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 1) development of mature vimentin+/1-smooth muscle actin+/desmin+ (V+A+D+) myofibroblasts from corneal stromal or bone marrow- derived precursor cells is regulated by the coordinated, sequential action of TGF? and PDGF, 2a) myofibroblast development can be modulated in vitro by TGF? and PDGF, 2b) myofibroblast development in vitro follows a similar developmental pathway of marker expression as it does in vivo, 2c) small molecules that interfere with TGF? and/or PDGF signaling can be used to modulate i) myofibroblast generation in vitro and ii) myofibroblast generation and stromal opacity in vivo, and 3a) IL-1 produced in the stroma to regulate myofibroblast viability in vivo after haze generating corneal surgery is expressed via autocrine IL-1 production by the myofibroblasts themselves and 3b) that knockout of IL-1 receptor, type I, in mice results in an augmented stromal haze and myofibroblast response to injury and myofibroblast persistence over time. These studies are likely to lead to better and safer treatments to prevent sight damaging stromal opacity that frequently occurs after surgical procedures on the cornea. It may also lead to treatments to increase scaring in the cornea where it is beneficial, for example at the donor-recipient junction in corneal transplantation.
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 histopathological, cellular, and molecular investigations in corneas and cultured cells from animal models.
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