The broad, long term objectives of this study are to (I) identify and characterize the growth factor-receptor systems through which the functions of corneal, immune, and other cells of the anterior segment of the eye are controlled during development, homeostasis, and wound healing; (II) understand at the molecular and cellular level, the factors that lead to corneal opacity and its resolution after excimer laser surface ablation procedures; (III) explore the importance of the epithelial basement membrane in modulating epithelial stromal interactions in the cornea.
The Specific aims of this proposal are to test the hypotheses that (1a) the appearance of corneal opacity-associated myofibroblasts after ? surface ablation is related to stromal surface irregularity that leads to abnormal basement membrane (BM) regeneration that affects BM structure and/or function; (1b) myofibroblasts participate in cytokine-mediated feedback loops with epithelial cells that regulate myofibroblast differentiation and disappearance; (2a) that alpha-smooth muscle actin expressing myofibroblasts that only appear in the cornea several weeks after injury are preceded by alpha-smooth muscle actin negative, vimentin-positive, desmin-positive myofibroblasts (VD type myofibroblasts) or alpha smooth muscle actin negative, vimentin-positive, desmin-negative myofibroblasts (V type myofibroblasts) adjacent to the BM; (2b) myofibroblasts that appear in the cornea are derived from keratocytes, not bone marrow-derived cells; (3a) spontaneous resolution of stromal opacity after surface ablation procedures in vivo is mediated, at least in part, by late apoptosis; (3b) myofibroblasts are resistant to apoptosis triggered by epithelial scrape injury; (3c) mitomycin C decreases haze by triggering myofibroblast apoptosis, not inhibiting proliferation of stromal cells; and (3d) that IL-1 alpha and beta are inducers of corneal myofibroblast apoptosis in vitro and TGF beta anti-apoptotic effects protect myofibroblasts from IL-1 alpha- and IL-1 beta induced apoptosis in vitro. The health relatedness of this project is that it is likely to (i) lead to better pharmacological control of wound healing following surgery or injury to the cornea; and (ii) provide a better understanding of the pathogenesis and treatment or scarring that occurs after corneal surgery. The research design is histopathologic, cellular, and molecular investigations in corneas and cultured cells from animal models. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010056-14
Application #
7454176
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
1994-08-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
14
Fiscal Year
2008
Total Cost
$367,560
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Medeiros, Carla S; Marino, Gustavo K; Santhiago, Marcony R et al. (2018) The Corneal Basement Membranes and Stromal Fibrosis. Invest Ophthalmol Vis Sci 59:4044-4053
Medeiros, Carla S; Lassance, Luciana; Saikia, Paramananda et al. (2018) Posterior stromal cell apoptosis triggered by mechanical endothelial injury and basement membrane component nidogen-1 production in the cornea. Exp Eye Res 172:30-35
Saikia, Paramananda; Thangavadivel, Shanmugapriya; Medeiros, Carla S et al. (2018) IL-1 and TGF-? Modulation of Epithelial Basement Membrane Components Perlecan and Nidogen Production by Corneal Stromal Cells. Invest Ophthalmol Vis Sci 59:5589-5598
Saikia, Paramananda; Medeiros, Carla S; Thangavadivel, Shanmugapriya et al. (2018) Basement membranes in the cornea and other organs that commonly develop fibrosis. Cell Tissue Res 374:439-453
Medeiros, Carla S; Marino, Gustavo K; Lassance, Luciana et al. (2018) The Impact of Photorefractive Keratectomy and Mitomycin C on Corneal Nerves and Their Regeneration. J Refract Surg 34:790-798
Lassance, Luciana; Marino, Gustavo K; Medeiros, Carla S et al. (2018) Fibrocyte migration, differentiation and apoptosis during the corneal wound healing response to injury. Exp Eye Res 170:177-187
Wilson, Steven E; Medeiros, Carla S; Santhiago, Marcony R (2018) Pathophysiology of Corneal Scarring in Persistent Epithelial Defects After PRK and Other Corneal Injuries. J Refract Surg 34:59-64
Santhanam, Abirami; Marino, Gustavo K; Torricelli, Andre A M et al. (2017) EBM regeneration and changes in EBM component mRNA expression in stromal cells after corneal injury. Mol Vis 23:39-51
Marino, Gustavo K; Santhiago, Marcony R; Santhanam, Abirami et al. (2017) Epithelial basement membrane injury and regeneration modulates corneal fibrosis after pseudomonas corneal ulcers in rabbits. Exp Eye Res 161:101-105
Wilson, Steven E; Marino, Gustavo K; Torricelli, Andre A M et al. (2017) Injury and defective regeneration of the epithelial basement membrane in corneal fibrosis: A paradigm for fibrosis in other organs? Matrix Biol 64:17-26

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