The focus of effort in our laboratory has been to identify cellular and molecular responses to corneal epithelial wounding that initiate, enhance or retard cell migration, proliferation and formation of hemidesmosomes. An improved understanding of these factors could provide modalities for improved treatment of debilitating epithelial problems including recurrent corneal erosions and neurotrophic keratitis, among others. Our recent exciting studies in live cell imaging have led us to evaluate the molecular mechanisms underlying the immediate and long term responses that are induced by injury and to evaluate how the release of growth factors and nucleotides from epithelial cells alters the cellular environment and induces signal transduction mediated events that regulate wound repair. When an injury to the corneal epithelium occurs a soluble factor is released that causes the rapid release of Ca2+ that propagates from the wound to neighboring cells in seconds and does not require gap junctions. We have demonstrated that the active component active component is less than 5 kDa, activates ERK1/2 and is inhibited by an enzyme that cleaves terminal phosphate groups off nucleotides, indicating that it is an extracellular nucleotide which initiates signaling events through the activation of a P2Y purinergic receptor on the cell surface. This is the first time that purinergic signaling pathways have been implicated in epithelial injury and repair. In addition, EGF receptors (ErbB1) are activated at the wound margin and mediate the expression of the integrin subunit, beta4, a critical component of hemidesmosomes. We have also demonstrated that stimulating both EGF and purinergic signaling pathways results in unparalled enhancement of epithelial cell migration leading us to examine how the two systems communicate.
The aims are to: I. Identify which ErbB receptor subtypes regulate Ca2+ wave propagation, cell migration and activation of adhesion proteins. II. Evaluate the role of purinergic receptors in wound repair and III. Examine cross-talk between ErbB and purinergic signaling systems to further understand the response to injury and disease.
Showing the most recent 10 out of 29 publications
