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.
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