The overall goal of this proposal is to determine the role and regulation of specific adhesion molecules in (1) the maintenance of corneal epithelial integrity, (2) epithelial migration following wounding, and (3) the re-establishment of the competent epithelial barrier upon healing of the wound. Our hypothesis is that the molecular components, which function in quiescent epithelia to ensure stable cell-matrix and intercellular adhesion, become dynamically involved in more supple adhesion interactions during epithelial migration subsequent to lesion of the ocular surface. Transformations of epithelial cells during the transition from sedentary to actively migrating, may involve the disassembly of dedicated adhesion structures, movements of adhesion molecules, changes in their molecular associations, and post-translational indications of adhesion related proteins. When the wound closure has been completed, the epithelium would need to reverse the above changes and again establish a stable epithelial configuration. To reach this goal, we will use a combination of morphological, immunological, biochemical and molecular biological methods to investigate various aspects of the molecules mediating epithelial cell adhesion. We will identify and characterize some family of cell surface adhesion proteins referred to as integrins. Members of the integrin family will be studied for potential roles in cell-cell as well as cell-matrix adhesion. We will examine the means by which the epithelial cell may discriminate between adhesive interactions with other cells vs. with the extracellular matrix. A new protein has been discovered in our laboratory that may play a crucial role in the establishment of stable corneal epithelial adhesion. We present plans to further characterize this protein and to determine its relationship to the mechanism of stable epithelial cell adhesion. Finally, we will examine the role and regulation of epithelial intercellular junctional components in epithelial cell migration and the re-establishing of a competent epithelial barrier following wound closure. Study of the specific molecules involved in epithelial adhesion and their regulation under varying physiological conditions, quiescent, migrating and recently healed, will provide valuable new information which is essential to the understanding of clinical conditions characterized by the loss of epithelial adhesion.
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