Pseudophakic and aphakic bullous keratopathy (PBK/ABK) are vision- threatening cornea disorders which are the most common indications for corneal transplantation in the United States. They cause significant visual disabilities that lead to high medical costs for office visits, hospital stays and surgical procedures. Decreased numbers of endothelial cells and/or functional impairment of their fluid pumping ability lead to chronic corneal edema in PBK/ABK corneas. However, our preliminary studies identified major extracellular matrix (ECM) abnormalities in PBK/ABK corneas that cannot be easily explained only by an altered fluid balance. The most striking is the appearance of tenascin, a protein with known antiadhesive properties, which is found in abundance in PBK/ABK corneas but is completely absent from normal corneas. In addition, we found changes of fibronectin, decreased laminin and entactin, and altered collagen phenotype. Take together, these represent a fibrotic process occurring within the PBK/ABK corneas. Our working hypothesis is that tenascin and other abnormal (fibrotic) extracellular matrix found in the pseudophakic/aphakic bullous keratopathy corneas influence adhesives migratory and functional properties of the endothelial cells. In this proposal we will (1) characterize tenascin and ECM components in corneas with early PBK/ABK before transplantation. This will allow us to determine the temporal occurrence of these matrices in relation to the disease progression. We will (2) identify tenascin splice variants since each has unique functional characteristics, and (3) their cellular origin. We will (4) study the influence of tenascin upon the adhesion, migration, growth and fluid pump function of corneal cells. Finally, we will (5) investigate growth factors which are present in the PBK/ABK corneas that may influence tenascin and ECM expression.
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