Elizabeth (2015) Glaucomatous MYOC mutations activate the IL-1/NF-?B inflammatory stress response and the glaucoma marker SELE in trabecular meshwork cells. Mol Vis 21:1071-84
Jeong, Shinwu; Patel, Nitin; Edlund, Christopher K et al. (2015) Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension. Invest Ophthalmol Vis Sci 56:2737-48
Patel, Nitin; Itakura, Tatsuo; Jeong, Shinwu et al. (2015) Expression and functional role of orphan receptor GPR158 in prostate cancer growth and progression. PLoS One 10:e0117758
Bauskar, Aditi; Mack, Wendy J; Mauris, Jerome et al. (2015) Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye. PLoS One 10:e0138958
Wu, Pei-Chang; Tsai, Chia-Ling; Gordon, Gabriel M et al. (2015) Chondrogenesis in scleral stem/progenitor cells and its association with form-deprived myopia in mice. Mol Vis 21:138-47
Patel, Nitin; Itakura, Tatsuo; Gonzalez Jr, Jose M et al. (2013) GPR158, an orphan member of G protein-coupled receptor Family C: glucocorticoid-stimulated expression and novel nuclear role. PLoS One 8:e57843
LaGier, Adriana J; Gordon, Gabriel M; Katzman, Lee R et al. (2013) Mechanisms for PDGF, a serum cytokine, stimulating loss of corneal keratocyte crystallins. Cornea 32:1269-75
Jeong, Shinwu; Ledee, Dolena R; Gordon, Gabriel M et al. (2012) Interaction of clusterin and matrix metalloproteinase-9 and its implication for epithelial homeostasis and inflammation. Am J Pathol 180:2028-39

Showing the most recent 10 out of 41 publications