The stratified squamous epithelium of the cornea accounts for approximately 80% of the refractive power of the eye; thus, a smooth, intact, and healthy corneal epithelium is requisite for normal vision. The corneal epithelium also resists pressures and provides a barrier to fluid loss and pathogen entrance, qualities that require the epithelial cells to remain tightly adherent to neighboring cells as well as to the underlying matrix. While over the last many years we have learned a great deal about the molecular composition of epithelial adhesion complexes, we know far less about the molecular regulation of adhesion between epithelial cells and details pertaining to the determinants of the epithelial phenotype. The long-term goal of this project is to discover the molecular determinants of the regulation of cell-cell adhesion in the corneal epithelium. Substantial data now support the notion that loss/modification of cell-cell adhesion is a key step in progression to the loss of the corneal epithelial barrier. In this proposal, I present plans to study a nuclear and cell adhesion-related protein, pinin (Pnn), that we discovered and now propose functions as a regulator cell-cell adhesion and the epithelial phenotype. Here we will examine the mechanism by which Pnn affects downstream gene expression pertaining to epithelial adhesion through its specific association with transcriptional co-repressors, such as CtBP. We will explore the impact that transcriptional repressors, which modify epithelial adhesion, have on Pnn. Next, we will conduct proteomic identification and classification the specific molecular complex(es) that contain Pnn. Finally, we will examine the consequences of loss of pnn expression in the corneal epithelium by generation of Pnn knock-out mice. The data derived from these studies will provide important new information pertaining to epithelial adhesion and will contribute towards our ability to modify the adhesive capacity of the epithelial cells, thus bringing us closer to reversing the phenotypes of adhesion related diseases of the corneal epithelium.
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