The failure of the epithelium to migrate over the wound or of the migrated epithelium to remain adherent to the substratum may lead to the development of a number of debilitating clinical conditions of the cornea including recurrent erosions and persistent epithelial defects. We established during the previous funding period that two carbohydrate binding proteins, galectins-3 and -7, are among the key molecules which mediate corneal epithelial cell migration. For an understanding of the mechanism by which galectins-3 and -7 mediate corneal epithelial cell migration, in Aim 1, we shall identify and characterize the corneal epithelial cell surface and extracellular matrix (ECM) glycoproteins which serve as counterreceptors of galectins-3 and -7, and will establish whether the lectins modulate corneal epithelial cell migration by binding to well-known integrins, growth factor receptors, and/or ECM molecules.
In Aim 2, using small interfering RNA (siRNA) and/or antisense adenoviral constructs, cDNA microarrays and glycogene arrays, we shall determine whether galectin-3 mediates corneal epithelial cell migration indirectly by modulating the expression of key adhesion and/or signal transduction molecules.
In Aim 3, by determining whether galectins-3 and/or -7 modulate the activation of specific kinases (focal adhesion kinase, protein kinase B, MAP kinases) that are well known for their role in cell migration, we shall establish whether the lectins mediate corneal epithelial cell migration by modulating specific signal transduction pathways. The proposed studies will contribute to a better understanding of the molecular basis of corneal epithelial cell migration and should ultimately help find novel therapeutic strategies for treating nonhealing corneal wounds. In addition, this study will contribute to the basic understanding of the general disorders of impaired or delayed re-epithelialization including chronic wounds in the elderly, decubitus ulcers, and venous stasis ulcer of the skin, conditions that together affect millions of individuals worldwide.
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