The structural and optical quality of the cornea is in part maintained by the finely regulated functions of the epithelial and keratocyte cells. Progeny epithelial cells normally undergo a relatively slow and orderly maturation and apical migration to maintain the stratified architecture of the epithelium. In contrast, when the cornea is wounded, the integrity of the corneal surface must be quickly reestablished and remodeled by a combination of proliferation, epithelial migration, and differentiation. The rate of epithelial proliferation increases during healing and returns to the maintenance level, once the normal architecture has been reestablished. Similarly, to maintain corneal clarity and regulate stromal healing, the proliferation of keratocytes in the corneal stroma must be modulated. Growth factors and cytokines have been shown to have essential roles in regulating wound healing in all tissues that have been studied in higher organisms. The wound healing process in the corneal epithelium and stroma is modulated by autocrine and/or paracrine systems involving the coordinated production of specific growth factors and receptors by the epithelial cells and keratocytes. In order to fully understand the wound healing process in the cornea, it is essential that we probe interactions that occur between keratocytes and epithelial cells. These interactions have yet to be characterized, although progress has been made recently. The objective of this study is to explore the endogenous epidermal growth factor (EGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and interleukin-1 alpha (IL-1 alpha) modulator-receptor systems that likely regulate the proliferation, motility, differentiation, and death (apoptosis) of corneal epithelial cells and keratocytes. We will: I) Examine the roles of HGF, KGF, EGF, and their receptors in regulating cellular interactions in the normal and wounded corneas and conclusively demonstrate the production of the modulator proteins in isolated corneal epithelial and stromal fibroblast cells in vitro. II) Explore the mechanisms through which endogenous corneal epithelial and lacrimal gland EGF, TGF alpha, and HGF function in regulating corneal epithelial cell proliferation, motility, and differentiation. III) Examine the role of interleukin-l alpha that is produced by corneal epithelial cells in the modulation of keratocyte viability and function. IV) Characterize in depth (at the molecular level) the structure, ligand binding specificity, affinities, expression, and proliferation-controlling functions of the putative soluble KGF receptor coding sequence expressed in corneal epithelial cells.
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